Li Yuehua, Li Pengfei, Wang Na
College of Information and Computer, Taiyuan University of Technology, Taiyuan, Shanxi 030024, P.R. China.
Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China.
Oncol Lett. 2021 Feb;21(2):96. doi: 10.3892/ol.2020.12357. Epub 2020 Dec 6.
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 G 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.
肝细胞癌（LIHC）的早期诊断和治疗仍然是一项重大挑战。因此，加强对LIHC的基础研究对于改善该疾病的防治具有重要意义。众多研究表明，PI3K/Akt和FoxO信号通路在LIHC发生发展过程中介导细胞增殖、存活和迁移。因此，它们已成为LIHC治疗的靶点。此外，let-7c已被证明可抑制LIHC细胞的增殖、迁移和侵袭，并诱导细胞G期阻滞和凋亡。然而，其作用机制尚不清楚。在本研究中，利用癌症基因组图谱（The Cancer Genome Atlas）和各种公共数据库（Tumor-miRNA-Pathway、OncomiR、DIANA-TarBase v8、KOBAS 3.0、ONCOMINE、Kaplan-Meier plotter、LinkedOmics、UALCAN和cBioPortal）研究了let-7c与PI3K/Akt/FoxO信号通路之间的关联及其在LIHC发生发展中的作用。通过逆转录-定量PCR在MHCC-97H细胞系中过表达let-7c-5p后，分析let-7c-5p对PI3K/Akt/FoxO信号通路相关靶基因的影响，并筛选出LIHC中属于PI3K/Akt/FOXO信号通路的let-7c-5p靶基因。使用g:Profiler、gOST对这些靶基因进行GO和KEGG富集分析。此外，分别使用GeneMANIA和检索相互作用基因/蛋白质的搜索工具（Search Tool for the Retrieval of Interacting Genes/Proteins，STRING）数据库来确定基因-基因和蛋白质-蛋白质相互作用网络。数据表明，细胞周期蛋白B2（CCNB2）、细胞周期蛋白E2（CCNE2）、细胞周期蛋白依赖性激酶4（CDK4）、荷马支架蛋白1（HOMER1）、热休克蛋白90α家族A类成员1（HSP90AA1）、神经母细胞瘤RAS病毒癌基因同源物（NRAS）、蛋白磷酸酶2催化亚基α（PPP2CA）、蛋白激酶AMP激活的催化亚基α2（PRKAA2）和Rac家族小GTP酶1（RAC1）可能是let-7c-5p的靶基因。这些基因，尤其是CCNE2，与较差的总生存期相关，可能是LIHC疾病和不良预后的有前景的候选生物标志物。其中，7个基因（CCNE2、CDK4、HSP90AA1、NRAS、PPP2CA、PRKAA2和RAC1）属于PI3K-Akt信号通路，4个基因（CCNB2、HOMER1、NRAS和PRKAA2）属于FoxO信号通路。这些基因中的大多数与细胞周期密切相关，其表达升高可能会加剧细胞周期紊乱。因此，let-7c可被视为LIHC的一种抑癌基因。本研究可能为LIHC的诊断和治疗提供新的靶点和策略。
