Transcriptomic analysis reveals the oncogenic role of S6K1 in hepatocellular carcinoma.
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ABSTRACT:
SUBMITTER: Lai KP
PROVIDER: S-EPMC7065997 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Objective:This study is aimed at investigating the predictive value of CENPA in hepatocellular carcinoma (HCC) development. Methods:Using integrated bioinformatic analysis, we evaluated the CENPA mRNA expression in tumor and adjacent tissues and correlated it with HCC survival and clinicopathological features. A Cox regression hazard model was also performed. Results:CENPA mRNA was significantly upregulated in tumor tissues compared with that in adjacent tissues, which were validated in The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) series (all P < 0.01). In the Kaplan-Meier plotter platform, the high level of CENPA mRNA was significantly correlated with overall survival (OS), disease-free survival (DFS), recurrence-free survival (RFS), and progression-free survival (PFS) in HCC patients (all log rank P < 0.01). For validation in GSE14520 and pan-TCGA dataset, HCC patients with CNEPA mRNA overexpression had poor OS compared with those with low CENPA mRNA (log rank P = 0.025 and P < 0.0001, respectively), and those with high CENPA had poor DFS in TCGA (log rank P = 0.0001). Additionally, CENPA mRNA were upregulated in HCC patients with alpha-fetoprotein (AFP) elevation, advanced TNM stage, larger tumor size, advanced AJCC stage, advanced pathology grade, and vascular invasion (all P < 0.05). A Cox regression model including CENPA, OIP5, and AURKB could predict OS in HCC patients effectively (AUC = 0.683). Conclusion:Overexpressed in tumors, CENPA might be an oncogenic factor in the development of HCC patients.
| S-EPMC7168693 | biostudies-literature
Project description:Recent studies indicate that Glypican 1 (GPC-1) is aberrantly expressed and plays a key role in certain cancers, but little is known in the hepatocellular carcinoma. Raw data from TCGA, GTEx and TIMER databases were utilized to comprehensively analyze GPC-1 expression landscape in pan-cancer, and the biological function of GPC-1 was investigated in liver cancer cells. The results revealed that GPC-1 is highly expressed in HCC, negatively correlated with survival, and also positively correlated with immune infiltration and clinical stage. Furthermore, GPC-1 promoted cell proliferation and inhibited apoptosis in the HCC cell lines. WGCNA analysis and HCCDB database revealed that Akt acted as a key molecule related to GPC-1, influencing biological functions and regulating cell malignant behaviors via the AKT signaling pathway. In conclusion, our findings provide a relatively comprehensive understanding of the oncogenic role of GPC-1 in HCC, implying that GPC-1 could serve as an innovative therapeutic target.
| S-EPMC11233571 | biostudies-literature
Project description:Cytoskeleton-associated protein 2-like (CKAP2L) exerts crucial function in the cell-cycle progression and mitotic spindle formation of neural stem/progenitor cells. However, in hepatocellular carcinoma (HCC), the expression pattern, clinical significance and biologic role of CKAP2L remain unexplored. We analysed The Cancer Genome Atlas (TCGA) database and found that CKAP2L was dramatically upregulated in HCC tissues at the mRNA level compared to adjacent tissues, which was validated in 48 paired HCC and para-tumor tissues using quantitative real-time PCR (qRT-PCR). Immunohistochemical analysis of tissue microarray revealed that CKAP2L was also significantly overexpressed at the protein level. Further clinical and survival analysis of the TCGA cohort revealed that increased CKAP2L expression was strongly associated with reduced overall survival. We further validated that higher CKAP2L protein expression was associated with worse prognosis in the Peking Union Medical College Hospital (PUMCH) cohort. Univariate and multivariate Cox regression analyses in the TCGA and PUMCH cohort suggested that CKAP2L overexpression was an independent risk factor for poor prognosis in HCC patients. Then, we validated that CKAP2L silencing inhibited HCC cell proliferation, migration, and invasion abilities. Knockdown of CKAP2L in Huh7 cells suppressed the growth of xenograft tumors in vivo. Furthermore, qRT-PCR and western blotting results demonstrated that the expression of Class I Phosphoinositide 3-Kinase PIK3CA/p110α and PIK3CB/p110β isoforms reduced obviously in Huh7 cells after depleting CKAP2L. This study demonstrated for the first time that high CKAP2L expression in HCC tissues is significantly correlated with poor prognosis in HCC patients and greatly facilitate the malignancy of HCC, thus providing a new prognostic biomarker and potential therapeutic target.
