MicroRNAs contribute to ATP-binding cassette transporter- and autophagy-mediated chemoresistance in hepatocellular carcinoma

ESPELT M.V; BACIGALUPO ML; CARABIAS P; TRONCOSO, MF

World Journal of Hepatology

Baishideng Publishing Group Co

Año: 2019 vol. 11 p. 344 - 358

1948-5182

carcinoma (HCC) has an elevated mortality rate, largely because of high recurrence and metastasis. Additionally, the main obstacle during treatment of HCC is that patients usually develop resistance to chemotherapy. Cancer drug resistance involves many different mechanisms, including alterations in drug metabolism and processing, impairment of the apoptotic machine, activation of cell survival signaling and escape of drug sensitivity, and autophagy, among others. Drug efflux is mediated by ABC (ATP-binding cassette) transporters which limit cell exposure to chemotherapeutics, allowing tumor cell survival and resistance to death. Autophagy occurs mainly as a response to cellular stress, acting as a cytoprotective mechanism. In normal liver, damaged mitochondria and mutated cells are removed through autophagy, and this mechanism suppresses tumor initiation. But once the tumor is established, autophagy promotes tumor growth and confers protection to HCC cells against antineoplastic drugs. Nowadays, microRNAs (miRNAs) are emerging as master regulators of normal physiology- and tumor-related gene expression. In HCC, aberrant expression of many miRNAs leads to chemoresistance. Herein, we particularly analyzed miRNA impact on HCC chemoresistance, by modulating ABC transporter family protein expression or function and autophagy. Recent findings reveal that certain miRNAs regulate ABC transporter expression by specifically targeting, for instance, ABCB1 and/or ABCC1 genes. As most of these miRNAs are downregulated in HCC tissues and cells, P-gp and/or MRP1 expression levels increase and intracellular therapeutic drug accumulation decrease, turning HCC cells less sensitive to death. Further, others miRNAs target autophagy-related gene expression, inhibiting autophagy and acting as tumor suppressors. Nevertheless, many of these molecules are downregulated in HCC, or their levels are reduced after therapeutic drug treatment, thus these miRNAs do not inhibit autophagy or tumor growth and, resistance is favored. Concluding, modulation of ABC transporter and/or autophagy-related gene expression or function by miRNAs could be determinant for HCC cell survival under chemotherapeutic drug treatment. Undoubtedly, more insights on the biological processes, signaling pathways and/or molecular mechanisms regulated by miRNAs are needed. Anyway, miRNA-based therapy together with conventional chemotherapeutic drugs has a great future in cancer therapy.