Targeting STK26 and ATG4B: miR-22-3p as a modulator of autophagy and tumor progression in HCC

Drug-induced protective autophagy significantly affects the efficacy of anticancer therapies. Enhancing tumor cell sensitivity to treatment by inhibiting autophagy is essential for effective cancer therapy. Our study, analyzing data from The Cancer Genome Atlas (TCGA) public database, HCC cell lines, and liver cancer tissue samples, found that miR-22-3p is expressed at low levels in HCC and is significantly associated with clinicopathological features and patient prognosis. Functional assays and xenograft models demonstrated that miR-22-3p suppresses HCC progression. Moreover, Western blot analysis and the LC3B double reporter (mRFP1-EGFP-LC3B) confirmed that miR-22-3p inhibits autophagy in HCC cells. Further investigation identified Sterile 20-like kinase 26 (STK26) and Autophagy Related 4B Cysteine Peptidase (ATG4B) as targets of miR-22-3p. STK26, which is overexpressed in HCC, promotes malignant characteristics such as proliferation, migration, and invasion. Additionally, STK26 facilitates autophagy in HCC by phosphorylating ATG4B at serine 383. miR-22-3p inhibits autophagy by targeting STK26 and ATG4B, thus preventing the phosphorylation of ATG4B at serine 383. Sorafenib treatment increases the levels and phosphorylation of STK26 and ATG4B, inducing protective autophagy. The combination of miR-22-3p with sorafenib demonstrated enhanced antitumor effects both in vitro and in vivo. In conclusion, our findings suggest that miR-22-3p inhibits HCC progression by regulating the expression of STK26 and ATG4B, potentially through autophagy inhibition, thereby increasing sensitivity to sorafenib treatment. This offers a new therapeutic approach for effective HCC.