AUTHOR=Li Li-Man , Chen Chang , Ran Ruo-Xi , Huang Jing-Tao , Sun Hui-Lung , Zeng Chang , Zhang Zhou , Zhang Wei , Liu Song-Mei 

TITLE=Loss of TARBP2 Drives the Progression of Hepatocellular Carcinoma via miR-145-SERPINE1 Axis

JOURNAL=Frontiers in Oncology

VOLUME=11

YEAR=2021

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2021.620912

DOI=10.3389/fonc.2021.620912

ISSN=2234-943X

ABSTRACT=<p>The clinical outcomes of hepatocellular carcinoma (HCC) remain dismal. Elucidating the molecular mechanisms for the progression of aggressive HCC holds the promise for developing novel intervention strategies. The transactivation response element RNA-binding protein (TRBP/TARBP2), a key component of microRNA (miRNA) processing and maturation machinery has been shown to play conflicting roles in tumor development and progression. We sought to investigate the expression of <italic>TARBP2</italic> in HCC using well-characterized HCC cell lines, patient-derived tissues and blood samples. Additionally, the potential prognostic and diagnostic value of <italic>TARBP2</italic> in HCC were analyzed using Kaplan-Meier plots and ROC curve. Cell counting kit‐8 (CCK‐8), wound healing and transwell assays examined the ability of <italic>TARBP2</italic> to induce cell proliferation, migration, and invasion in HCC cell lines. RNA sequencing was applied to identify the downstream elements of <italic>TARBP2</italic>. The interaction of potential targets of <italic>TARBP2</italic>, miR‐145 and serpin family E member 1 (<italic>SERPINE1</italic>), was assessed using luciferase reporter assay. <italic>TARBP2</italic> expression was down-regulated in HCC cell lines relative to normal hepatocyte cells, with a similar pattern further confirmed in tissue and blood samples. Notably, the loss of <italic>TARBP2</italic> was demonstrated to promote proliferation, migration, and invasion in HCC cell lines. Interestingly, the reduction of <italic>TARBP2</italic> was shown to result in the upregulation of <italic>SERPINE1</italic>, also known as plasminogen activator inhibitor (<italic>PAI-1</italic>), which is a vital gene of the HIF-1 signaling pathway. Knockdown of <italic>SERPINE1</italic> rescued the <italic>TARBP2</italic>-lost phenotype. Moreover, <italic>TARBP2</italic> depletion induced the upregulation of <italic>SERPINE1</italic> through reducing the processing of miR-145, which directly targets <italic>SERPINE1</italic>. Finally, overexpression of miR-145 repressed <italic>SERPINE1</italic> and rescued the functions in sh-<italic>TARBP2</italic> HCC cells. Our findings underscore a linear TARBP2-miR-145-SERPINE1 pathway that drives HCC progression, with the potential as a novel intervention target for aggressive HCC.</p>