| S-EPMC7270663 | biostudies-literature
Project description:Hepatitis delta virus (HDV) is a small defective virus that needs hepatitis B virus (HBV) to replicate and propagate. HDV infection affects 20-40 million people worldwide and pegylated interferon (PegIFN) is the only recommended therapy. There is limited data on the contribution of HDV infection to HBV-related liver disease or liver cancer. Evidence from retrospective and cohort studies suggests that HBV/HDV coinfection accelerates progression to cirrhosis and is associated with an increased risk of hepatocellular carcinoma (HCC) development compared to HBV monoinfection. Although the life cycle of HDV is relatively well known, there is only ancillary information on the molecular mechanisms that can drive specific HDV-related oncogenesis. No thorough reports on the specific landscape of mutations or molecular classes of HDV-related HCC have been published. This information could be critical to better understand the uniqueness, if any, of HDV-related HCC and help identify novel targetable mutations. Herein, we review the evidence supporting an oncogenic role of HDV, the main reported mechanisms of HDV involvement and their impact on HCC development.
| S-EPMC7001537 | biostudies-literature
Project description:SND1, a subunit of the miRNA regulatory complex RISC, has been implicated as an oncogene in hepatocellular carcinoma (HCC). In this study, we show that hepatocyte-specific SND1 transgenic mice (Alb/SND1 mice) develop spontaneous HCC with partial penetrance and exhibit more highly aggressive HCC induced by chemical carcinogenesis. Livers from Alb/SND1 mice exhibited a relative increase in inflammatory markers and spheroid-generating tumor-initiating cells (TIC). Mechanistic investigations defined roles for Akt and NF-κB signaling pathways in promoting TIC formation in Alb/SND1 mice. In human xenograft models of subcutaneous or orthotopic HCC, administration of the selective SND1 inhibitor 3', 5'-deoxythymidine bisphosphate (pdTp), inhibited tumor formation without effects on body weight or liver function. Our work establishes an oncogenic role for SND1 in promoting TIC formation and highlights pdTp as a highly selective SND1 inhibitor as a candidate therapeutic lead to treat advanced HCC. Cancer Res; 77(12); 3306-16. ©2017 AACR.
| S-EPMC5488274 | biostudies-literature
Project description:Dual-phenotype hepatocellular carcinoma (DPHCC) expresses both hepatocyte and cholangiocyte markers, and is characterized by high recurrence and low survival rates. The underlying molecular mechanisms of DPHCC pathogenesis are unclear. We performed whole exome sequencing and RNA sequencing of three subtypes of HCC (10 DPHCC, 10 CK19-positive HCC, and 14 CK19-negative HCC), followed by integrated bioinformatics analysis, including somatic mutation analysis, mutation signal analysis, differential gene expression analysis, and pathway enrichment analysis. Cox proportional hazard regression analyses were applied for exploring survival related characteristics. We found that mutated genes in DPHCC patients were associated with carcinogenesis and immunity, and the up-regulated genes were mainly enriched in transcription-related and cancer-related pathways, and the down-regulated genes were mainly enriched in immune-related pathways. CXCL9 was selected as the hub gene, which is associated with immune cells and survival prognosis. Our results showed that low CXCL9 expression was significantly associated with poor prognosis, and its expression was significantly reduced in DPHCC samples. In conclusion, we explored the molecular mechanisms governing DPHCC development and progression and identified CXCL9, which influences the immune microenvironment and prognosis of DPHCC and might be new clinically significant biomarkers for predicting prognosis.
| S-EPMC8040886 | biostudies-literature
Project description:Hepatocellular carcinoma (HCC) develops in the context of chronic inflammatory liver disease and has an extremely poor prognosis. An immunosuppressive tumor microenvironment may contribute to therapeutic failure in metastatic HCC. Here, we identified unique molecular signatures pertaining to HCC disease progression and tumor immunity by analyzing genome-wide RNA-Seq data derived from HCC patient tumors and non-tumor cirrhotic tissues. Unsupervised clustering of gene expression data revealed a gradual suppression of local tumor immunity that coincided with disease progression, indicating an increasingly immunosuppressive tumor environment during HCC disease advancement. IHC examination of the spatial distribution of CD8+ T cells in tumors revealed distinct intra- and peri-tumoral subsets. Differential gene expression analysis revealed an 85-gene signature that was significantly upregulated in the peri-tumoral CD8+ T cell-excluded tumors. Notably, this signature was highly enriched with components of underlying extracellular matrix, fibrosis, and epithelial-mesenchymal transition (EMT). Further analysis condensed this signature to a core set of 23 genes that are associated with CD8+ T cell localization, and were prospectively validated in an independent cohort of HCC specimens. These findings suggest a potential association between elevated fibrosis, possibly modulated by TGF-β, PDGFR, SHH or Notch pathway, and the T cell-excluded immune phenotype. Indeed, targeting fibrosis using a TGF-β neutralizing antibody in the STAM™ model of murine HCC, we found that ameliorating the fibrotic environment could facilitate redistribution of CD8+ lymphocytes into tumors. Our results provide a strong rationale for utilizing immunotherapies in HCC earlier during treatment, potentially in combination with anti-fibrotic therapies.
