Hypoxia-Induced Epithelial-Mesenchymal Transition in Cancers: HIF-1α and Beyond

Metastasis is the main cause of cancer-related mortality. Although the actual process of metastasis remains largely elusive, epithelial-mesenchymal transition (EMT) has been considered as a major event in metastasis. Besides, hypoxia is common in solid cancers and has been considered as an important factor for adverse treatment outcomes including metastasis. Since EMT and hypoxia potentially share several signaling pathways, many recent studies focused on investigate the issue of hypoxia-induced EMT. Among all potential mediators of hypoxia-induced EMT, hypoxia-inducible factor-1α (HIF-1α) has been studied extensively. Moreover, there are other potential mediators that may also contribute to the process. This review aims to summarize the recent reports on hypoxia-induced EMT by HIF-1α or other potential mediators and provide insights for further investigations on this issue. Ultimately, better understanding of hypoxia-induced EMT may allow us to develop anti-metastatic strategies and improve treatment outcomes.

Introduction

Metastasis is the major cause of cancer-associated deaths (1). It is a sequential event of uncontrolled cell proliferation, angiogenesis, detachment, motility, invasion into bloodstream, settle in the microvasculature, and finally extravasation from the blood vessel and proliferation in secondary sites. It is a complicated process involving multiple genes and signaling pathways for each step (2–4). Although much of the exact mechanism remains unknown, epithelial-mesenchymal transition (EMT), which is a cellular process that enables a polarized epithelial cell to undergo changes to be a mesenchymal cell phenotype, has been regarded as an important event for metastasis (4). Apart from EMT, hypoxia, which is cell having a lower oxygen tension than normal condition, is a common phenomenon in most solid tumors (5). Hypoxia could trigger various signaling pathways which may lead to adverse clinical outcomes in cancer including higher invasiveness and tendency to metastasize (5–7). Studies in the field of cancer biology have linked these two important tumorigenesis events together when unraveling the process of metastasis (8). Among different hypoxia-related pathways, hypoxia-inducible factor-1α (HIF-1α) has been studied extensively (9). In this review, we summarize previous researches and recent findings of the effect of hypoxia on EMT induction with emphasis in various hypoxia-related mediators.

EMT in Cancer

EMT is involved during the implantation of the embryo and the initiation of placenta formation (Type 1), inflammation and fibrosis (Type 2), and in the change of primary epithelial cancer cell to invasive and metastatic mesenchymal cell (Type 3) (10). Type 3 EMT (hereby referred as EMT) comprises activation of transcription factors, expression of specific cell surface proteins, reorganization and expression of cytoskeletal proteins, production of extracellular matrix (ECM)-degrading enzymes and changes in the specific microRNA (miRNA) expressions (10). This leads to increased invasiveness, migratory capacity, production of ECM components and resistance to apoptosis of cancer cells (10). Furthermore, EMT could affects the immune cell functions in the tumor microenvironment and promotes an immunosuppressive tumor microenvironment to escape immune surveillance by immune cells (11).

Epithelial cells are held together by various cell adhesion molecules including claudins and E-cadherin for attachment to both the basement membrane and adjacent cells and maintenance of epithelial phenotype. The loss of function or expression of E-cadherin and tight junction proteins, and also the increase of mesenchymal markers including vimentin, fibronectin, and N-cadherin, have been considered as the main molecular events of EMT (12). Cadherins are transmembrane components of the adherens junction, which play important role in cell-cell adhesion and actin cytoskeleton (13). E-cadherin is pre-dominantly expressed by normal epithelial tissues. However, many epithelial cancer cells have reduced E-cadherin expression and the loss of E-cadherin is correlated to poor prognosis in a variety of cancers (14). While N-cadherin is typically expressed in mesenchymal cells, which are more spindle-shaped and less polarized than epithelial cells (13). Hence, the transition from E-cadherin to N-cadherin is considered as the major process in EMT induction. Nonetheless, the disintegration of adherens junctions between cells changes the cytoskeletal composition and cell polarity to a more spindle-shaped form. In cancer cells undergoing EMT, the actin cytoskeleton is reorganized from cortical thin bundles into thick contractile stress fibers at the ventral cell surface (15). The monomers of actin, i.e., globular-actin (G-actin), polymerize to form filamentous-actin (F-actin) to start the formation of various migratory protrusions including podosomes, invadopodia, filopodia, and lamellipodia. This process is known as dynamic actin reorganization (16). It is a prerequisite for the morphology change, migration and invasion of cancer cells (16, 17). Another protein, vimentin, is a Type III intermediate filament protein that is a major cytoskeletal component of mesenchymal cells (18). Whereas, fibronectin is a stromal ECM protein that binds to integrin receptors to link the ECM with cytoskeleton (19). The up-regulations of these mesenchymal markers also mark the EMT induction process. Moreover, cells undergoing EMT could degrade and invade basal extracellular matrix by matrix metalloproteinases (MMPs) (11).

There are several EMT transcription factors including the zinc-finger binding transcription factors: Snail1 (Snail) and Snail2 (Slug), zinc finger E-box-binding homebox 1/2 (ZEB1/2), TWIST, and lymphoid enhancer-binding factor-1 (LEF-1). They bind to the promoter region of cell adhesion genes and repress their transcription. The reduced cell adhesion initiates EMT. These core EMT transcription factors have non-redundant functions yet they may cooperate to promote EMT (20). Snail and Slug bind to the promoter of cadherin-1 (CDH1), which encodes E-cadherin, to repress its transcription. The other molecules, ZEB1 and ZEB2, mediate the bipartite E-box regions of DNA for flanking the CDH1 gene, resulting in E-cadherin repression. Both Twist-related protein 1 (TWIST1) and Twist-related protein 2 (TWIST2) belong to the basic helix-loop-helix (bHLH) transcription family. They also flank the CDH1 gene to repress E-cadherin. In addition, it has been reported that TWIST1 binds with Slug promoter to stimulate EMT in human mammary cells (21). LEF-1 could also directly repress E-cadherin and induce EMT (22). Its overexpression in colon carcinoma cell lines could promote EMT by nuclear β-catenin activation (23). In general, these factors are usually associated with poor prognosis in different types of cancer (24–35).

Multiple signaling pathways that are involved in these EMT-inducing factors have been reviewed recently (12). Furthermore, miRNA-transcription factor regulatory circuits, along with long non-coding RNAs, have also been proposed recently for complex control of EMT process (11, 36). In this review, we focus on the pathways related to hypoxia.

Tumor Hypoxia

Hypoxia is a common phenomenon in most solid tumors (5). Even though tumors are developed by clonal expansion, the cells are in different stages of maturation and differentiation. Tumor cells are also arranged in different geometry. Therefore, each individual tumor is a heterogeneous population of cells and each individual tumor cell has its own microenvironment (37). Although tumor cells can promote angiogenesis that stimulate the growth of endothelial cells from neighbor blood vessels for the supply of nutrients, over-population, increase in oxygen diffusion distances of cells, anarchic tumor vasculature with irregular blood flow and low oxygen diffusion are common causes of poor oxygenation (37–39). In addition, hypoxia could be more prominent due to tumor-induced or treatment-induced anemia and low hemoglobin levels in blood (39). In normal tissues, the oxygen tension (pO₂) is normally 10–80 mmHg, while tumors often contain low oxygen concentration regions of severe hypoxia (<0.5 mmHg) and intermediate hypoxia (0.5–20 mmHg) (5). Hypoxia could pose a variety of adverse clinical outcome during the treatment of cancer. It has been reported to increase radioresistance at pO₂ level of <1–10 mmHg, genomic instability, angiogenesis, vasculogenesis, invasiveness, boosted stem cell properties. Most importantly, cells under hypoxia may have higher tendency to metastasize and improved survival in nutrient deprived environment (5, 7).

Hypoxia-inducible factors (HIFs) are the major transcriptional regulators in response to hypoxia, which consist of an oxygen-regulated HIF-α subunit (HIF-1α or HIF-2α) dimerizing with HIF-1β in hypoxia. It activates target gene transcription with CREB-cAMP-response element binding protein (CBP) in hypoxia responsive elements (HRE). In normoxia, HIF-1α is hydroxylated at proline 402 and 531 while HIF-2α is hydroxylated at proline 405 and 531 by HIF-α prolyl hydroxylases (PHDs) and factor inhibiting HIF (FIH) proteins within its oxygen-dependent degradation domain (ODD) of PHDs. This process regulates the binding of von Hippel-Lindau (VHL) tumor suppressor E3 ligase for Lys48-linked polyubiquitination of HIF-α and finally results in proteasomal degradation. Whereas, FIH hydroxylates HIF-1α and HIF-2α at asparagine 803 and 847 within the C-terminal transactivation domain, respectively. This action blocks HIF interaction with p300 or CBP and prevents transcription of target genes (40–42).

HIF-1α and HIF-2α have distinct physiological roles though they are similar in overall amino acid sequence, domain structure and activation mechanisms (43). HIF-1α is usually up-regulated more prominently in shorter time interval (2–24 h) and lower oxygen level (<0.1% O₂) whereas HIF-2α is usually up-regulated in a higher oxygen level (<5% O₂) with longer maintenance time (48–72 h) in some cell lines (39, 40). HIF-1α regulates a variety of tumor processes for adaptation, such as metabolism, erythropoiesis, angiogenesis, invasion, cell survival and proliferation (40, 44). HIF-1α could regulate various EMT transcription factors, histone modifiers [e.g., histone lysine-specific demethylase 4B (KDM4B)], enzymes [e.g., lysyl oxidase (LOX), MMP1, MMP3], chemokine receptors 1 and 4 (CX3CR1, CXCR4), adhesion molecules [e.g., angiopoietin-like 4 (ANGPTL4), L1 cell adhesion molecule (L1CAM)], and miRNA targets to promote metastasis (45). Its expression was associated with poor treatment outcome in different types of cancer (44, 46, 47).

