miR-15a and miR-20b sensitize hepatocellular carcinoma cells to sorafenib through repressing CDC37L1 and consequent PPIA downregulation

Abstract

Sorafenib is a classical targeted drug for the treatment of advanced hepatocellular carcinoma (HCC), but intrinsic resistance severely limited its therapeutic effects. In the present study, we aimed to identify crucial genes in HCC cells that affect sorafenib resistance by a CRISPR/Cas9 genome-scale screening. The results indicated that the deficiency of miR-15a and miR-20b contributed to sorafenib resistance, whereas exogenous expression of miR-15a and miR-20b enhanced sorafenib sensitivity of HCC cells by cell viability, colony formation, and flow cytometry analyses. Further analyses revealed that cell division cycle 37 like 1 (CDC37L1) as a common target of miR-15a and 20b, was negatively regulated by the two miRNAs and could enhance sorafenib resistance of HCC cells in vitro and in vivo. Mechanistically, CDC37L1, as a cochaperone, effectively increased the expression of peptidylprolyl isomerase A (PPIA) through strengthening the binding between heat shock protein 90 (HSP90) and PPIA. The results from immunohistochemical staining of a HCC tissue microarray revealed a positive association between CDC37L1 and PPIA expression, and high expression of CDC37L1 and PPIA predicted worse prognosis of HCC patients after sorafenib therapy. Taken together, our findings reveal crucial roles of miR-15a, miR-20b, CDC37L1, and PPIA in sorafenib response of HCC cells. These factors may serve as therapeutic targets and predict prognosis for HCC treated with sorafenib.

Fisetin, a dietary flavonoid, increases the sensitivity of chemoresistant head and neck carcinoma cells to cisplatin possibly through HSP90AA1/IL‐17 pathway

“…The proteomic analysis found that PPIA may be a potential diagnostic marker for salivary gland tumors (de Lima‐Souza et al, 2022). In hepatocellular carcinoma, the binding between heat shock protein 90 (HSP90) and PPIA effectively increased the expression of PPIA, making cancer cells more resistant to sorafenib, reducing the efficacy of this targeted drug, and resulting in poor prognosis in patients (L. Li et al, 2022). PTPRS is a receptor‐type protein tyrosine phosphatase, which has been reported to modulate numerous signaling pathways (Bunin et al, 2015).…”

Transcriptional regulation of NDUFA4L2 by NFIB induces sorafenib resistance by decreasing reactive oxygen species in hepatocellular carcinoma

“…However, the clinical efficacy of Sorafenib treatment in HCC is modest, and it can only extend patients’ median overall survival by 3 months 30 . The existence of intrinsic or acquired drug resistance is considered a major obstacle contributing to the failure of sorafenib treatment in HCC patients 31,32 . Previous studies have shown that sorafenib treatment restrained tumor growth partly through suppression of tumor angiogenesis.…”

“… 30 The existence of intrinsic or acquired drug resistance is considered a major obstacle contributing to the failure of sorafenib treatment in HCC patients. 31 , 32 Previous studies have shown that sorafenib treatment restrained tumor growth partly through suppression of tumor angiogenesis. However, sorafenib treatment can lead to the activation of HIF‐1α or HIF‐2α in cancer cells, which in turn induce the expression of VEGF and other proangiogenic factors to confer HCC resistance to sorafenib treatment.…”

The dual role of microRNA (miR)-20b in cancers: Friend or foe?

“…An investigation of hepatocellular carcinoma cells has indicated that drug resistance negatively associates with reduced levels of miR-20b [ 80 ]. Overexpression of miR-20b leads to the sensitivity of hepatocellular cancer cells to chemotherapy drugs.…”

“…Overexpression of miR-20b leads to the sensitivity of hepatocellular cancer cells to chemotherapy drugs. From the molecular aspect, the cell division cycle 37-like 1 (CDC37L1) gene enhances drug resistance of hepatocellular cancer cells [ 80 ]. Targeting CDC37L1 by miR-20b reverses its effects.…”