AUTHOR=Xiang Xue , Ma Hai-zhong , Chen Ya-qiong , Zhang Dong-zhi , Ma Shi-xu , Wang Hong-jing , Liu De-ming , Yuan Yuan , Cai Hui 

TITLE=GM-CSF-miRNA-Jak2/Stat3 Signaling Mediates Chemotherapy-Induced Cancer Cell Stemness in Gastric Cancer

JOURNAL=Frontiers in Pharmacology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.855351

DOI=10.3389/fphar.2022.855351

ISSN=1663-9812

ABSTRACT=<p>Chemotherapy serves as the first choice in clinic to treat advanced gastric cancer. However, emerging evidence indicated the induction of drug resistance and cancer stem cells occasionally by chemotherapy, which seriously limit the therapeutic effects, but the regulatory mechanism remains unclear. Here we treated two human gastric cancer cell lines SGC7901 and BGC823 with 5-Fluorouracil (5-Fu) or Cisplatin (DDP) <italic>in vitro</italic>. The survived cells showed significant increase of drug resistance, cell stemness and cytokine <italic>GM-CSF</italic> expression and secretion. As such, <italic>GM-CSF</italic> was applied to stimulate gastric cancer cells, followed by the subpopulation of <italic>CD133<sup><bold>+</bold></sup></italic> CSC analysis, sphere formation assay and stemness genes expression analysis. As a result, CSCs showed induction by <italic>GM-CSF</italic> treatment. A gastric cancer animal model further indicated that the gastric cancer cells significantly promoted tumor growth after <italic>GM-CSF</italic> treatment <italic>in vivo</italic>. High-throughput miRNA and mRNA sequencing analyses identified a subset of miRNAs and mRNAs under regulation of both 5-Fu and <italic>GM-CSF</italic> in gastric cancer cells, including upregulation of <italic>miR-877-3p</italic> and downregulation of <italic>SOCS2</italic>. Targeted overexpression or knockdown of <italic>miR-877-3p</italic> in gastric cancer cells revealed the oncogenic function of <italic>miR-877-3p</italic> in regulating gastric cancer by suppressing target gene <italic>SOCS2. Jak2/Stat3</italic> signaling pathway, as a downstream target of <italic>SOCS2</italic>, showed activation <italic>in vitro</italic> and <italic>in vivo</italic> after treatment with <italic>miR-877-3p</italic> or <italic>GM-CSF</italic>. Our findings not only revealed a novel mechanism through which chemotherapy induced CSCs in gastric cancer via <italic>GM-CSF-miRNA-Jak2/Stat3</italic> signaling, but also provided an experimental evidence for appropriate dose reduction of adjuvant chemotherapy in treatment of cancer patients.</p>