Apart from hypoxia-induced HIF-1α activation, HIF-1α could be controlled by oxygen-independent oncogenic regulation, which includes growth factor signaling pathways such as phosphatidylinositol-3-kinase (PI3K) activation, mouse double minute 2 homolog (Mdm2) pathway and heat shock protein 90 (Hsp90) (48). In addition, HIF-1α activation is associated with the Warburg metabolites including glucose transporters and glycolytic enzymes (49). Furthermore, reactive oxygen species (ROS) could stabilize HIF-1α under normoxia via several proposed models (50).

Though HIF-1α has been intensively researched, HIF-2α was less studied. A recent study by Li et al. (51) found that HIF-2α was significantly expressed in the cancer stem cell population but not in other tumor cells. Moreover, HIF-2α was proposed to promote stem cell marker expression, a stem cell phenotype and tumorosphere formation in hypoxic conditions (38). Therefore, HIFs are required for cancer stem cell survival and tumor progression (38). In fact, HIF-1α and HIF-2α may have antagonistic roles in some cellular functions including cell growth. For example, HIF-1α promoted the growth of SW-480 colon cancer cells while HIF-2α suppressed the tumor growth (41). It is important not to generalize because HIF-1α and HIF-2α may have different effect in other tumor cell lines (43). Recent studies also showed HIF-1α and HIF-2α regulate various non-coding RNAs for facilitating tumorigenesis (52).

HIF-Mediated EMT

Initially, both EMT and hypoxia are considered as separate events promoting invasion and metastasis of various types of cancer. Recently, the term hypoxia-induced EMT has been proposed because the signaling pathways are inter-related. Among all the signaling pathways involved in hypoxia, the HIF pathway was proposed to be the most important one for hypoxia-induced EMT though it may also be regulated by oxygen-independent mechanisms (Figure 1). In earlier studies, HIF-1α has been linked with transforming growth factor β (TGF-β) activation in hepatocyte during liver fibrosis and human umbilical vein endothelial cells (53, 54). TGF-β can also suppress both mRNA and protein expressions of PHD2 and consequently increases HIF-1α stability (55). TGF-β is the most studied EMT signaling pathway, which includes the HIF-1α related mothers against decapentaplegic homologs (SMAD) signaling and non-SMAD signaling. For SMAD signaling, the phosphorylation of TGF-βRI activates SMAD signaling after binding to TGF-βRII and TGF-βRIII. Then the oligomerization of SMAD2/3 with SMAD4 and the nuclear import of the R-SMAD/SMAD4 complex are enabled for binding regulatory elements inside the nucleus and inducing the transcription of EMT associated genes. While non-SMAD signaling involved various mitogen-activated protein kinases (MAPKs) and PI3K- protein kinase B (Akt)- mechanistic target of rapamycin (mTOR), which will be introduced in later parts of this review (56). HIF-1α was found to regulate TGF-β-SMAD3 pathway in breast cancer patients (57). Apart from the crosstalk between HIF-1α and TGF-β, another important EMT pathway Wnt/β-catenin could also enhance hypoxia-induced EMT by potentiating with HIF-1α signaling in hepatocellular carcinoma (58). Moreover, HIF-1α is linked to the expression of immunosuppressive molecules in tumor cells, which could potentiate EMT induction through TGF-β signaling (59, 60). EMT could in turn elicit multiple immune-regulatory effects causing natural killer (NK) and T-cell apoptosis and increase of regulatory T and B cells (61). Furthermore, HIF-1α was found to mediate hedgehog signaling for EMT and invasion in pancreatic cancer cells and the silencing of HIF-1α would reverse hypoxia-induced hedgehog signaling activation (62). Therefore, there were definitive cross-talks between HIF-1α and other EMT signaling pathways yet the relationship could be tumor-type and context-dependent.

FIGURE 1

Figure 1. HIF-1α mediated EMT. HIF-1α promotes EMT induction in various cancer types by multiple ways. Various pathways promote EMT induction, resulting in loss of cell-cell adhesion and dynamic actin reorganization.

Aside from the studies concerning the cross-talks between HIF-1α and other EMT pathways, more researches have focused on HIF-1α modulation of various EMT transcription factors including TWIST, Snail, Slug, SIP1, and ZEB1 (Table 1). For HIF-1α-TWIST interaction, HIF-1α could bind directly to TWIST by HRE in the TWIST proximal promoter in hypopharyngeal and breast cancer cell lines. It also promoted metastasis and the over-expression of TWIST was essential for HIF-1α-mediated EMT and non-redundant when compared with other EMT inducers such as Snail (63). The co-expression of HIF-1α, TWIST, and Snail in primary tumors of head and neck cancer patients correlated with the poorest prognosis (63). The up-regulation of TWIST by HIF-1α was also found among clinical samples of ovarian epithelial cancers and was associated with lower overall survival rate (26).

TABLE 1

Table 1. HIF-1α-EMT transcription factors association studies in different cancer types.

For HIF-1α-Snail interaction, HIF-1α first activates histone deacetylase 3 (HDAC3). HDAC3 could then bind to the promoters of CDH1 and junction plakoglobin (JUP) and eventually promote transcription of Snail (12, 72). In an in silio analysis by Luo et al. (73), HIF was found to bind with a putative HRE within minimal Snail promoter of mouse, demonstrating possible direct interaction between HIF and Snail. HIF-1α-induced Snail activation was found in liver and lung cancers (34, 64). Zhang et al. (34) found both HIF-1α and Snail overexpression were correlated with pathological classification, TNM staging, and tumor volume in hepatocellular carcinoma patients. The disease-free survival was also significantly shorter in HIF-1α positive group than HIF-1α negative group. This study also showed the elevation of Snail mRNA expression level after HIF-1α stabilization accompanied with E-cadherin repression plus vimentin and N-cadherin up-regulation. Meanwhile, in a shorter path, HDAC3 also regulates the formation of histone methyltransferase complexes by WD repeat-containing protein 5 (WDR5) recruitment to induce vimentin and N-cadherin expression (12, 72). As a chromatin modifier, HDAC3 could directly deacetylate histone H3 Lys4 acetylation (H3K4Ac) for promotion of EMT marker genes and indirectly increased the levels of histone H3 Lys4 di/trimethylation (H3K4me2/3) through WDR5, yet the exact molecular mechanisms remained to be explored (74).

For another important zinc-finger binding transcription factor Slug, HIF-1α was associated with its expression in head and neck squamous carcinoma, lung, and pancreatic cancer cells (33, 64, 66, 67). Similar to Snail, Slug was also suggested to contain HRE in its promoter for direct interaction between HIF-1α and Slug (75). SIP1 activation, together with Snail activation and E-cadherin repression, were found to be HIF-1α-mediated in VHL^−/− renal clear-cell carcinoma cell line (65). The reintroduction of wild-type VHL could suppress SIP1 and Snail but not Slug, and removed the suppression of E-cadherin (65).

HIF-1α could bind directly to the proximal promoter of ZEB1 via HRE in colorectal cancer cells (68). Additionally, this research group demonstrated the importance of ZEB1 in HIF-1α induced metastasis with higher percentage of HIF-1α and ZEB1 positive staining and lower percentage of E-cadherin positive staining in patients' metastatic lymph nodes compared with primary colorectal cancer tissues (68). The influence of HIF-1α on ZEB1 was also evaluated among bladder cancer (69), glioblastoma (70) and pancreatic cancer cells (67, 71). Joseph et al. (70) has evaluated HIF-1α but not HIF-2α up-regulated ZEB1 under hypoxia in glioblastoma cells.

HIF-1α may also act on some EMT transcription factors indirectly through FoxM1 signaling pathway in prostate cancer cell lines (76) and through PAFAH1B2 gene in pancreatic cancer (77). HIF-1α also facilitated the regulatory loop with integrin-linked kinase (ILK) to promote epithelial-mesenchymal transition in breast and prostate cancer cell lines (78). In the view of previous research findings, it is clear that HIF-1α takes important roles in hypoxia-induced EMT through promoting wide range of EMT transcription factors through multiple signaling pathways in various cancer types. Whereas, for HIF-2α-mediated EMT, researches in this area remained scarce. Notably, HIF-2α could also activate EMT transcription factors including TWIST2 in lung and pancreatic cancer cells and WDR5 for promoting mesenchymal gene expression (72, 79, 80). As HIF-2α has longer activation period at higher oxygen level than HIF-1α, it could be an important mediator of EMT induction at milder hypoxia and thus further studies of HIF-2α-mediated EMT are warranted.

Hypoxia-Induced Non-HIF EMT Pathways

In addition to HIF pathways, other signaling pathways involved in hypoxia may have distinctive characters in inducing EMT [Summarized in Figure 2; (12, 81–85)].

FIGURE 2

Figure 2. Hypoxia-induced Non-HIF EMT pathways. Apart from HIF-1α, there are several potential hypoxia-induced pathways for EMT induction.

AMPK

Hypoxia can cause up-regulation of AMP-activated protein kinase (AMPK) as adenosine monophosphate (AMP)/adenosine triphosphate (ATP), or adenosine diphosphate (ADP)/ATP ratios are increased in physiological stresses. AMPK regulates cancer progression, lipid synthesis and oxidation, DNA repair and autophagy (86). Traditionally, AMPK was considered as a metabolic tumor suppressor for tumor cell survival under nutrient depletion (87). However, in the context of AMPK-mediated EMT, contradictive results have been reported. Saxena et al. (88) claimed that AMPK activation by AMPK activator A769662 could increase the expression and nuclear localization of TWIST1 and thus promote EMT induction in breast cancer, melanoma and lung adenocarcinoma cell lines. On the contrary, Chou et al. (89) showed that AMPK activation by another AMPK activator OSU-53 could suppress EMT by modulating the Akt-MDM2-Foxo3 signaling axis. The silencing of AMPK could abrogate the reverse of the mesenchymal phenotype among breast and prostate cancer cell lines. Other researches demonstrated that AMPK could suppress EMT of pancreatic cancer and hepatocellular carcinoma cells (90–92). In the previous researches, specific AMPK activators or inhibitors were used to evaluate AMPK-mediated EMT. The results are controversial, hence, further researches on the character of AMPK in hypoxia-induced EMT are needed.

