Androgen activates PEG10 to promote carcinogenesis in hepatic cancer cells

Xiong, Jie; Chen, Lang; Qi, Ji; Liang, Chaoqun; Yang, Dehua; Yi, Shengguo; Jin, Yanping; Xie, Lin; Zhang, Qiuping; Wang, Hui; Gong, Feili; Jin, Boquan; Jin, Youxin; Jinquan, Tan

doi:10.1038/sj.onc.1210362

Cited by 37 publications

(28 citation statements)

References 22 publications

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“…Moreover, PEG10 knockdown inhibits the proliferation of pancreatic carcinoma and HepG2 HCC cells [6], while knockout of PEG gene caused early embryonic lethality [10]. A recent report demonstrated that PEG10 expression can be regulated by the proto-oncogene c-myc via the binding of c-myc oncoprotein to the E-box containing region of the first intron of PEG10 [6][7][8]. PEG10 also interacts with TGF-β type I receptor ALK1 [9].…”

Section: Introductionmentioning

confidence: 95%

Identification of PEG10 and TSG101 as Carcinogenesis, Progression, and Poor-Prognosis Related Biomarkers for Gallbladder Adenocarcinoma

Liu

Yang

Jiang

2011

Pathol. Oncol. Res.

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PEG10 is a transcriptional factor while TSG101 is involved in numerous cellular processes, including apoptotic resistance. Overexpression of PEG10 and TSG101 were observed in a variety of human cancers. However, their expression and clinical significance in gallbladder cancer (GBC) have not yet been identified. To understand the tumor biology of GBC at the molecular level, we examined PEG10 and TSG101 expression in 108 adenocarcinomas, 15 gallbladder polyps, 35 chronic cholecystitis tissues, and 46 peritumoral tissues by using immunohistochemistry. Overexpression of PEG10 and TSG101 was detected in gallbladder adenocarcinoma (48.1% and 47.2%, respectively). Conversely, there was less expression detected in the peritumoral tissues (19.6%), adenomatous polyps (13.3%), and gallbladder epithelium with chronic cholecystitis (5.1%) (p < 0.01, p < 0.05, and p < 0.01, respectively). Notably, the benign lesions with positive PEG10 and/or TSG101 expression showed moderately or severely atypical hyperplasia in gallbladder epithelium. The overexpression of PEG10 and TSG101 was significantly associated with differentiation, tumor mass, lymph node metastasis and invasion of adenocarcinoma. Univariate Kaplan-Meier analysis showed that overexpression of PEG10 (p = 0.041) and TSG101 (p = 0.025) was closely associated with decreased overall survival. Multivariate Cox regression analysis revealed that positive expression of PEG10 (p = 0.036) or TSG101 (p = 0.022) is a predictor of poor prognosis in gallbladder adenocarcinoma. Our study suggested that overexpression of PEG10 and TSG101 might be closely related to the carcinogenesis, progression, clinical biological behaviors, and prognosis of gallbladder adenocarcinoma.

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Section: Introductionmentioning

confidence: 95%

Identification of PEG10 and TSG101 as Carcinogenesis, Progression, and Poor-Prognosis Related Biomarkers for Gallbladder Adenocarcinoma

Liu

Yang

Jiang

2011

Pathol. Oncol. Res.

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“…cDNA synthesis was performed using random hexamers. PCR amplification was performed on cDNA templates using primers specific for AR (sense primer [5Ј-AAGGCTATGAATGTCAGCCCA-3Ј] and antisense primer [5Ј-CA TTGAGGCTAGAGAGCAAGGC-3Ј]) (20) and for VEGF (sense primer [5Ј-CGAAACCATGAACTTTCTGC-3Ј] and antisense primer [5Ј-CCTCAGTGG GCACACACTCC-3Ј]). The primers for GAPDH (glyceraldehyde-3-phosphate dehydrogenase) were chosen as described previously (21).…”

