Expression of Bile Duct Transcription Factor HNF1β Predicts Early Tumor Recurrence and Is a Stage-Independent Prognostic Factor in Hepatocellular Carcinoma

Yuan, Ray-Hwang; Lai, Hung-Wen; Hsu, Hey‐Chi; Lai, Po-Lin; Jeng, Yung‐Ming

doi:10.1007/s11605-014-2596-z

Cited by 14 publications

(11 citation statements)

References 35 publications

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“…The CA-IX protein was detected in the formalin-fixed, paraffin-embedded sections of HCC and liver tissue using a labeled streptavidin-biotin method after antigen retrieval, as previous studies [ 29 ]. The tissue sections were dewaxed and rehydrated.…”

Section: Methodsmentioning

confidence: 99%

Expression of Hypoxic Marker Carbonic Anhydrase IX Predicts Poor Prognosis in Resectable Hepatocellular Carcinoma

et al. 2015

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Carbonic anhydrase IX (CA-IX), a hypoxia marker, correlates with tumor progression in a variety of human cancers. However, the role of CA-IX in hepatocellular carcinomas (HCCs) remains largely unknown. We examined the expression of 277 unifocal, resectable, primary HCC tumors using immunohistochemistry. The CA-IX protein was expressed in 110 of the 227 (48.5%) HCC tumors. The expression of CA-IX correlated with younger age (P = 0.0446), female sex (P = 0.0049), high serum α-fetoprotein levels (P<1x10-6), larger tumor size (P = 0.0031), high tumor grade P<1x10-6) and high tumor stage (P = 1.5x10-6). Patients with HCC tumors that expressed CA-IX were more likely to have lower 5-year disease-free survival (DFS; P = 0.0001) and 5-year overall survival (OS; P<1x10-6). The multivariate analysis indicated that CA-IX expression was an independent predictor for high tumor stage (P = 0.0047) and DFS (P = 0.0456), and a borderline predictor for OS (P = 0.0762). Furthermore, CA-IX expression predicted poor DFS and OS in patients with high tumor stage (P = 0.0004 and P<1x10-6, respectively). Interestingly, CA-IX expression might contribute to the worse prognosis of female patients with advanced HCCs. Our study indicates the expression of the CA-IX protein is a crucial predictor of poor prognosis in resectable HCC, and it is also an unfavorable prognostic predictor in HCC patients with high tumor stage.

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Section: Methodsmentioning

confidence: 99%

Expression of Hypoxic Marker Carbonic Anhydrase IX Predicts Poor Prognosis in Resectable Hepatocellular Carcinoma

et al. 2015

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“…Previously, research on HNF-1β has mainly focused on a variety of diseases caused by HNF-1β mutations during organ development, such as maturity-onset diabetes of the young type 5 (MODY5), renal cysts, neonatal diabetes, pancreatic hypoplasia, abnormal liver function, cholestasis, etc. 14, 15 . HNF-1β down-regulation probably promotes fetal liver stem/progenitor cells differentiation into hepatocytes 16 .…”

Section: Introductionmentioning

confidence: 99%

Hepatocyte nuclear factor-1beta enhances the stemness of hepatocellular carcinoma cells through activation of the Notch pathway

Zhu

Jiang

et al. 2017

Sci Rep

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Hepatocyte nuclear factor-1beta plays an important role in the development and progression of liver cancer. In recent years, the expression of HNF-1β has been reported to be associated with risk for a variety of cancers. The purpose of this study is to investigate whether the expression of HNF-1β promotes the malignancy of HCC and its mechanism. We retrospectively investigated the expression of HNF-1β in 90 patients with hepatocellular carcinoma and found that the high expression of HNF-1β indicated poor prognosis. We overexpressed HNF-1β in liver cancer cell lines and found the expression of liver progenitor cell markers and stemness were upregulated. The invasion ability and epithelial-mesenchymal transition (EMT)-associated genes were also significantly higher in liver cancer cells overexpressing HNF-1β than in the control group. A mechanistic study suggested the activation of the Notch signalling pathway probably plays a key role downstream of HNF-1β. More importantly, HNF-1β promoted tumourigenesis of HCC cells in vivo. In conclusion, high expression of HNF-1β not only promoted the de-differentiation of HCC cells into liver cancer stem cells through activating the Notch pathway but also enhanced the invasive potential of HCC cells and EMT occurrence, which would contribute to the enhancement of cell migration and invasion.

