The survival prediction analysis and preliminary study of the biological function of YEATS2 in hepatocellular carcinoma.
Our study aims to develop and validate a novel molecular marker for the prognosis and diagnosis of hepatocellular carcinoma (HCC) MATERIALS & METHODS: We retrospectively analyzed mRNA expression profile and clinicopathological data of HCC patients fetched from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO) and The International Cancer Genome Consortium (ICGC) datasets. Univariate Cox regression analysis was performed to collect differentially expressed mRNA (DEmRNAs) from HCC and non-tumor tissues, and YEATS2, a prognostic marker, was identified by further analysis. ROC curve, survival analysis and multivariate Cox regression analysis as well as nomograms were used to evaluate the prognosis of this gene. Finally, the biological function of this gene was preliminarily discussed by using single gene Gene Set Enrichment Analysis (GSEA), and the YEATS2 overexpression and knockdown hepatoma cell line was used to verify the results in vitro and in vivo.
Based on the clinical information of HCC in TCGA, GEO and ICGC databases, the gene YEATS2 with significant differences from HCC was identified. There was a statistical difference in the survival prognosis between the two databases and the ROC curve showed that the survival of HCC in both TCGA, GSE14520 and ICGC groups had a satisfactory predictive effect. Univariate and multivariate Cox regression analysis showed that YEATS2 was an independent prognostic factor for HCC, and Nomograms, which combined this prognostic feature with significant clinical features, provided an important reference for the clinical prognostic diagnosis of HCC. Next, we constructed overexpression and knockdown YEATS2 cell line in Hep3B and LM3 cells, and further proved that overexpression YEATS2 promote the proliferation and migration of HCC cells by CCK8, colony formation experiment, and transwell assays, and knockdown YEATS2 inhibited the proliferation and migration of HCC cells by CCK8, colony formation experiment, and transwell assays. Finally, the biological function of YEATS2 was preliminarily explored through GSEA analysis of a single gene, and it was found that it was significantly correlated with cell cycle and DNA repair, which provided us with ideas for further analysis. Furthermore, the knockdown of YEATS2 promoted radiation-induced DNA damage, enhanced radiosensitivity, and ultimately inhibited the proliferation of hepatocellular carcinoma cells in vitro and in vivo.
Our study identified a promising prognostic marker for hepatocellular carcinoma that is useful for clinical decision-making and individualized treatment.
Long Y
，Wang W
，Liu S
，Wang X
，Tao Y
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MFSD2A Overexpression Inhibits Hepatocellular Carcinoma Through TGF-β/Smad Signaling.
Hepatocellular carcinoma (HCC) is a common primary malignancy of the liver and has a high mortality. Major facilitator superfamily domain containing 2 (MFSD2A) was previously demonstrated to inhibit tumor progression in several cancers. Here, we elucidated the association between MFSD2A expression and HCC progression and also investigated the underlying mechanism. The online tools were utilized to evaluate MFSD2A expression in HCC samples and predict the prognostic significance of MFSD2A in HCC patients. The biological role of MFSD2A in HCC cellular processes was examined by colony formation, wound healing, transwell, and western blotting. The in vivo role of MFSD2A in HCC was investigated in a xenograft tumor model. The miRNAs and RNA-binding proteins potentially targeting MFSD2A were identified using bioinformatics prediction tools. Luciferase reporter, RNA immunoprecipitation, actinomycin D, and immunofluorescence assays were performed to investigate the molecule mechanisms of MFSD2A. Transforming growth factor (TGF)-β1/Small mothers against decapentaplegic (Smad) signaling was detected using western blot analysis. We found that MFSD2A expression was significantly downregulated in HCC patients and cells and its downregulation predicted a poor prognosis. MFSD2A overexpression repressed HCC cell proliferation, migration, invasion, the epithelial-to-mesenchymal transition in vitro, as well as inhibited HCC tumor growth in vivo. MFSD2A was targeted by miR-3189-3p. High-density lipoprotein binding protein (HDLBP) inhibited MFSD2A expression by binding to and destabilizing MFSD2A mRNA. MFSD2A significantly suppressed activation of TGF-β/Smad signaling in HCC cells. Knockdown of MFSD2A abrogated the inhibitory effect of miR-3189-3p inhibitor on HCC cellular processes, and overexpression of MFSD2A reversed the tumor-promoting effect of HDLBP overexpression. Overall, MFSD2A exerts a tumor-inhibiting effect in HCC via suppression of TGF-β/Smad signaling, suggesting that MFSD2A may be a promising target for HCC therapy.
Xiao C
，Zhao X
，Hu Z
，Long G
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M6A modification-mediated LIMA1 promotes the progression of hepatocellular carcinoma through the wnt-βcatenin/Hippo pathway.
Hepatocellular carcinoma (HCC), considered as one of the most common and lethal cancers worldwide, has drawn significant attention from researchers.Extensively studied diverse cancers, the function of LIMA1 in tumorigenesis and cancer progression remains ambiguous.. Moreover, the role of LIMA1 in HCC remains controversial.
The expression difference of LIMA1 in hepatocellular carcinoma, which was verified by TMT quantitative proteomics, immunohistochemistry, western blot, and the TCGA database, has been investigated in this study. Demonstrated by using transwell, cck8, sphere formation, and other experiments, the effects of LIMA1 on the migration, proliferation, stemness, and other aspects of hepatocellular carcinoma were significant. Moreover, the effect of LIMA1 on the wnt-βcatenin/Hippo pathway was revealed by using RNA sequencing and western blot, and the relationship between LIMA1 and βcatenin was verified by using COIP. Finally, the effect of m6a modification on LIMA1 was further verified using Western blotting, actinomycin D and MeRip experiments.
In HCC tissues and several HCC cell lines, LIMA1 was expressed at a relatively high level.LIMA1 positively regulated the invasion, migration, proliferation and stemness of hepatocellular carcinoma, and silencing of LIMA1 inhibited the tumorigenic ability of HCC cells in nude mice. Moreover, it was shown that LIMA1 can have an impact on the wnt-β-catenin/Hippo pathway. And silencing β-catenin suppressed the invasion, migration, proliferation and stemness of hepatocellular carcinoma cells mediated by LIMA1. Finally, it was further verified that the activation of LIMA1 in hepatocellular carcinoma cells is due to m6-methyladenosine methylation that is dependent on METTL3.
In HCC, LIMA1 functions as a tumor promoter and engages with the WNT-β-catenin and Hippo signaling pathways,, affecting the characteristics of tumor cells. LIMA1 expression is regulated by METTL3-mediated m6A modification, leading to its high expression in HCC. Our research presents a hopeful objective for the detection and therapy of HCC.
Zhang C
，Wang X
，Song H
，Yuan J
，Zhang X
，Yuan Y
，Wang Z
，Lei Z
，He J
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ResearchGate
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钛学术
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