Functional relevance of the tumor suppressor activity of mir-107 in liver cancer

Background Hepatocellular carcinoma (HCC) accounts for 90 % of all primary liver cancers, and it is the third leading cause of cancer-related mortality worldwide. Treatment options are limited and survival after diagnosis is poor, as the incidence of hepatocellular carcinoma is still almost equal to its mortality rate. Previously we hypothesized that HCC development in murine models might feature more homogenous transcriptional profiles, thus leading to the discovery of novel transcriptional networks in HCC. Based on this hypothesis our research group has conceived, and recently published (Gastroenterology 2019), an innovative approach that starting from the integrated analyses of three different HCC mouse models has led to the discovery of previously unrecognized transcriptional networks driving hepatocarcinogenesis in human. Preliminary analysis of microarray data indicated that miR-107 is downregulated in the liver of animal models for HCC, hence suggesting a tumor suppressor role for miR-107.

Method Mouse and human HCC cell lines were transiently transfected with either miRNA mimics or siRNA (e.g., inhibition of miRNA targets), and the effect on cell survival was assessed by performing proliferation assays (MTT), cell death assays (TUNEL), and migration assays (soft agar).

Results Administration of miR-107 mimics to liver cancer cell lines caused a significant reduction in proliferation and migration capacity, and increased cell death. In accordance, a significant delay in wound healing in cells over-expressing miR-107 was detected. Unbiased genome-wide analysis identified 12 unfavorable prognostic markers, among them KIF23, was found of particular interest. Here we show that KIF23, a member of the kinesin superfamily of microtubule-based motors proteins, was found to be directly regulated by miR-107. Notably, significantly reduced migratory and invasive properties were observed after targeting cancer cell lines with KIF23 siRNAs.

Conclusion Collectively, our work lead to a more comprehensive view of the role played by miR-107 signaling in hepatocarcinogenesis. Our work supports the hypothesis that miR-107 acts as a tumor suppressor gene in the context of hepatocarcinoma. We show that KIF23, a component of the centralspindlin complex, is a novel miR-107 target gene. Due to continued progress in the field of kinesine inhibitors, KIF23 represents a promising candidate for pharmacological targeting of signaling pathways downstream of miR-107.

Publikationsverlauf

Artikel online veröffentlicht:
04. Januar 2021