PI3K-Akt-mTOR

PI3K-Akt-mTOR is commonly activated in cancer cells. It has important roles in cell proliferation, nutrient uptake, anabolic reactions, and autophagy (93, 94). This pathway can also be activated by hypoxia and interacts with HIF-1α in different cell types (9, 95–97). PI3K-Akt-mTOR has been considered as a mediator of TGF-β signaling through non-SMAD pathway. TGF-β may activate PI3K directly or by activation of epidermal growth factor (EGF) and platelet-derived growth factor (PDGF) receptors in various cell types (12). The mutations in PIK3CA or loss of PTEN is associated with colorectal cancer progression through activation of PI3K-Akt pathway with Akt signaling found to up-regulate Snail and Slug (98). Similar Akt-Snail activation for EMT induction was also found among tongue squamous cell carcinoma cell lines (99). Inhibition of Akt could reverse EMT by restoring E-cadherin in oral squamous cell carcinoma cells (100). In addition, Akt activates both mTORC1 and mTORC2, which are found to induce EMT, motility and metastasis of colorectal cancer by RhoA and Rac1 signaling (101). PI3K-Akt-mTOR could also influence HIF-1α activation as mTOR is an upstream mediator of HIF-1α (97). mTOR regulates translation via phosphorylation of 4E-BP1, which in turn inhibits interaction of eIF4E with translation initiation complex and results in mRNA translation activation and facilitate HIF-1α protein synthesis (102). Although there are plenty of researches demonstrating PI3K-Akt-mTOR mediated EMT, there are no research published to date concerning the hypoxia-driven PI3K-Akt-mTOR in EMT induction.

MAPKs

MAPKs are evolutionarily conserved kinases for controlling fundamental cellular processes such as cell differentiation, growth, proliferation, apoptosis, autophagy and migration (94, 103). Mainly, three MAPKs extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 MAPK are hypoxia-related and involved in EMT induction through non-SMAD TGF-β signaling (9, 12, 84, 104). MAPK signaling also plays a role in HIF α-subunit nuclear accumulation and transcriptional activity (102). For ERK pathway, the ERK-associated oncogene RAS overexpression promotes EMT through CyclinD1 and E-cadherin regulation (105). The disruption of ERK1 and ERK2 activation could prevent the delocalization of E-cadherin (104). ERK2 could also regulate EMT by DOCK10-dependent Rac1/FoxO1 signaling (106). For the studies on ERK influence in EMT transcription factors, Slug is a target of RAS pathway among colorectal cancer cell lines with mutant RAS (107). While ZEB1, but not Snail nor Slug, was reported to be the target of ERK for EMT induction in lung cancer cell lines (108). Demonstration of ERK-mediated EMT was also found in pancreatic and prostate cancer cell lines (109, 110). Moreover, FGFR3 and WISP1 overexpression in melanoma could also promote ERK-mediated EMT (111, 112). ERK1 and ERK2, together with other MAPKs JNK and p38 MAPK, were found to stabilize the phosphorylation site of TWIST1 for EMT induction in breast cancer cells (113).

JNK and p38 MAPK mediations of EMT start with the E3 ligase member TRAF6, which in turn activates TGF-βRI for EMT induction (12). In earlier studies, JNK phosphorylation is found to mediate TGF-β1-induced EMT by promoting fibronectin and vimentin synthesis in fibroblasts and keratinocytes (114–116). Additionally, JNK activation of the proliferating cell nuclear antigen (PCNA) and DNA methyltransferase 1 associated protein 1 (DMAP1) domains of DNA methyltransferase 1 (DNMT1) can directly interact with Snail and suppress E-cadherin in colorectal cancer, glioma, and nasopharyngeal carcinoma cell lines (117–119). Furthermore, JNK may be associated with Snail and TWIST1 via c-Jun in multi-drug resistant epidermoid carcinoma and as a downstream effector of Akt in gastric cancer cells (120, 121). Other researches also associated JNK with EMT induction in colorectal cancer (122) and non-small cell lung cancer cells (123). Whereas, for p38 MAPK-mediated EMT, Lin et al. (124) evaluated that p38 MAPK regulated p38 interacting protein (p38IP) and Snail in head and neck squamous cell carcinoma. Another study revealed that p38 MAPK participated in TGF-β induced EMT in glioma cells (125).

To date, there was only one published report on the participation of MAPKs in hypoxia-induced EMT despite MAPKs were found to be important EMT regulators from the view of previous researches. Tam et al. (126) demonstrated that JNK pathway mediates EMT and stemness maintenance of colorectal cancer cells under low oxygen level including hypoxia (1%) and blood oxygen level (10%). This was the first report that showed even the seemingly non-hypoxic 10% oxygen level could affect EMT progression in cancer as that in the traditional hypoxic oxygen level (1–2%). Therefore, MAPK signaling could be an important regulator for hypoxia-induced EMT.

NF-κB

Nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) presents in almost all animal cell types and involves in inflammation, immunity, cell proliferation, apoptosis, angiogenesis, tumor metabolism, metastasis, and EMT (127). It can be activated by various stimuli including cytokines, growth factors, radiation, DNA damage and hypoxia (127). NF-κB mediates EMT by cooperating with Ras and TGF-β in breast cancer cells (128). NF-κB was also associated with ezrin and EGF-induced EMT and promoted metastasis in colorectal cancer cells (129). For NF-κB influence on EMT transcription factors, it could directly promote Slug, SIP1, and TWIST1 in breast cancer cells (130). While for the study of hypoxia-induced NF-κB mediated EMT, Cheng et al. (131) concluded that HIF-1α-activated NF-κB could promote EMT in pancreatic cancer cells by inhibiting E-cadherin and promoting N-cadherin. TWIST was promoted by NF-κB but no significant changes of Snail, ZEB1 or ZEB2 were found. Whereas, Kara et al. (132) demonstrated TNF-α-NF-κB axis together with PI3K-Akt axis, contributed to HIF-1α-mediated EMT induction. Therefore, close relationships between NF-κB and HIF-1α may exist in hypoxia-induced EMT.

Notch

Notch signaling is an evolutionarily conserved pathway which regulates cell differentiation, proliferation and death in all metazoans (133). Notch also involves in tumorigenesis and EMT by the interaction with Delta/Serrate/Lag-2 (DSL) ligands, which subsequently causes a proteolytic cleavage of the Notch receptor protein at the S2 cleavage site with involvement of ADAM10 or ADAM17 (134). Then the second g-secretase-mediated cleavage of the residual part of the Notch protein resulted in the release of the Notch intracellular domain (ICD), which can then directly activate EMT signaling genes (12). For the character of Notch in hypoxia, Notch signaling is important for maintenance of undifferentiated cell state and its intracellular domain cooperates with HIF-1α (135). Notch can directly induce Slug, but not Snail and TWIST1, in breast cancer cell lines (136, 137). However, another study of prostate cancer cells found Notch1 was associated with Snail and ZEB1 (138). Notch can also induce HIF-1α, NF-κB, and miR-200 for EMT induction in various cancer cell lines (139–141). Studies on Notch-mediated hypoxia-induced EMT mainly concentrated on breast cancer cells, which showed Notch worked closely with HIF-1α in hypoxia-induced EMT and the inhibition of Notch could effectively block EMT induction (142, 143). Notch target genes including HES1 and HEY1 were increased by hypoxia and both HIF-1α and HIF-2α synergized with the Notch co-activator MAML1 in promoting Notch activity among breast cancer cells (143). In addition, another study also showed Notch participated in hypoxia-induced EMT in colon cancer, ovarian cancer and glioblastoma with regulation of Snail and HIF-1α (139). Thus, similar to NF-κB, Notch potentiates HIF-1α-induced EMT in hypoxic conditions.

Future Perspectives

Hypoxia has been conclusively established as a major promoter of EMT. Among various hypoxia-related EMT signaling pathways, HIF-1α is an important mediator of hypoxia-induced EMT in various cancer types. Since HIF-1α is a poor prognosis indicator which also promotes other adverse treatment outcomes, such as chemo and radioresistance, targeting HIF-1α shall increase treatment efficacy and limit metastasis in cancers (144). Inhibiting HIF-1α in different cancer types have found to effectively limit metastasis in both in vitro and in vivo experiments (145). However, there is a lack of selective HIF-1 inhibitors and clinical trials in this area (145). Thus, the clinical potential of this treatment strategy is yet to be revealed. While for other potential pathways for hypoxia-induced EMT, researches on the characters of these pathways in hypoxic conditions are limited especially for PI3K-Akt-mTOR and MAPKs. Since they have proven roles in mediating EMT induction, exploration of their roles in hypoxia-induced EMT shall provide a better picture for hypoxia-induced EMT. They may be activated in different time period and oxygen tension when compared with HIF-1α. This will be essential for better understanding of metastasis mechanism as metastasis involves complex procedures with tumor cells experiencing different oxygen levels from hypoxia in primary tumor site to blood oxygen level in bloodstream (9). Furthermore, potential therapeutic strategies involving multiple EMT effector inhibitions may effectively inhibit EMT at a wider range of oxygen level, which might reduce tumor metastasis and improve treatment outcome.

Conclusion

In sum, hypoxia-induced EMT has been established as important route for EMT induction and metastasis in wide range of cancer types in vitro and in vivo. HIF-1α has proved to be the major mediator of hypoxia-induced EMT. In addition, there are other potential pathways involved in hypoxia-induced EMT which may provide clues for controlling hypoxia-induced EMT by developing new anti-metastatic methods and improving prognosis of cancers.

Author Contributions

ST and HL contributed in conception and design of the study. ST wrote the original draft. VW and HL supervised the study. HL reviewed and edited the manuscript. All authors read and approved the submitted version.