Section: Methodsmentioning

confidence: 99%

Hepatitis C Virus Core Protein Augments Androgen Receptor-Mediated Signaling

Kanda

Steele²,

Ray

2008

J Virol

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Hepatitis C virus (HCV) infection is frequently associated with the development of hepatocellular carcinoma (HCC), which is one of the male-dominant diseases. Androgen signaling in liver may be related to carcinogenesis. In this study, we investigated whether HCV proteins cross talk with the androgen receptor (AR) signaling pathway for promotion of carcinogenesis. We have demonstrated that HCV core protein alone or in context with other HCV proteins enhances AR-mediated transcriptional activity and further augments in the presence of androgen. Subsequent study suggested that HCV core protein activates STAT3, which in turn enhances AR-mediated transcription. This activity was blocked by a pharmacological inhibitor of the Jak/Stat signaling pathway, AG490. Vascular endothelial growth factor (VEGF) is a target gene of AR in liver and plays an important role in angiogenesis. Therefore, we examined whether HCV infection modulates VEGF expression in hepatocytes. Our results demonstrated that HCV enhances VEGF expression and facilitates tube formation in human coronary microvascular endothelial cells in the presence of AR. Together, our results suggest that HCV core protein acts as a positive regulator in AR signaling, providing further insight into oncogenic potential in the development of HCC in HCV-infected individuals.Hepatitis C virus (HCV) infection affects nearly 4 million people and is the most common cause of cirrhosis and hepatocellular carcinoma (HCC) in the United States (23). The current approved therapy for treatment for HCV is pegylated interferon in combination with ribavirin (43). Although several advances have shown promise for improving the management of HCV infection, it nevertheless remains as a major health problem (2, 7, 60). Regardless of the etiology, chronic liver diseases progress at unequal rates in the two sexes, with the major sequelae, such as cirrhosis and HCC, being more common in men than in women (16,54). The significance of androgen receptor (AR) expression in HCC and the surrounding liver has been studied extensively (18,31,33). With this background, we decided to investigate the relationship between AR and HCC after HCV infection, knowing that human liver expresses both estrogen receptors and ARs.AR is a ligand-dependent transcription factor that belongs to the nuclear receptor superfamily (14, 17). The transcriptional activation function of AR is not only essential for normal sexual development in men but is also implicated in the progression of cancer (9). AR has a modular structure containing the N terminus harboring transcriptional activation domain(s), a central DNA-binding domain, and a C-terminal ligand-binding domain. Binding of androgen to the ligand-binding domain induces conformational change in AR and leads to the shuttling of receptor from the cytoplasm to the nucleus, where it forms a homodimer and is recruited to the AR element (ARE). ARE is present in the regulatory elements on the target genes such as vascular endothelial growth factor (VEGF) and transforming growt...

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“…Dihydrotestosterone (DHT) promotes hepatoma formation in nude mice through PEG 10 activation. In addition, DHT treatment is shown to up-regulate hTERT expression in hepatoma cell lines in a PEG-10 dependent manner [146] . These studies indicate that PEG-10-mediated transactivation of target genes by AR has an essential role in hepatocarcinogenesis.…”

Section: Androgen Receptormentioning

confidence: 99%

“…Yoon et al [145] demonstrated that androgen can directly regulate the expression of transformation growth factor-beta 1 (TGF-β1) through binding of AR to ARE in TGF-β1 promoter, suggesting that such activation might regulate the progression of HCC in both human and animal models [145] . Furthermore, AR has been shown to interact with a newly identified transcription factor, paternally expressed gene 10 (PEG 10) in hepatoma cell line [146] . PEG 10 has growth promoting properties and is implicated in hepatocarcinogenesis [147,148] .…”

Section: Androgen Receptormentioning

confidence: 99%

Role of sex steroid receptors in pathobiology of hepatocellular carcinoma

Kalra¹,

Mayes²,

Assefa³

et al. 2008

WJG

133

116

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The striking gender disparity observed in the incidence of hepatocellular carcinoma (HCC) suggests an important role of sex hormones in HCC pathogenesis. Though the studies began as early as in 1980s, the precise role of sex hormones and the significance of their receptors in HCC still remain poorly understood and perhaps contribute to current controversies about the potential use of hormonal therapy in HCC. A comprehensive review of the existing literature revealed several shortcomings associated with the studies on estrogen receptor (ER) and androgen receptor (AR) in normal liver and HCC. These shortcomings include the use of less sensitive receptor ligand binding assays and immunohistochemistry studies for ERα alone until 1996 when ERβ isoform was identified. The animal models of HCC utilized for studies were primarily based on chemical-induced hepatocarcinogenesis with less similarity to virus-induced HCC pathogenesis. However, recent in vitro studies in hepatoma cells provide newer insights for hormonal regulation of key cellular processes including interaction of ER and AR with viral proteins. In light of the above facts, there is an urgent need for a detailed investigation of sex hormones and their receptors in normal liver and HCC. In this review, we systematically present the information currently available on androgens, estrogens and their receptors in normal liver and HCC obtained from in vitro , in vivo experimental models and clinical studies. This information will direct future basic and clinical research to bridge the gap in knowledge to explore the therapeutic potential of hormonal therapy in HCC.

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Androgen activates PEG10 to promote carcinogenesis in hepatic cancer cells

Cited by 37 publications

References 22 publications

Identification of PEG10 and TSG101 as Carcinogenesis, Progression, and Poor-Prognosis Related Biomarkers for Gallbladder Adenocarcinoma

Identification of PEG10 and TSG101 as Carcinogenesis, Progression, and Poor-Prognosis Related Biomarkers for Gallbladder Adenocarcinoma

Hepatitis C Virus Core Protein Augments Androgen Receptor-Mediated Signaling

Role of sex steroid receptors in pathobiology of hepatocellular carcinoma

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