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“…Because H3K36me3 was detected in the biliary epithelium but hepatocytes were not detected in nontumorous liver parenchyma, and because our published studies indicated that HCC with biliary differentiation is associated with poor prognosis [ 18 , 19 ], we were interested in the association of H3K36me3 positivity with biliary markers. We found a strong association between H3K36me3 positivity and biliary marker expression.…”

Section: Discussionmentioning

confidence: 99%

“…Archival formalin-fixed, paraffin-embedded sections of nontumorous liver tissue and HCC specimens were used to analyze the expression of H3K36me3, CK19, and HNF1β using the streptavidin-biotin immunoperoxidase technique, as described previously [ 19 , 21 ]. The primary antibodies used were a rabbit polyclonal antibody against human H3K36me3 (1:100 dilution, Abcam, Cambridge, MA, USA), a mouse monoclonal antibody against human CK19 (1:200 dilution, Leica Biosystems, Newcastle, UK), and a rabbit polyclonal antibody against human HNF1β (1:100 dilution; Sigma-Aldrich, St. Louis, MO, USA).…”

Section: Methodsmentioning

confidence: 99%

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Increased Trimethylation of histone H3K36 associates with biliary differentiation and predicts poor prognosis in resectable hepatocellular carcinoma

et al. 2018

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IntroductionTrimethylation of histone H3K36 (H3K36me3), an epigenetic marker of transcription-associated histone modification and stem cell regulation, is expressed in a variety of human cancers. This study elucidated the prognostic significance of H3K36me3 in patients with resectable hepatocellular carcinoma (HCC).MethodsExpression of H3K36me3 was retrospectively evaluated through immunohistochemistry in 152 surgically resected primary HCCs.ResultsIn nontumorous liver parenchyma, H3K36Me3 was detected in bile ducts but not in hepatocytes. H3K36me3 was positive in 104 (68.4%) of the HCCs. Positivity for H3K36me3 was associated with high level of serum α-fetoprotein (>200 ng/mL, P = 0.0148), high tumor grade (P = 0.0017), and high tumor stage (P = 0.0008). Patients with H3K36me3-positive tumors were more likely to have lower 5-year disease-free survival and 5-year overall survival than those with H3K36me3-negative tumors (P = 0.0484 and P = 0.0213, respectively). Multivariate analysis showed that H3K36me3 positivity was an independent predictor of high tumor grade (P = 0.0475) and high tumor stage (P = 0.0114) and thus contributed to poor prognosis. Furthermore, H3K36me3 positivity was significantly correlated with the expression of biliary markers cytokeratin 19 (CK19) and hepatocyte nuclear factor 1β (HNF1β) (P < 0.0001 and P = 0.0005, respectively). Combinatorial analysis revealed that CK19 and HNF1β expression individually exerted additive prognostic adverse effects on HCCs with H3K36me3 positivity.ConclusionsOur study indicates that H3K36me3 positivity is associated with the expression of biliary markers and is a crucial predictor of poor prognosis in resectable HCC.

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Expression of Bile Duct Transcription Factor HNF1β Predicts Early Tumor Recurrence and Is a Stage-Independent Prognostic Factor in Hepatocellular Carcinoma

Cited by 14 publications

References 35 publications

Expression of Hypoxic Marker Carbonic Anhydrase IX Predicts Poor Prognosis in Resectable Hepatocellular Carcinoma

Expression of Hypoxic Marker Carbonic Anhydrase IX Predicts Poor Prognosis in Resectable Hepatocellular Carcinoma

Hepatocyte nuclear factor-1beta enhances the stemness of hepatocellular carcinoma cells through activation of the Notch pathway

Increased Trimethylation of histone H3K36 associates with biliary differentiation and predicts poor prognosis in resectable hepatocellular carcinoma

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