Funding

This research was funded by Postgraduate Studentship to ST, Institutional Research Fund (UAHS), internal start up and Seeding Fund for HL from the Hong Kong Polytechnic University.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

References

1. Chaffer CL, Weinberg RA. A perspective on cancer cell metastasis. Science. (2011) 331:1559–64. doi: 10.1126/science.1203543

PubMed Abstract | CrossRef Full Text | Google Scholar

2. Hunter KW, Crawford NPS, Alsarraj J. Mechanisms of metastasis. Breast Cancer Res. (2008) 10(Suppl. 1):S2. doi: 10.1186/bcr1988

PubMed Abstract | CrossRef Full Text | Google Scholar

3. Joseph JP, Harishankar MK, Pillai AA, Devi A. Hypoxia induced EMT: A review on the mechanism of tumor progression and metastasis in OSCC. Oral Oncol. (2018) 80:23–32. doi: 10.1016/j.oraloncology.2018.03.004

PubMed Abstract | CrossRef Full Text | Google Scholar

4. Yao D, Dai C, Peng S. Mechanism of the mesenchymal-epithelial transition and its relationship with metastatic tumor formation. Mol Cancer Res. (2011) 9:1608–20. doi: 10.1158/1541-7786.MCR-10-0568

PubMed Abstract | CrossRef Full Text | Google Scholar

5. Hill RP, Bristow RG, Fyles A, Koritzinsky M, Milosevic M, Wouters BG. Hypoxia and predicting radiation response. Sem Radiat Oncol. (2015) 25:260–72. doi: 10.1016/j.semradonc.2015.05.004

PubMed Abstract | CrossRef Full Text | Google Scholar

6. Kunz M, Ibrahim SM. Molecular responses to hypoxia in tumor cells. Mol Cancer. (2003) 2:23. doi: 10.1186/1476-4598-2-23

PubMed Abstract | CrossRef Full Text | Google Scholar

7. Wilson WR, Hay MP. Targeting hypoxia in cancer therapy. Nat Rev Cancer. (2011) 11:393–410. doi: 10.1038/nrc3064

PubMed Abstract | CrossRef Full Text | Google Scholar

8. Yeo CD, Kang N, Choi SY, Kim BN, Park CK, Kim JW, et al. The role of hypoxia on the acquisition of epithelial-mesenchymal transition and cancer stemness: a possible link to epigenetic regulation. Korean J Int Med. (2017) 32:589–99. doi: 10.3904/kjim.2016.302

PubMed Abstract | CrossRef Full Text | Google Scholar

9. Tam SY, Wu VWC, Law HKW. Dynamics of oxygen level-driven regulators in modulating autophagy in colorectal cancer cells. Biochem Biophys Res Commun. (2019) 517:193–200. doi: 10.1016/j.bbrc.2019.07.043

PubMed Abstract | CrossRef Full Text | Google Scholar

10. Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Investig. (2009) 119:1420–8. doi: 10.1172/JCI39104

PubMed Abstract | CrossRef Full Text | Google Scholar

11. Lu W, Kang Y. Epithelial-mesenchymal plasticity in cancer progression and metastasis. Dev Cell. (2019) 49:361–74. doi: 10.1016/j.devcel.2019.04.010

PubMed Abstract | CrossRef Full Text | Google Scholar

12. Gonzalez DM, Medici D. Signaling mechanisms of the epithelial-mesenchymal transition. Sci Signal. (2014) 7:re8. doi: 10.1126/scisignal.2005189

PubMed Abstract | CrossRef Full Text | Google Scholar

13. Wheelock MJ, Shintani Y, Maeda M, Fukumoto Y, Johnson KR. Cadherin switching. J Cell Sci. (2008) 121(Pt 6):727–35. doi: 10.1242/jcs.000455

PubMed Abstract | CrossRef Full Text | Google Scholar

14. Onder TT, Gupta PB, Mani SA, Yang J, Lander ES, Weinberg RA. Loss of E-cadherin promotes metastasis via multiple downstream transcriptional pathways. Cancer Res. (2008) 68:3645–54. doi: 10.1158/0008-5472.CAN-07-2938

PubMed Abstract | CrossRef Full Text | Google Scholar

15. Haynes J, Srivastava J, Madson N, Wittmann T, Barber DL. Dynamic actin remodeling during epithelial-mesenchymal transition depends on increased moesin expression. Mol Biol Cell. (2011) 22:4750–64. doi: 10.1091/mbc.e11-02-0119

PubMed Abstract | CrossRef Full Text | Google Scholar

16. Sun BO, Fang Y, Li Z, Chen Z, Xiang J. Role of cellular cytoskeleton in epithelial-mesenchymal transition process during cancer progression. Biomed Rep. (2015) 3:603–10. doi: 10.3892/br.2015.494

PubMed Abstract | CrossRef Full Text | Google Scholar

17. Olson MF, Sahai E. The actin cytoskeleton in cancer cell motility. Clin Exp Metastasis. (2009) 26:273–87. doi: 10.1007/s10585-008-9174-2

PubMed Abstract | CrossRef Full Text | Google Scholar

18. Kidd ME, Shumaker DK, Ridge KM. The role of vimentin intermediate filaments in the progression of lung cancer. Am J Respir Cell Mol Biol. (2014) 50:1–6. doi: 10.1165/rcmb.2013-0314TR

PubMed Abstract | CrossRef Full Text | Google Scholar

19. Li C-L, Yang D, Cao X, Wang F, Hong D-Y, Wang J, et al. Fibronectin induces epithelial-mesenchymal transition in human breast cancer MCF-7 cells via activation of calpain. Oncol Lett. (2017) 13:3889–95. doi: 10.3892/ol.2017.5896

PubMed Abstract | CrossRef Full Text | Google Scholar

20. Stemmler MP, Eccles RL, Brabletz S, Brabletz T. Non-redundant functions of EMT transcription factors. Nat Cell Biol. (2019) 21:102–12. doi: 10.1038/s41556-018-0196-y

PubMed Abstract | CrossRef Full Text | Google Scholar

21. Yang J, Mani SA, Donaher JL, Ramaswamy S, Itzykson RA, Come C, et al. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell. (2004) 117:927–39. doi: 10.1016/j.cell.2004.06.006

PubMed Abstract | CrossRef Full Text | Google Scholar

22. Jamora C, DasGupta R, Kocieniewski P, Fuchs E. Links between signal transduction, transcription and adhesion in epithelial bud development. Nature. (2003) 422:317–22. doi: 10.1038/nature01458

PubMed Abstract | CrossRef Full Text | Google Scholar

23. Kim K, Lu Z, Hay ED. Direct evidence for a role of β-catenin/LEF-1 signaling pathway in induction of EMT. Cell Biol Int. (2002) 26:463–76. doi: 10.1006/cbir.2002.0901

PubMed Abstract | CrossRef Full Text | Google Scholar

24. Peinado H, Olmeda D, Cano A. Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nat Rev Cancer. (2007) 7:415–28. doi: 10.1038/nrc2131

PubMed Abstract | CrossRef Full Text | Google Scholar

25. Chen B, Chen B, Zhu Z, Ye W, Zeng J, Liu G, et al. Prognostic value of ZEB-1 in solid tumors: a meta-analysis. BMC Cancer. (2019) 19:635. doi: 10.1186/s12885-019-5830-y

PubMed Abstract | CrossRef Full Text | Google Scholar

26. Kim K, Park EY, Yoon MS, Suh DS, Kim KH, Lee JH, et al. The role of TWIST in ovarian epithelial cancers. Korean J Pathol. (2014) 48:283–91. doi: 10.4132/KoreanJPathol.2014.48.4.283

PubMed Abstract | CrossRef Full Text | Google Scholar

27. Kim YH, Kim G, Kwon CI, Kim JW, Park PW, Hahm KB. TWIST1 and SNAI1 as markers of poor prognosis in human colorectal cancer are associated with the expression of ALDH1 and TGF-β1. Oncol Rep. (2014) 31:1380–8. doi: 10.3892/or.2014.2970

PubMed Abstract | CrossRef Full Text | Google Scholar

28. Lee HH, Lee SH, Song KY, Na SJ, O JH, Park JM, et al. Evaluation of Slug expression is useful for predicting lymph node metastasis and survival in patients with gastric cancer. BMC Cancer. (2017) 17:670. doi: 10.1186/s12885-017-3668-8

PubMed Abstract | CrossRef Full Text | Google Scholar

29. Sasaki K, Natsugoe S, Ishigami S, Matsumoto M, Okumura H, Setoyama T, et al. Significance of Twist expression and its association with E-cadherin in esophageal squamous cell carcinoma. J Exp Clin Cancer Res. (2009) 28:158. doi: 10.1186/1756-9966-28-158

PubMed Abstract | CrossRef Full Text | Google Scholar

30. Shioiri M, Shida T, Koda K, Oda K, Seike K, Nishimura M, et al. Slug expression is an independent prognostic parameter for poor survival in colorectal carcinoma patients. Br J Cancer. (2006) 94:1816–22. doi: 10.1038/sj.bjc.6603193

PubMed Abstract | CrossRef Full Text | Google Scholar

31. Xu S, Yang Z, Zhang J, Jiang Y, Chen Y, Li H, et al. Increased levels of β-catenin, LEF-1, and HPA-1 correlate with poor prognosis for acral melanoma with negative BRAF and NRAS mutation in BRAF exons 11 and 15 and NRAS exons 1 and 2. DNA Cell Biol. (2015) 34:69–77. doi: 10.1089/dna.2014.2590

PubMed Abstract | CrossRef Full Text | Google Scholar

32. Zeng J, Zhan P, Wu G, Yang W, Liang W, Lv T, et al. Prognostic value of Twist in lung cancer: systematic review and meta-analysis. Transl Lung Cancer Res. (2015) 4:236–41. doi: 10.3978/j.issn.2218-6751.2015.04.06

