Effect of let-7c on the PI3K/Akt/FoxO signaling pathway in hepatocellular carcinoma.

Abstract

The early diagnosis and treatment of liver hepatocellular carcinoma (LIHC) remains a major challenge. Therefore, it is of great significance to strengthen basic research on LIHC in order to improve the prevention and treatment of the disease. Numerous studies have indicated that the PI3K/Akt and FoxO signaling pathways mediate proliferation, survival and migration during the development of LIHC. Therefore, they have become a target for LIHC treatment. Furthermore, let-7c has been demonstrated to repress cell proliferation, migration and invasion, and to induce G1 phase arrest and apoptosis of LIHC cells. However, the mechanism of its action is not clear. In the present study, the association between let-7c and the PI3K/Akt/FoxO signaling pathway, as well as their roles in the development of LIHC were investigated using The Cancer Genome Atlas and various public databases (Tumor-miRNA-Pathway, OncomiR, DIANA-TarBase v8, KOBAS 3.0, ONCOMINE, Kaplan-Meier plotter, LinkedOmics, UALCAN and cBioPortal). The effects of let-7c-5p on PI3K/Akt/FoxO signaling pathway-related target genes were analyzed following overexpression of let-7c-5p in the MHCC-97H cell line via reverse transcription-quantitative PCR, and the let-7c-5p target genes belonging to the PI3K/Akt/FOXO signaling pathway in LIHC were screened out. GO and KEGG enrichment analyses of these target genes was performed using g:Profiler, gOST. In addition, GeneMANIA and Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) databases were used to determine the gene-gene and protein-protein interaction networks, respectively. The data demonstrated that cyclin B2 (CCNB2), cyclin E2 (CCNE2), cyclin dependent kinase 4 (CDK4), homer scaffold protein 1 (HOMER1), heat shock protein 90 α family class A member 1 (HSP90AA1), neuroblastoma RAS viral oncogene homolog (NRAS), protein phosphatase 2 catalytic subunit α (PPP2CA), protein kinase AMP-activated catalytic subunit α2 (PRKAA2) and Rac family small GTPase 1 (RAC1) may be target genes of let-7c-5p. These genes, particularly CCNE2, were associated with poor overall survival and could be promising candidate biomarkers for disease and poor prognosis in LIHC. Among them, seven genes (CCNE2, CDK4, HSP90AA1, NRAS, PPP2CA, PRKAA2 and RAC1) belonged to the PI3K-Akt signaling pathway and four genes (CCNB2, HOMER1, NRAS and PRKAA2) belonged to the FoxO signaling pathway. The majority of these genes were closely associated with the cell cycle and their elevated expression may aggravate cell cycle disorders. Therefore, let-7c may be considered to be an anti-oncogene of LIHC. The present study may provide novel targets and strategies for the diagnosis and treatment of LIHC.