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

Abstract

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 TARBP2 in HCC using well-characterized HCC cell lines, patient-derived tissues and blood samples. Additionally, the potential prognostic and diagnostic value of TARBP2 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 TARBP2 to induce cell proliferation, migration, and invasion in HCC cell lines. RNA sequencing was applied to identify the downstream elements of TARBP2. The interaction of potential targets of TARBP2, miR‐145 and serpin family E member 1 (SERPINE1), was assessed using luciferase reporter assay. TARBP2 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 TARBP2 was demonstrated to promote proliferation, migration, and invasion in HCC cell lines. Interestingly, the reduction of TARBP2 was shown to result in the upregulation of SERPINE1, also known as plasminogen activator inhibitor (PAI-1), which is a vital gene of the HIF-1 signaling pathway. Knockdown of SERPINE1 rescued the TARBP2-lost phenotype. Moreover, TARBP2 depletion induced the upregulation of SERPINE1 through reducing the processing of miR-145, which directly targets SERPINE1. Finally, overexpression of miR-145 repressed SERPINE1 and rescued the functions in sh-TARBP2 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.

AKR1C1 overexpression leads to lenvatinib resistance in hepatocellular carcinoma

“…When HCC cells were exposed to various doses of lenvatinib, the expression of AKR1C1 was upregulated, while that of SERPINE1 was downregulated. According to the obtained results, lenvatinib can inhibit the expression of SERPINE1 (an oncogene in HCC) in HCC cells, regardless of the concentration (16,17). This indicated that SERPINE1 was the target of lenvatinib, and in HCC patients with a high expression of SERPINE1, lenvatinib can be used for targeted treatment.…”

“…The PPI network of DEGs demonstrated that AKR1C1 was the most prominent upregulated gene in LEN-MHCC-97H cells, and serpin family E member 1 (SERPINE1) was a considerably downregulated gene in LEN-MHCC-97H cells (Figure 3B,3C, Tables 2,3). SERPINE1 promotes the proliferation, invasion, migration, and epithelial-mesenchymal transition (EMT) of HCC cells (16,17). However, the function of AKR1C1 in HCC is not clear.…”

Histone Deacetylase Inhibitor Trichostatin A Reduces Endothelial Cell Proliferation by Suppressing STAT5A-Related Gene Transcription

“…The luciferase reporter assay was performed in 48-well plates as described previously ( 14 ) with the protocol of the manufacturer using the dual luciferase assay kit from Promega (Madison, WI, USA). HUVEC cells were grown and co-transfected with 100 ng of a firefly luciferase reporter plasmid pGL3 carrying different wild-type or mutant constructs or the Renilla luciferase vector pRL-TK (5 ng; for normalization) from Promega using Lipofectamine 2000 transfection reagent (Invitrogen, Carlsbad, USA) according to the protocol of the manufacturer.…”

Integrated analysis of multiple transcriptomic data identifies ST8SIA6‑AS1 and LINC01093 as potential biomarkers in HBV‑associated liver cancer

“…Multiple studies have reported that HBV contributes to the proliferation and metastasis of liver cells, playing a crucial role in the high recurrence and mortality of liver cancer (3)(4)(5). Despite improvements that have been made in surgical resection and transplantation, the prognosis of patients with liver cancer remains unsatisfactory with a 5-year survival rate of <50% (6,7). Therefore, exploring the molecular mechanism underlying the pathogenesis of HBV-associated liver cancer has important clinical significance.…”