PubMed Abstract | CrossRef Full Text | Google Scholar

33. Zhang J, Cheng Q, Zhou Y, Wang Y, Chen X. Slug is a key mediator of hypoxia induced cadherin switch in HNSCC: correlations with poor prognosis. Oral Oncol. (2013) 49:1043–50. doi: 10.1016/j.oraloncology.2013.08.003

PubMed Abstract | CrossRef Full Text | Google Scholar

34. Zhang L, Huang G, Li X, Zhang Y, Jiang Y, Shen J, et al. Hypoxia induces epithelial-mesenchymal transition via activation of SNAI1 by hypoxia-inducible factor−1α in hepatocellular carcinoma. BMC Cancer. (2013) 13:108. doi: 10.1186/1471-2407-13-108

PubMed Abstract | CrossRef Full Text | Google Scholar

35. Zhang YQ, Wei XL, Liang YK, Chen WL, Zhang F, Bai JW, et al. Over-expressed twist associates with markers of epithelial mesenchymal transition and predicts poor prognosis in breast cancers via ERK and Akt activation. PLoS ONE. (2015) 10:e0135851. doi: 10.1371/journal.pone.0135851

PubMed Abstract | CrossRef Full Text | Google Scholar

36. Nieto MA, Huang RY, Jackson RA, Thiery JP. EMT: 2016. Cell. (2016) 166:21–45. doi: 10.1016/j.cell.2016.06.028

PubMed Abstract | CrossRef Full Text | Google Scholar

37. Koos B, Kamali-Moghaddam M, David L, Sobrinho-Simoes M, Dimberg A, Nilsson M, et al. Next-generation pathology–surveillance of tumor microecology. J Mol Biol. (2015) 427:2013–22. doi: 10.1016/j.jmb.2015.02.017

PubMed Abstract | CrossRef Full Text | Google Scholar

38. Moncharmont C, Levy A, Gilormini M, Bertrand G, Chargari C, Alphonse G, et al. Targeting a cornerstone of radiation resistance: cancer stem cell. Cancer Lett. (2012) 322:139–47. doi: 10.1016/j.canlet.2012.03.024

PubMed Abstract | CrossRef Full Text | Google Scholar

39. Zhao J, Du F, Luo Y, Shen G, Zheng F, Xu B. The emerging role of hypoxia-inducible factor-2 involved in chemo/radioresistance in solid tumors. Cancer Treat Rev. (2015) 41:623–33. doi: 10.1016/j.ctrv.2015.05.004

PubMed Abstract | CrossRef Full Text | Google Scholar

40. Bracken CP, Fedele AO, Linke S, Balrak W, Lisy K, Whitelaw ML, et al. Cell-specific regulation of hypoxia-inducible factor HIF-1α and HIF-2α stabilization and transactivation in a graded oxygen environment. J Biol Chem. (2006) 281:22575–85. doi: 10.1074/jbc.M600288200

PubMed Abstract | CrossRef Full Text | Google Scholar

41. Imamura T, Kikuchi H, Herraiz MT, Park DY, Mizukami Y, Mino-Kenduson M, et al. HIF-1α and HIF-2α have divergent roles in colon cancer. Int J Cancer. (2009) 124:763–71. doi: 10.1002/ijc.24032

PubMed Abstract | CrossRef Full Text | Google Scholar

42. Ortmann B, Druker J, Rocha S. Cell cycle progression in response to oxygen levels. Cell Mol Life Sci. (2014) 71:3569–82. doi: 10.1007/s00018-014-1645-9

PubMed Abstract | CrossRef Full Text | Google Scholar

43. Keith B, Johnson RS, Simon MC. HIF1α and HIF2α: sibling rivalry in hypoxic tumour growth and progression. Nat Rev Cancer. (2011) 12:9–22. doi: 10.1038/nrc3183

PubMed Abstract | CrossRef Full Text | Google Scholar

44. Shioya M, Takahashi T, Ishikawa H, Sakurai H, Ebara T, Suzuki Y, et al. Expression of hypoxia-inducible factor 1a predicts clinical outcome after preoperative hyperthermo-chemoradiotherapy for locally advanced rectal cancer. J Radiat Res. (2014) 52:821–7. doi: 10.1269/jrr.11117

CrossRef Full Text | Google Scholar

45. Tsai YP, Wu KJ. Hypoxia-regulated target genes implicated in tumor metastasis. J Biomed Sci. (2012) 19:102. doi: 10.1186/1423-0127-19-102

PubMed Abstract | CrossRef Full Text | Google Scholar

46. Russell J, Carlin S, Burke SA, Wen B, Yang KM, Ling CC. Immunohistochemical detection of changes in tumor hypoxia. Int J Radiat Oncol Biol Phys. (2009) 73:1177–86. doi: 10.1016/j.ijrobp.2008.12.004

PubMed Abstract | CrossRef Full Text | Google Scholar

47. Schrijvers ML, van der Laan BF, de Bock GH, Pattje WJ, Mastik MF, Menkema L, et al. Overexpression of intrinsic hypoxia markers HIF1α and CA-IX predict for local recurrence in stage T1-T2 glottic laryngeal carcinoma treated with radiotherapy. Int J Radiat Oncol Biol Phys. (2008) 72:161–9. doi: 10.1016/j.ijrobp.2008.05.025

PubMed Abstract | CrossRef Full Text | Google Scholar

48. Masoud GN, Li W. HIF-1α pathway: role, regulation and intervention for cancer therapy. Acta Pharm Sin B. (2015) 5:378–89. doi: 10.1016/j.apsb.2015.05.007

PubMed Abstract | CrossRef Full Text | Google Scholar

49. Courtnay R, Ngo DC, Malik N, Ververis K, Tortorella SM, Karagiannis TC. Cancer metabolism and the Warburg effect: the role of HIF-1 and PI3K. Mol Biol Rep. (2015) 42:841–51. doi: 10.1007/s11033-015-3858-x

PubMed Abstract | CrossRef Full Text | Google Scholar

50. Movafagh S, Crook S, Vo K. Regulation of hypoxia-inducible factor-1a by reactive oxygen species: new developments in an old debate. J Cell Biochem. (2015) 116:696–703. doi: 10.1002/jcb.25074

PubMed Abstract | CrossRef Full Text | Google Scholar

51. Li Z, Bao S, Wu Q, Wang H, Eyler C, Sathornsumetee S, et al. Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells. Cancer Cell. (2009) 15:501–13. doi: 10.1016/j.ccr.2009.03.018

PubMed Abstract | CrossRef Full Text | Google Scholar

52. Choudhry H, Harris AL. Advances in hypoxia-inducible factor biology. Cell Metab. (2018) 27:281–98. doi: 10.1016/j.cmet.2017.10.005

PubMed Abstract | CrossRef Full Text | Google Scholar

53. Copple BL. Hypoxia stimulates hepatocyte epithelial to mesenchymal transition by hypoxia-inducible factor and transforming growth factor-beta-dependent mechanisms. Liver Int. (2010) 30:669–82. doi: 10.1111/j.1478-3231.2010.02205.x

PubMed Abstract | CrossRef Full Text | Google Scholar

54. Zhang H, Akman HO, Smith EL, Zhao J, Murphy-Ullrich JE, Batuman OA. Cellular response to hypoxia involves signaling via Smad proteins. Blood. (2003) 101:2253–60. doi: 10.1182/blood-2002-02-0629

PubMed Abstract | CrossRef Full Text | Google Scholar

55. McMahon S, Charbonneau M, Grandmont S, Richard DE, Dubois CM. Transforming growth factor β1 induces hypoxia-inducible factor-1 stabilization through selective inhibition of PHD2 expression. J Biol Chem. (2006) 281:24171–81. doi: 10.1074/jbc.M604507200

PubMed Abstract | CrossRef Full Text | Google Scholar

56. Zhang YE. Non-Smad pathways in TGF-beta signaling. Cell Res. (2009) 19:128–39. doi: 10.1038/cr.2008.328

PubMed Abstract | CrossRef Full Text | Google Scholar

57. Peng J, Wang X, Ran L, Song J, Luo R, Wang Y. Hypoxia-inducible factor 1α regulates the transforming growth factor beta1/SMAD family member 3 pathway to promote breast cancer progression. J Breast Cancer. (2018) 21:259–66. doi: 10.4048/jbc.2018.21.e42

PubMed Abstract | CrossRef Full Text | Google Scholar

58. Zhang Q, Bai X, Chen W, Ma T, Hu Q, Liang C, et al. Wnt/β-catenin signaling enhances hypoxia-induced epithelial-mesenchymal transition in hepatocellular carcinoma via crosstalk with hif-1α signaling. Carcinogenesis. (2013) 34:962–73. doi: 10.1093/carcin/bgt027

PubMed Abstract | CrossRef Full Text | Google Scholar

59. Li Y, Patel SP, Roszik J, Qin Y. Hypoxia-driven immunosuppressive metabolites in the tumor microenvironment: new approaches for combinational Immunotherapy. Front Immunol. (2018) 9:1591. doi: 10.3389/fimmu.2018.01591

PubMed Abstract | CrossRef Full Text | Google Scholar

60. Terry S, Savagner P, Ortiz-Cuaran S, Mahjoubi L, Saintigny P, Thiery JP, et al. New insights into the role of EMT in tumor immune escape. Mol Oncol. (2017) 11:824–46. doi: 10.1002/1878-0261.12093

PubMed Abstract | CrossRef Full Text | Google Scholar

61. Ricciardi M, Zanotto M, Malpeli G, Bassi G, Perbellini O, Chilosi M, et al. Epithelial-to-mesenchymal transition (EMT) induced by inflammatory priming elicits mesenchymal stromal cell-like immune-modulatory properties in cancer cells. Br J Cancer. (2015) 112:1067–75. doi: 10.1038/bjc.2015.29