| S-EPMC6237857 | biostudies-literature
Project description:Hepatocellular carcinoma (HCC) is a heterogeneous tumor that develops via activation of multiple pathways and molecular alterations. It has been a challenge to identify molecular classes of HCC and design treatment strategies for each specific subtype. MicroRNAs (miRNAs) are involved in HCC pathogenesis, and their expression profiles have been used to classify cancers. We analyzed miRNA expression in human HCC samples to identify molecular subclasses and oncogenic miRNAs.We performed miRNA profiling of 89 HCC samples using a ligation-mediated amplification method. Subclasses were identified by unsupervised clustering analysis. We identified molecular features specific for each subclass using expression pattern (Affymetrix U133 2.0; Affymetrix, Santa Clara, CA), DNA change (Affymetrix STY Mapping Array), mutation (CTNNB1), and immunohistochemical (phosphor[p]-protein kinase B, p-insulin growth factor-IR, p-S6, p-epidermal growth factor receptor, ?-catenin) analyses. The roles of selected miRNAs were investigated in cell lines and in an orthotopic model of HCC.We identified 3 main clusters of HCCs: the wingless-type MMTV integration site (32 of 89; 36%), interferon-related (29 of 89; 33%), and proliferation (28 of 89; 31%) subclasses. A subset of patients with tumors in the proliferation subclass (8 of 89; 9%) overexpressed a family of poorly characterized miRNAs from chr19q13.42. Expression of miR-517a and miR-520c (from ch19q13.42) increased proliferation, migration, and invasion of HCC cells in vitro. MiR-517a promoted tumorigenesis and metastatic dissemination in vivo.We propose miRNA-based classification of 3 subclasses of HCC. Among the proliferation class, miR-517a is an oncogenic miRNA that promotes tumor progression. There is rationale for developing therapies that target miR-517a for patients with HCC.
| S-EPMC3680790 | biostudies-literature
Project description:BackgroundActivation of Wnt/β-catenin pathway is a frequent event in hepatocellular carcinoma and is associated with enhanced cell survival and proliferation. Therefore, targeting this signaling pathway is discussed as an attractive therapeutic approach for HCC treatment. BCL9 and BCL9L, two homologous coactivators of the β-catenin transcription factor complex, have not yet been comprehensively characterized in HCC. We aimed to elucidate the roles of BCL9 and BCL9L, especially regarding Wnt/β-catenin signaling and their prognostic value in HCC.MethodsExpression of BCL9/BCL9L was determined in HCC cell lines (HLE, HLF, Huh7, HepG2, Hep3B, and Huh6) and normal liver cell lines (THLE-2 and THLE-3). To analyze proliferation and apoptosis, BCL9 and/or BCL9L were knocked down in Wnt-inactive HLE and Wnt-active HepG2 and Huh6 cells using siRNA. Subsequently, Wnt reporter assays were performed in HepG2 and Huh6 cells. BCL9 and BCL9L expression, clinicopathological and survival data of public HCC datasets were analyzed, taking the Wnt signaling status into account.ResultsKnockdown of BCL9L, but not of BCL9, reduced Wnt signaling activity. Knockdown of BCL9 and/or BCL9L reduced cell viability and increased apoptosis of Wnt-inactive HCC cells, but had no effect in Wnt-active cells. Expression of BCL9 and BCL9L was upregulated in human HCC and increased with progressing dedifferentiation. For BCL9L, higher expression was observed in tumors of larger size. Overexpression of BCL9 and BCL9L correlated with poor overall survival, especially in HCC without activated Wnt signaling.ConclusionOncogenic BCL9 proteins represent promising targets for cancer therapy and inhibiting them may be particularly beneficial in Wnt-inactive HCCs.
| S-EPMC7220899 | biostudies-literature
Project description:Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide, occurring predominantly in patients with underlying chronic liver disease and cirrhosis. Here, we describe a case of a 62-year-old man that was admitted to our hospital and diagnosed with HCC where the cancer has already metastasized to the retroperitoneum and peritoneum. In order to better characterize the HCC, both the cancerous liver tissue and the adjacent normal liver tissue of the patient were collected and subjected to a genomic, transcriptomic and proteomic analysis. Our patient carries a highly mutated HCC, which is characterized by both somatic mutation in the following genes ALK, CDK6, TP53, PGR. In addition, we observe several molecular alterations that are associated with potential therapy resistance, for example the expression of the organic-anion-transporting polypeptide (OATP) family members B1 and B3, that mediate the transport of the anticancer drugs, has been found decreased. Overall, our molecular profiling potentially classify the patient with poor prognosis and possibly displaying resistance to pharmacological therapy.
| S-EPMC10792141 | biostudies-literature