Decreased miR-122 Leads to Multi-Drug Resistance in Hepatocellular Cancer

Kayla Hudson

Introduction. Hepatocellular cancer (HCC) is the third most common cancer cause of death in the world due to late detection.1 Early stages of HCC are asymptomatic. Treatment options include liver resection, liver transplant, chemotherapy, and use of cancer drugs to which HCC cells are highly resistant.2-4 MicroRNA (miR)-122, a liver specific miRNA, is expressed at low levels in drug resistant HCC cells.5-8 MiR-122 has multiple mechanisms of action that help increase susceptibility of HCC cells to drug therapies and hopefully improve outcomes of HCC patients. These mechanisms include efflux of cancer drugs, increasing intracellular nitric oxide (NO) to negatively affect cancer drug treated HCC cells, and suppression of apoptotic pathways.6-8 Methods. Bel and SMMC, HCC cell lines, were transfected with miR-122 to have high expression and then western blotting was used to determine expression of multidrug resistant receptor 1 (MDR1).6 Gene editing system CRISPR-Cas9 was used to increase miR-122 expression in Hep3B, an HCC cell line. Intracellular NO levels and cell number after treatment with sorafenib, a cancer drug, were measured.7 Huh7 and PLCDR3, sorafenib resistant cells, were transfected with miR-122 to increase expression.8 Cell viability, tumor weight, and tumor volume after treatment with sorafenib was compared to silencing overexpression of IGF-1R, a receptor for growth factor that inhibits the RAS pathway.8 Results. When activated, MDR1 turns on gene for a drug efflux pump, and miR-122 binds to MDR1 to prevent drug efflux.6 Increased miR-122 caused decreased expression of MDR1, p<0.01.6 Bel and SMMC with increased miR-122 expression had less cell activity, p<0.05, and more apoptosis, p<0.01.6 Increased miR-122 showed decrease in intracellular NO expression, p<0.05, and the effect was reversed by increasing an arginine transporter that normally increases intracellular NO, p<0.05.7 Hep3B with increased miR-122 showed decreased relative cell number when treated with sorafenib, p<0.05.7 IGF-1R can activate the RAS pathway to evade apoptosis. MiR-122 binds to IGF-1R to inhibit the RAS pathway and cause apoptosis.8 Increased miR-122 in Huh7 and PCLDR3 showed decrease in cell colony formation, p<0.05, and the effect of increased miR-122 was reversed when IGF-1R was overexpressed.8 Overexpression of IGF-1R caused increased tumor weight and tumor volume, p<0.05.8 Conclusions. Increasing miR-122 was found to inhibit MDR1 to prevent drug efflux, decrease intracellular NO, and inhibit IGF-1R to inactivate the RAS pathway, resulting in increased drug sensitivity in HCC cells.6-8 Having multiple mechanisms to combat drug resistance make miR-122 a promising possible therapeutic target.

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