PubMed Abstract | CrossRef Full Text | Google Scholar

62. Lei J, Ma J, Ma Q, Li X, Liu H, Xu Q, et al. Hedgehog signaling regulates hypoxia induced epithelial to mesenchymal transition and invasion in pancreatic cancer cells via a ligand-independent manner. Mol Cancer. (2013) 12:66. doi: 10.1186/1476-4598-12-66

PubMed Abstract | CrossRef Full Text | Google Scholar

63. Yang MH, Wu MZ, Chiou SH, Chen PM, Chang SY, Liu CJ, et al. Direct regulation of TWIST by HIF-1α promotes metastasis. Nat Cell Biol. (2008) 10:295–305. doi: 10.1038/ncb1691

PubMed Abstract | CrossRef Full Text | Google Scholar

64. Liu KH, Tsai YT, Chin SY, Lee WR, Chen YC, Shen SC. Hypoxia stimulates the epithelial-to-mesenchymal transition in lung cancer cells through accumulation of nuclear β-catenin. Anticancer Res. (2018) 38:6299–308. doi: 10.21873/anticanres.12986

PubMed Abstract | CrossRef Full Text | Google Scholar

65. Evans AJ, Russell RC, Roche O, Burry TN, Fish JE, Chow VW, et al. VHL promotes E2 box-dependent E-cadherin transcription by HIF-mediated regulation of SIP1 and snail. Mol Cell Biol. (2007) 27:157–69. doi: 10.1128/MCB.00892-06

PubMed Abstract | CrossRef Full Text | Google Scholar

66. Iwasaki K, Ninomiya R, Shin T, Nomura T, Kajiwara T, Hijiya N, et al. Chronic hypoxia-induced slug promotes invasive behavior of prostate cancer cells by activating expression of ephrin-B1. Cancer Sci. (2018) 109:3159–70. doi: 10.1111/cas.13754

PubMed Abstract | CrossRef Full Text | Google Scholar

67. Salnikov AV, Liu L, Platen M, Gladkich J, Salnikova O, Ryschich E, et al. Hypoxia Induces EMT in low and highly aggressive pancreatic tumor cells but only cells with cancer stem cell characteristics acquire pronounced migratory potential. PLoS ONE. (2012) 7:e46391. doi: 10.1371/journal.pone.0046391

PubMed Abstract | CrossRef Full Text | Google Scholar

68. Zhang W, Shi X, Peng Y, Wu M, Zhang P, Xie R, et al. HIF-1α promotes epithelial-mesenchymal transition and metastasis through direct regulation of ZEB1 in colorectal cancer. PLoS ONE. (2015) 10:e0129603. doi: 10.1371/journal.pone.0129603

PubMed Abstract | CrossRef Full Text | Google Scholar

69. Zhu J, Huang Z, Zhang M, Wang W, Liang H, Zeng J, et al. HIF-1α promotes ZEB1 expression and EMT in a human bladder cancer lung metastasis animal model. Oncol Lett. (2018) 15:3482–9. doi: 10.3892/ol.2018.7764

PubMed Abstract | CrossRef Full Text | Google Scholar

70. Joseph JV, Conroy S, Pavlov K, Sontakke P, Tomar T, Eggens-Meijer E, et al. Hypoxia enhances migration and invasion in glioblastoma by promoting a mesenchymal shift mediated by the HIF1α-ZEB1 axis. Cancer Lett. (2015) 359:107–16. doi: 10.1016/j.canlet.2015.01.010

PubMed Abstract | CrossRef Full Text | Google Scholar

71. Deng SJ, Chen HY, Ye Z, Deng SC, Zhu S, Zeng Z, et al. Hypoxia-induced LncRNA-BX111 promotes metastasis and progression of pancreatic cancer through regulating ZEB1 transcription. Oncogene. (2018) 37:5811–28. doi: 10.1038/s41388-018-0382-1

PubMed Abstract | CrossRef Full Text | Google Scholar

72. Wu MZ, Tsai YP, Yang MH, Huang CH, Chang SY, Chang CC, et al. Interplay between HDAC3 and WDR5 is essential for hypoxia-induced epithelial-mesenchymal transition. Mol Cell. (2011) 43:811–22. doi: 10.1016/j.molcel.2011.07.012

PubMed Abstract | CrossRef Full Text | Google Scholar

73. Luo D, Wang J, Li J, Post M. Mouse snail is a target gene for HIF. Mol Cancer Res. (2011) 9:234–45. doi: 10.1158/1541-7786.MCR-10-0214

PubMed Abstract | CrossRef Full Text | Google Scholar

74. Wu CY, Tsai YP, Wu MZ, Teng SC, Wu KJ. Epigenetic reprogramming and post-transcriptional regulation during the epithelial-mesenchymal transition. Trends Genet. (2012) 28:454–63. doi: 10.1016/j.tig.2012.05.005

PubMed Abstract | CrossRef Full Text | Google Scholar

75. Storci G, Sansone P, Mari S, D'Uva G, Tavolari S, Guarnieri T, et al. TNFalpha up-regulates SLUG via the NF-kappaB/HIF1alpha axis, which imparts breast cancer cells with a stem cell-like phenotype. J Cell Physiol. (2010) 225:682–91. doi: 10.1002/jcp.22264

PubMed Abstract | CrossRef Full Text | Google Scholar

76. Tang C, Liu T, Wang K, Wang X, Xu S, He D, et al. Transcriptional regulation of FoxM1 by HIF-1α mediates hypoxia-induced EMT in prostate cancer. Oncol Rep. (2019) 42:1307–18. doi: 10.3892/or.2019.7248

CrossRef Full Text | Google Scholar

77. Ma C, Guo Y, Zhang Y, Duo A, Jia Y, Liu C, et al. PAFAH1B2 is a HIF1a target gene and promotes metastasis in pancreatic cancer. Biochem Biophys Res Commun. (2018) 501:654–60. doi: 10.1016/j.bbrc.2018.05.039

PubMed Abstract | CrossRef Full Text | Google Scholar

78. Chou CC, Chuang HC, Salunke SB, Kulp SK, Chen CS. A novel HIF-1alpha-integrin-linked kinase regulatory loop that facilitates hypoxia-induced HIF-1alpha expression and epithelial-mesenchymal transition in cancer cells. Oncotarget. (2015) 6:8271–85. doi: 10.18632/oncotarget.3186

PubMed Abstract | CrossRef Full Text | Google Scholar

79. Kim WY, Perera S, Zhou B, Carretero J, Yeh JJ, Heathcote SA, et al. HIF2α cooperates with RAS to promote lung tumorigenesis in mice. J Clin Investig. (2009) 119:2160–70. doi: 10.1172/JCI38443

PubMed Abstract | CrossRef Full Text | Google Scholar

80. Yang J, Zhang X, Zhang Y, Zhu D, Zhang L, Li Y, et al. HIF-2α promotes epithelial-mesenchymal transition through regulating Twist2 binding to the promoter of E-cadherin in pancreatic cancer. J Exp Clin Cancer Res. (2016) 35:26. doi: 10.1186/s13046-016-0298-y

PubMed Abstract | CrossRef Full Text | Google Scholar

81. Culver C, Sundqvist A, Mudie S, Melvin A, Xirodimas D, Rocha S. Mechanism of hypoxia-induced NF-κB. Mol Cell Biol. (2010) 30:4901–21. doi: 10.1128/MCB.00409-10

PubMed Abstract | CrossRef Full Text | Google Scholar

82. Laderoute KR, Calaoagan JM, Gustafson-Brown C, Knapp AM, Li GC, Mendonca HL, et al. The response of c-Jun/AP-1 to chronic hypoxia is hypoxia-inducible factor 1α dependent. Mol Cell Biol. (2002) 22:2515–23. doi: 10.1128/MCB.22.8.2515-2523.2002

CrossRef Full Text | Google Scholar

83. Laderoute KR, Amin K, Calaoagan JM, Knapp M, Le T, Orduna J, et al. 5′-AMP-Activated Protein Kinase (AMPK) is induced by low-oxygen and glucose deprivation conditions found in solid-tumor microenvironments. Mol Cell Biol. (2006) 26:5336–47. doi: 10.1128/MCB.00166-06

PubMed Abstract | CrossRef Full Text | Google Scholar

84. Minet E, Arnould T, Michel G, Roland I, Mottet D, Raes M, et al. ERK activation upon hypoxia: involvement in HIF-1 activation. FEBS Lett. (2000) 468:53–8. doi: 10.1016/S0014-5793(00)01181-9

PubMed Abstract | CrossRef Full Text | Google Scholar

85. Wouters BG, Koritzinsky M. Hypoxia signalling through mTOR and the unfolded protein response in cancer. Nat Rev Cancer. (2008) 8:851–64. doi: 10.1038/nrc2501

PubMed Abstract | CrossRef Full Text | Google Scholar

86. Kim I, He YY. Targeting the AMP-activated protein kinase for cancer prevention and therapy. Front Oncol. (2013) 3:175. doi: 10.3389/fonc.2013.00175

PubMed Abstract | CrossRef Full Text | Google Scholar

87. Luo Z, Zang M, Guo W. AMPK as a metabolic tumor suppressor: control of metabolism and cell growth. Future oncology. (2010) 6:457–70. doi: 10.2217/fon.09.174

PubMed Abstract | CrossRef Full Text | Google Scholar

88. Saxena M, Balaji SA, Deshpande N, Ranganathan S, Pillai DM, Hindupur SK, et al. AMP-activated protein kinase promotes epithelial-mesenchymal transition in cancer cells through Twist1 upregulation. J Cell Sci. (2018) 131. doi: 10.1242/jcs.208314

PubMed Abstract | CrossRef Full Text | Google Scholar

89. Chou CC, Lee KH, Lai IL, Wang D, Mo X, Kulp SK, et al. AMPK reverses the mesenchymal phenotype of cancer cells by targeting the Akt-MDM2-Foxo3a signaling axis. Cancer Res. (2014) 74:4783–95. doi: 10.1158/0008-5472.CAN-14-0135

