Abstract 5887: A microRNA signature panel predicts differential sensitivity of liver cancer cells to chemotherapeutic drugs
Authors: Tryndyak Volodymyr , Kindrat Iryna , McDannell Brigit , Beland Frederick A. , Pogribny Igor P. 
Published: August 2018

Hepatocellular carcinoma (HCC) is one of the deadliest human cancers, with a steadily rising incidence in the United States and worldwide. Most HCC patients are diagnosed at intermediate and advanced stages of the disease when treatment options are limited to systematic therapy; however, the individual patient response to treatment varies significantly. In the present study, we investigated an ability of the base-line mircoRNA (miRNA) expression profile in human liver cancer cells to predict the response to chemotherapeutic drugs currently used in the clinical management of HCC. Next-generation sequencing analysis of the base-line miRNA expression in naïve SK-Hep-1, Hep3B, HepG2, Huh7, and PLC/PRF/5 cells showed different miRNA expression profiles, among which 70 miRNAs were in common among all cell lines. A detailed analysis of the common miRNAs revealed that SK-Hep-1 and HepG2 cells exhibited the major differences in their base-line miRNA expression. The cancer cells were then treated with sorafenib, doxorubicin hydrochloride, 5-fluorouracil, and cisplatin, and cell survival was determined by cell viability assays. The sensitivity of liver cancer cells to these chemotherapeutic drugs varied among the cell lines, with SK-Hep-1 cells being the most resistant to sorafenib and the most sensitive to 5-fluorouracil. In contrast, HepG2 cells were the most sensitive to sorafenib, doxorubicin hydrochloride, and cisplatin treatment and the most resistant to 5-fluorouracil. Further analysis of miRNA expression in these two cell lines identified 107 distinct differentially expressed miRNAs (cut-off &gt; 5-fold) involved in the regulation of critical cancer-related pathways. Among these differentially expressed miRNAs, the basal expression pattern of several miRNAs corresponded to the miRNA expression patterns associated with an acquired cancer-cell-resistant phenotype to sorafenib. Specifically, miR-10a and miR-181 were up-regulated and miR-27b, miR-34a, miR-122, miR-200a, and miR-200b were down-regulated in naïve SK-Hep-1 cells. Likewise, the low basal expression of miR-30a, miR-30b, miR-27a, miR-125b, miR-135b, miR-149, and miR-218 and over-expression of miR-143 and miR-200a in naïve HepG2 were similar to that in cells with an acquired 5-fluorouracil cancer-resistant phenotype. These findings were confirmed in functional transfection experiments that showed ectopic modulation of miRNA levels in SK-Hep-1 and HepG2 modified their drug sensitivity to sorafenib and 5-fluorouracil. These results suggest that analysis of the expression of these miRNAs in HCC at the onset of chemotherapy may help to determine the optimal treatment options, prevent the development of multidrug resistance, and improve overall clinical management of HCC.

Citation Format: Volodymyr Tryndyak, Iryna Kindrat, Brigit McDannell, Frederick A. Beland, Igor P. Pogribny. A microRNA signature panel predicts differential sensitivity of liver cancer cells to chemotherapeutic drugs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5887.