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Inactivation of Hippo Pathway Is Significantly Associated with Poor Prognosis in Hepatocellular Carcinoma.

ABSTRACT: PURPOSE:The Hippo pathway is a tumor suppressor in the liver. However, the clinical significance of Hippo pathway inactivation in HCC is not clearly defined. We analyzed genomic data from human and mouse tissues to determine clinical relevance of Hippo pathway inactivation in HCC. EXPERIMENTAL DESIGN:We analyzed gene expression data from Mst1/2(-/-) and Sav1(-/-) mice and identified a 610-gene expression signature reflecting Hippo pathway inactivation in the liver [silence of Hippo (SOH) signature]. By integrating gene expression data from mouse models with those from human HCC tissues, we developed a prediction model that could identify HCC patients with an inactivated Hippo pathway and used it to test its significance in HCC patients, via univariate and multivariate Cox analyses. RESULTS:HCC patients (National Cancer Institute cohort, n = 113) with the SOH signature had a significantly poorer prognosis than those without the SOH signature [P < 0.001 for overall survival (OS)]. The significant association of the signature with poor prognosis was further validated in the Korean (n = 100, P = 0.006 for OS) and Fudan University cohorts (n = 242, P = 0.001 for OS). On multivariate analysis, the signature was an independent predictor of recurrence-free survival (HR, 1.6; 95% confidence interval, 1.12-2.28: P = 0.008). We also demonstrated significant concordance between the SOH HCC subtype and the hepatic stem cell HCC subtype that had been identified in a previous study (P < 0.001). CONCLUSIONS:Inactivation of the Hippo pathway in HCC is significantly associated with poor prognosis.

SUBMITTER: Sohn BH

PROVIDER: S-EPMC5536176 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Inactivation of Hippo Pathway Is Significantly Associated with Poor Prognosis in Hepatocellular Carcinoma.

Sohn Bo Hwa BH Shim Jae-Jun JJ Kim Sang-Bae SB Jang Kyu Yun KY Kim Soo Mi SM Kim Ji Hoon JH Hwang Jun Eul JE Jang Hee-Jin HJ Lee Hyun-Sung HS Kim Sang-Cheol SC Jeong Woojin W Kim Sung Soo SS Park Eun Sung ES Heo Jeonghoon J Kim Yoon Jun YJ Kim Dae-Ghon DG Leem Sun-Hee SH Kaseb Ahmed A Hassan Manal M MM Cha Minse M Chu In-Sun IS Johnson Randy L RL Park Yun-Yong YY Lee Ju-Seog JS

Clinical cancer research : an official journal of the American Association for Cancer Research 20151012 5

<h4>Purpose</h4>The Hippo pathway is a tumor suppressor in the liver. However, the clinical significance of Hippo pathway inactivation in HCC is not clearly defined. We analyzed genomic data from human and mouse tissues to determine clinical relevance of Hippo pathway inactivation in HCC.<h4>Experimental design</h4>We analyzed gene expression data from Mst1/2(-/-) and Sav1(-/-) mice and identified a 610-gene expression signature reflecting Hippo pathway inactivation in the liver [silence of Hipp ...[more]

PMID: 26459179

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Project description:BackgroundHepatocellular carcinoma (HCC) is one of the most leading causes of cancer death worldwide. The 5-year survival rate of HCC patients remains low due to the lack of early-stage symptoms. Human complement factor H-related protein 4 (CFHR4) is a critical gene that belongs to the factor H family of plasma glycoproteins, which has not been linked to HCC development. The correlations between CFHR4 and prognosis and tumor-infiltrating lymphocytes in HCC are yet unknown. The present study demonstrated the involvement of CFHR4 in HCC via data mining approaches.ResultsA total of 18 upregulated and 67 down-regulated differentially expressed genes (DEGs) were identified. Importantly, CFHR4, which was screened from DEGs, was shown to express at a lower level in HCC tumor tissue than normal tissues. Western blotting (WB), immunohistochemical (IHC) and quantitative reverse transcription PCR (qRT-PCR) experiments of clinical samples further validated CFHR4 was aberrantly expressed in HCC patients; Data from TCGA showed that CFHR4 was inversely correlated with a cancer family history, histological grade, tumor node metastasis (TNM) stage, and serum AFP level of HCC patients; Univariate and multivariate analyses revealed that low expression of CFHR4 was an independent predictive marker in patients with HCC; Kaplan-Meier analysis showed that the lower expression of CFHR4 was significantly associated with the progression of HCC and poor prognosis rates. Furthermore, TIMER analysis indicated that CFHR4 expression levels had correlations with infiltrating levels of immune cells in HCC.ConclusionCFHR4 expression was low in HCC and was significantly related to the poor prognosis of HCC and the level of immune infiltration. CFHR4 played important roles in regulating the initiation and progression of HCC and could be a potential biomarker for the diagnosis and prognosis of HCC.MethodsThe expression of CFHR4 was analyzed by GEO and TCGA-LIHC database and verified by WB and IHC assay. The biological function of CFHR4 was performed by GO and KEGG enrichment analysis, and the genomic alteration of CFHR4 was investigated by cBioPortal database.The correlation between CFHR4 expression and clinical relevance was evaluated through Cox proportional hazards model, and the correlation between CFHR4 expression and tumor immune infiltrates were studied by TIMER database.

Project description:Background - Hepatocellular carcinomas (HCCs) are heterogeneous tumors with respect to etiology, cell of origin and biology. The course of the disease is unpredictable and is in part dependent on the tumor microenvironment. One of the microenvironmental factors is hypoxia, which is known to promote aggressiveness in other malignant tumors. We hypothesized that certain regions in HCC exist with chronic hypoxia and a characteristic gene expression pattern. Moreover, during the development of HCC there is an important contribution of this chronic hypoxia on prognosis via this gene expression. Until now, most research has been performed in acute hypoxic models (< 24 hours). Methods – Human hepatoblastoma cells HepG2 were cultured in either normoxic (20% O2) or hypoxic (2% O2) conditions for 72 hrs, the time it takes to adapt to chronic hypoxia. After 3 days the cells were harvested and analyzed by microarray technology. The highly significant differentially expressed genes were selected and used to assess the clinical value of our in vitro chronic hypoxia gene signature in four published patient studies. Three of these independent microarray studies on HCC patients were used as training sets to determine a minimal prognostic gene set and one study was used for validation. Gene expression analysis and correlation with clinical outcome was assessed with the bioinfomatic method of Goeman et al (). Results – In the HepG2 cells, 3592 genes were differentially expressed in cells cultured at 2% oxygen for 72 hrs. Out of these, 265 showed a high significant change (2-fold change and p=0.0001). The level of gene expression after 72 hrs was different from the acute hypoxic response (during the first 24 hours) and represented chronicity. Using computational methods we identified 7 out of the 265 highly significant genes that showed correlation with prognosis in all three different training sets and this was independently validated in a 4th dataset. With our approach we could include the largest number of HCC patients in one single study. Conclusion – We identified a 7-gene signature, which is associated with chronic hypoxia and predicts prognosis in patients with HCC. In the future this signature could be used as a diagnostic tool. In addition, chronic hypoxia gene expression information can be used in the search for new therapeutic targets. Two conditions were compared and each sample has a biological replicate. Samples are hybridized in dye-swap, resulting in 4 hybridizations.

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Inactivation of Hippo Pathway Is Significantly Associated with Poor Prognosis in Hepatocellular Carcinoma.

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Inactivation of Hippo Pathway Is Significantly Associated with Poor Prognosis in Hepatocellular Carcinoma.

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