PubMed Abstract | CrossRef Full Text | Google Scholar

90. Ferretti AC, Hidalgo F, Tonucci FM, Almada E, Pariani A, Larocca MC, et al. Metformin and glucose starvation decrease the migratory ability of hepatocellular carcinoma cells: targeting AMPK activation to control migration. Sci Rep. (2019) 9:2815. doi: 10.1038/s41598-019-39556-w

PubMed Abstract | CrossRef Full Text | Google Scholar

91. Liu J, Song N, Huang Y, Chen Y. Irisin inhibits pancreatic cancer cell growth via the AMPK-mTOR pathway. Scientific reports. (2018) 8:15247. doi: 10.1038/s41598-018-33229-w

PubMed Abstract | CrossRef Full Text | Google Scholar

92. Sun L, Cao J, Chen K, Cheng L, Zhou C, Yan B, et al. Betulinic acid inhibits stemness and EMT of pancreatic cancer cells via activation of AMPK signaling. Int J Oncol. (2019) 54:98–110. doi: 10.3892/ijo.2018.4604

PubMed Abstract | CrossRef Full Text | Google Scholar

93. Yu JS, Cui W. Proliferation, survival and metabolism: the role of PI3K/AKT/mTOR signalling in pluripotency and cell fate determination. Development. (2016) 143:3050–60. doi: 10.1242/dev.137075

PubMed Abstract | CrossRef Full Text | Google Scholar

94. Tam SY, Wu VWC, Law HKW. Influence of autophagy on the efficacy of radiotherapy. Radiat Oncol. (2017) 12:57. doi: 10.1186/s13014-017-0795-y

PubMed Abstract | CrossRef Full Text | Google Scholar

95. Liu F, Huang X, Luo Z, He J, Haider F, Song C, et al. Hypoxia-activated PI3K/Akt inhibits oxidative stress via the regulation of reactive oxygen species in human dental pulp cells. Oxid Med Cell Longev. (2019) 2019:6595189. doi: 10.1155/2019/6595189

PubMed Abstract | CrossRef Full Text | Google Scholar

96. Zhang J, Guo H, Zhu JS, Yang YC, Chen WX, Chen NW. Inhibition of phosphoinositide 3-kinase/Akt pathway decreases hypoxia inducible factor-1α expression and increases therapeutic efficacy of paclitaxel in human hypoxic gastric cancer cells. Oncol Lett. (2014) 7:1401–8. doi: 10.3892/ol.2014.1963

PubMed Abstract | CrossRef Full Text | Google Scholar

97. Lu L, Sheng Y, Zhang G, Li Y, OuYang PY, Ge Y, et al. Temporal lobe injury patterns following intensity modulated radiotherapy in a large cohort of nasopharyngeal carcinoma patients. Oral Oncol. (2018) 85:8–14. doi: 10.1016/j.oraloncology.2018.07.020

PubMed Abstract | CrossRef Full Text | Google Scholar

98. Wouters BG, Brown JM. Cells at intermediate oxygen levels can be more important than the “hypoxic fraction” in determining tumor response to fractionated radiotherapy. Radiat Res. (1997) 147:541–50. doi: 10.2307/3579620

PubMed Abstract | CrossRef Full Text | Google Scholar

99. Grille SJ, Bellacosa A, Upson J, Klein-Szanto AJ, van Roy F, Lee-Kwon W, et al. The protein kinase Akt induces epithelial mesenchymal transition and promotes enhanced motility and invasiveness of squamous cell carcinoma lines. Cancer Res. (2003) 63:2172–8.

PubMed Abstract | Google Scholar

100. Hong KO, Kim JH, Hong JS, Yoon HJ, Lee JI, Hong SP, et al. Inhibition of Akt activity induces the mesenchymal-to-epithelial reverting transition with restoring E-cadherin expression in KB and KOSCC-25B oral squamous cell carcinoma cells. J Exp Clin Cancer Res. (2009) 28:28. doi: 10.1186/1756-9966-28-28

PubMed Abstract | CrossRef Full Text | Google Scholar

101. Gulhati P, Bowen KA, Liu J, Stevens PD, Rychahou PG, Chen M, et al. mTORC1 and mTORC2 regulate EMT, motility, and metastasis of colorectal cancer via RhoA and Rac1 signaling pathways. Cancer Res. (2011) 71:3246–56. doi: 10.1158/0008-5472.CAN-10-4058

PubMed Abstract | CrossRef Full Text | Google Scholar

102. Kietzmann T, Mennerich D, Dimova EY. Hypoxia-inducible factors (HIFs) and Phosphorylation: impact on stability, localization, and transactivity. Front Cell Dev Biol. (2016) 4:11. doi: 10.3389/fcell.2016.00011

PubMed Abstract | CrossRef Full Text | Google Scholar

103. Dhillon AS, Hagan S, Rath O, Kolch W. MAP kinase signalling pathways in cancer. Oncogene. (2007) 26:3279–90. doi: 10.1038/sj.onc.1210421

PubMed Abstract | CrossRef Full Text | Google Scholar

104. Xie L, Law BK, Chytil AM, Brown KA, Aakre ME, Moses HL. Activation of the Erk pathway is required for TGF-β1-induced EMT in vitro. Neoplasia. (2004) 6:603–10. doi: 10.1593/neo.04241

PubMed Abstract | CrossRef Full Text | Google Scholar

105. Pelaez IM, Kalogeropoulou M, Ferraro A, Voulgari A, Pankotai T, Boros I, et al. Oncogenic RAS alters the global and gene-specific histone modification pattern during epithelial-mesenchymal transition in colorectal carcinoma cells. Int J Biochem Cell Biol. (2010) 42:911–20. doi: 10.1016/j.biocel.2010.01.024

PubMed Abstract | CrossRef Full Text | Google Scholar

106. Shin S, Buel GR, Nagiec MJ, Han MJ, Roux PP, Blenis J, et al. ERK2 regulates epithelial-to-mesenchymal plasticity through DOCK10-dependent Rac1/FoxO1 activation. Proc Natl Acad Sci USA. (2019) 116:2967–76. doi: 10.1073/pnas.1811923116

PubMed Abstract | CrossRef Full Text | Google Scholar

107. Wang Y, Ngo VN, Marani M, Yang Y, Wright G, Staudt LM, et al. Critical role for transcriptional repressor Snail2 in transformation by oncogenic RAS in colorectal carcinoma cells. Oncogene. (2010) 29:4658–70. doi: 10.1038/onc.2010.218

PubMed Abstract | CrossRef Full Text | Google Scholar

108. Chiu LY, Hsin IL, Yang TY, Sung WW, Chi JY, Chang JT, et al. The ERK–ZEB1 pathway mediates epithelial–mesenchymal transition in pemetrexed resistant lung cancer cells with suppression by vinca alkaloids. Oncogene. (2017) 36:242–53. doi: 10.1038/onc.2016.195

PubMed Abstract | CrossRef Full Text | Google Scholar

109. Amatangelo MD, Goodyear S, Varma D, Stearns ME. c-Myc expression and MEK1-induced Erk2 nuclear localization are required for TGF-beta induced epithelial-mesenchymal transition and invasion in prostate cancer. Carcinogenesis. (2012) 33:1965–75. doi: 10.1093/carcin/bgs227

PubMed Abstract | CrossRef Full Text | Google Scholar

110. Sheng W, Chen C, Dong M, Wang G, Zhou J, Song H, et al. Calreticulin promotes EGF-induced EMT in pancreatic cancer cells via Integrin/EGFR-ERK/MAPK signaling pathway. Cell Death Dis. (2017) 8:e3147. doi: 10.1038/cddis.2017.547

PubMed Abstract | CrossRef Full Text | Google Scholar

111. Deng W, Fernandez A, McLaughlin SL, Klinke DJ II. WNT1-inducible signaling pathway protein 1 (WISP1/CCN4) stimulates melanoma invasion and metastasis by promoting the epithelial-mesenchymal transition. J Biol Chem. (2019) 294:5261–80. doi: 10.1074/jbc.RA118.006122

PubMed Abstract | CrossRef Full Text | Google Scholar

112. Li L, Zhang S, Li H, Chou H. FGFR3 promotes the growth and malignancy of melanoma by influencing EMT and the phosphorylation of ERK, AKT, and EGFR. BMC Cancer. (2019) 19:963. doi: 10.1186/s12885-019-6161-8

PubMed Abstract | CrossRef Full Text | Google Scholar

113. Hong J, Zhou J, Fu J, He T, Qin J, Wang L, et al. Phosphorylation of serine 68 of Twist1 by MAPKs stabilizes Twist1 protein and promotes breast cancer cell invasiveness. Cancer Res. (2011) 71:3980–90. doi: 10.1158/0008-5472.CAN-10-2914

PubMed Abstract | CrossRef Full Text | Google Scholar

114. Hocevar BA, Brown TL, Howe PH. TGF-β induces fibronectin synthesis through a c-Jun N-terminal kinase-dependent, Smad4-independent pathway. EMBO J. (1999) 18:1345–56. doi: 10.1093/emboj/18.5.1345

PubMed Abstract | CrossRef Full Text | Google Scholar

115. Hocevar BA, Prunier C, Howe PH. Disabled-2 (Dab2) mediates transforming growth factor β (TGFβ)-stimulated fibronectin synthesis through TGFbeta-activated kinase 1 and activation of the JNK pathway. J Biol Chem. (2005) 280:25920–7. doi: 10.1074/jbc.M501150200

PubMed Abstract | CrossRef Full Text | Google Scholar

116. Santibanez JF. JNK mediates TGF-β1-induced epithelial mesenchymal transdifferentiation of mouse transformed keratinocytes. FEBS Lett. (2006) 580:5385–91. doi: 10.1016/j.febslet.2006.09.003

PubMed Abstract | CrossRef Full Text | Google Scholar

117. Espada J, Peinado H, Lopez-Serra L, Setién F, Lopez-Serra P, Portela A, et al. Regulation of SNAIL1 and E-cadherin function by DNMT1 in a DNA methylation-independent context. Nucleic Acids Res. (2011) 39:9194–205. doi: 10.1093/nar/gkr658

