PIMREG modulation of PI3K/Akt pathway enhances sorafenib resistance in Huh7 cells.

Abstract

Background and study aims: Sorafenib, as a novel multi-targeted oral tumor chemotherapeutic drug, has been found to exert an impact on the inhibition of cancer growth. Phosphatidylinositol-binding reticulin assembly protein interacting with mitotic regulatory factors (PIMREG) is strongly associated with oncology to drug resistance. However, how PIMREG modulates therapy tolerance to sorafenib in HCC and its potential regulatory mechanisms remain unclear. This study is abouta mechanistic approach to examine the action and mechanism of PIMREG in HCC-mediated sorafenib resistance.

Material and methods: The human hepatocellular carcinoma sensitive cell line Huh7 and drug-resistant cell line Huh7/SFB were used for the study, and different rates of PIMREG expansion in both cells were detected. Next, the study transfected PIMREG overexpression and interference vector into hepatoma cell line Huh7/SFB, and acted on the cells with solafenib exhibiting a concentration gradient. The growth inhibition rate and IC50 value of cells were detected by MTT method to determine the concentration and time of drug addition. Then, this study employed MTT, qRT-PCR, flow cytometry, and Western blot to assay the growth of these cells, which were induced through overexpression and disruption of PIMREG, in combination with sorafenib. The study also constructed an in vivo mouse tire sample test in order to investigate the influence of PIMREG upon the in vitro efficacy of sorafenib. In addition, the study used LY294002 inhibitors to explore the molecular mechanisms of PIMREG-mediated resistance to sorafenib in Huh7/SFB cells.

Results: The expression level of PIMREG in cells of the Huh7/SFB resistant strain was clearly higher than that in cells of the sensitive strain Huh7. After transfection of sh-PIMREG, the IC50 value decreased significantly, while OE-PIMREG significantly increased the IC50 value of sorafinib. Compared with the control group, inhibition of cell proliferation by sorafenib was enhanced after interference with PIMREG, while the effect of overexpression of PIMREG was on the contrary. The efficacy of sorafenib was enhanced by knockout of PIMREG in living organisms. In addition, the PI3K/AKT signal pathway was necessary for PIMREG-induced sorafenib resistance. Subsequently, PIMREG regulated sorafenib-induced inhibition of the PI3K/AKT signaling pathway, and LY294002 blocked the signal pathway to reduce PIMREG-induced resistance.

Conclusion: All in all, an increase in HCC resistance to sorafenib via the PIMREG-mediated PI3K/AKT pathway suggests that PIMREG is a key tumor-associated gene with significant implications for sorafenib resistance in tumor cells.