PubMed Abstract | CrossRef Full Text | Google Scholar

118. Tsai CL, Li HP, Lu YJ, Hsueh C, Liang Y, Chen CL, et al. Activation of DNA methyltransferase 1 by EBV LMP1 Involves c-Jun NH₂-terminal kinase signaling. Cancer Research. (2006) 66:11668–76. doi: 10.1158/0008-5472.CAN-06-2194

CrossRef Full Text | Google Scholar

119. Heiland DH, Ferrarese R, Claus R, Dai F, Masilamani AP, Kling E, et al. c-Jun-N-terminal phosphorylation regulates DNMT1 expression and genome wide methylation in gliomas. Oncotarget. (2016) 8:6940–54. doi: 10.18632/oncotarget.14330

PubMed Abstract | CrossRef Full Text | Google Scholar

120. Choi Y, Ko YS, Park J, Choi Y, Kim Y, Pyo JS, et al. HER2-induced metastasis is mediated by AKT/JNK/EMT signaling pathway in gastric cancer. World J Gastroenterol. (2016) 22:9141–53. doi: 10.3748/wjg.v22.i41.9141

PubMed Abstract | CrossRef Full Text | Google Scholar

121. Zhan X, Feng X, Kong Y, Chen Y, Tan W. JNK signaling maintains the mesenchymal properties of multi-drug resistant human epidermoid carcinoma KB cells through snail and twist1. BMC Cancer. (2013) 13:180. doi: 10.1186/1471-2407-13-180

PubMed Abstract | CrossRef Full Text | Google Scholar

122. Meng H, Wu J, Huang Q, Yang X, Yang K, Qiu Y, et al. NEDD9 promotes invasion and migration of colorectal cancer cell line HCT116 via JNK/EMT. Oncol Lett. (2019) 18:4022–9. doi: 10.3892/ol.2019.10756

PubMed Abstract | CrossRef Full Text | Google Scholar

123. Chang Y, Yan W, Sun C, Liu Q, Wang J, Wang M. miR-145-5p inhibits epithelial-mesenchymal transition via the JNK signaling pathway by targeting MAP3K1 in non-small cell lung cancer cells. Oncology letters. (2017) 14:6923–8. doi: 10.3892/ol.2017.7092

PubMed Abstract | CrossRef Full Text | Google Scholar

124. Lin Y, Mallen-St Clair J, Wang G, Luo J, Palma-Diaz F, Lai C, et al. p38 MAPK mediates epithelial-mesenchymal transition by regulating p38IP and Snail in head and neck squamous cell carcinoma. Oral Oncol. (2016) 60:81–9. doi: 10.1016/j.oraloncology.2016.06.010

PubMed Abstract | CrossRef Full Text | Google Scholar

125. Ling G, Ji Q, Ye W, Ma D, Wang Y. Epithelial-mesenchymal transition regulated by p38/MAPK signaling pathways participates in vasculogenic mimicry formation in SHG44 cells transfected with TGF-beta cDNA loaded lentivirus in vitro and in vivo. Int J Oncol. (2016) 49:2387–98. doi: 10.3892/ijo.2016.3724

PubMed Abstract | CrossRef Full Text | Google Scholar

126. Tam SY, Wu VWC, Law HKW. JNK pathway mediates low oxygen level induced epithelial–mesenchymal transition and stemness maintenance in colorectal cancer cells. Cancers. (2020) 12:224. doi: 10.3390/cancers12010224

PubMed Abstract | CrossRef Full Text | Google Scholar

127. Xia Y, Shen S, Verma IM. NF-κB, an active player in human cancers. Cancer Immunol Res. (2014) 2:823–30. doi: 10.1158/2326-6066.CIR-14-0112

PubMed Abstract | CrossRef Full Text | Google Scholar

128. Huber MA, Azoitei N, Baumann B, Grunert S, Sommer A, Pehamberger H, et al. NF-κB is essential for epithelial-mesenchymal transition and metastasis in a model of breast cancer progression. J Clin Investig. (2004) 114:569–81. doi: 10.1172/JCI200421358

PubMed Abstract | CrossRef Full Text | Google Scholar

129. Li Y, Lin Z, Chen B, Chen S, Jiang Z, Zhou T, et al. Ezrin/NF-kB activation regulates epithelial- mesenchymal transition induced by EGF and promotes metastasis of colorectal cancer. Biomed Pharmacother. (2017) 92:140–8. doi: 10.1016/j.biopha.2017.05.058

PubMed Abstract | CrossRef Full Text | Google Scholar

130. Pires BR, Mencalha AL, Ferreira GM, de Souza WF, Morgado-Diaz JA, Maia AM, et al. NF-kappaB is involved in the regulation of EMT genes in breast cancer cells. PLoS ONE. (2017) 12:e0169622. doi: 10.1371/journal.pone.0169622

PubMed Abstract | CrossRef Full Text | Google Scholar

131. Cheng ZX, Sun B, Wang SJ, Gao Y, Zhang YM, Zhou HX, et al. Nuclear factor-κB-dependent epithelial to mesenchymal transition induced by HIF-1alpha activation in pancreatic cancer cells under hypoxic conditions. PLoS ONE. (2011) 6:e23752. doi: 10.1371/journal.pone.0023752

PubMed Abstract | CrossRef Full Text | Google Scholar

132. Kara C, Selamet H, Gokmenoglu C, Kara N. Low level laser therapy induces increased viability and proliferation in isolated cancer cells. Cell Prolif . (2018) 51:e12417. doi: 10.1111/cpr.12417

PubMed Abstract | CrossRef Full Text | Google Scholar

133. Kopan R. Notch signaling. Cold Spring Harb Perspect Biol. (2012) 4:a011213. doi: 10.1101/cshperspect.a011213

PubMed Abstract | CrossRef Full Text | Google Scholar

134. Kar R, Jha NK, Jha SK, Sharma A, Dholpuria S, Asthana N, et al. A “NOTCH” deeper into the epithelial-to-mesenchymal transition (EMT) program in breast cancer. Genes. (2019) 10:961. doi: 10.3390/genes10120961

PubMed Abstract | CrossRef Full Text | Google Scholar

135. Gustafsson MV, Zheng X, Pereira T, Gradin K, Jin S, Lundkvist J, et al. Hypoxia requires notch signaling to maintain the undifferentiated cell state. Dev Cell. (2005) 9:617–28. doi: 10.1016/j.devcel.2005.09.010

PubMed Abstract | CrossRef Full Text | Google Scholar

136. Leong KG, Niessen K, Kulic I, Raouf A, Eaves C, Pollet I, et al. Jagged1-mediated Notch activation induces epithelial-to-mesenchymal transition through Slug-induced repression of E-cadherin. J Exp Med. (2007) 204:2935–48. doi: 10.1084/jem.20071082

PubMed Abstract | CrossRef Full Text | Google Scholar

137. Shao S, Zhao X, Zhang X, Luo M, Zuo X, Huang S, et al. Notch1 signaling regulates the epithelial-mesenchymal transition and invasion of breast cancer in a Slug-dependent manner. Mol Cancer. (2015) 14:28. doi: 10.1186/s12943-015-0295-3

PubMed Abstract | CrossRef Full Text | Google Scholar

138. Zhang L, Sha J, Yang G, Huang X, Bo J, Huang Y. Activation of Notch pathway is linked with epithelial-mesenchymal transition in prostate cancer cells. Cell Cycle. (2017) 16:999–1007. doi: 10.1080/15384101.2017.1312237

PubMed Abstract | CrossRef Full Text | Google Scholar

139. Sahlgren C, Gustafsson MV, Jin S, Poellinger L, Lendahl U. Notch signaling mediates hypoxia-induced tumor cell migration and invasion. Proc Natl Acad Sci USA. (2008) 105:6392–7. doi: 10.1073/pnas.0802047105

PubMed Abstract | CrossRef Full Text | Google Scholar

140. Yang Y, Ahn YH, Gibbons DL, Zang Y, Lin W, Thilaganathan N, et al. The Notch ligand Jagged2 promotes lung adenocarcinoma metastasis through a miR-200-dependent pathway in mice. J Clin Investig. (2011) 121:1373–85. doi: 10.1172/JCI42579

PubMed Abstract | CrossRef Full Text | Google Scholar

141. Zhang X, Zhao X, Shao S, Zuo X, Ning Q, Luo M, et al. Notch1 induces epithelial-mesenchymal transition and the cancer stem cell phenotype in breast cancer cells and STAT3 plays a key role. Int J Oncol. (2015) 46:1141–8. doi: 10.3892/ijo.2014.2809

PubMed Abstract | CrossRef Full Text | Google Scholar

142. De Francesco EM, Maggiolini M, Musti AM. Crosstalk between Notch, HIF-1α and GPER in Breast Cancer EMT. Int J Mol Sci. (2018) 19:2011. doi: 10.3390/ijms19072011

PubMed Abstract | CrossRef Full Text | Google Scholar

143. Chen J, Imanaka N, Chen J, Griffin JD. Hypoxia potentiates Notch signaling in breast cancer leading to decreased E-cadherin expression and increased cell migration and invasion. Br J Cancer. (2010) 102:351–60. doi: 10.1038/sj.bjc.6605486

PubMed Abstract | CrossRef Full Text | Google Scholar

144. Wigerup C, Pahlman S, Bexell D. Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer. Pharmacol Ther. (2016) 164:152–69. doi: 10.1016/j.pharmthera.2016.04.009

PubMed Abstract | CrossRef Full Text | Google Scholar

145. Noman MZ, Hasmim M, Lequeux A, Xiao M, Duhem C, Chouaib S, et al. Improving cancer immunotherapy by targeting the hypoxic tumor microenvironment: new opportunities and challenges. Cells. (2019) 8:1083. doi: 10.3390/cells8091083

PubMed Abstract | CrossRef Full Text | Google Scholar