Significant down-regulation of growth hormone receptor expression revealed as a new unfavorable prognostic factor in hepatitis C virus-related hepatocellular carcinoma
2
조회
0
다운로드
0
인용
0
참고문헌
키워드
초록
Background/Aims: Growth hormone (GH) is the main regulator of somatic growth, metabolism, and gender dimorphism in the liver. GH receptor (GHR) signaling in cancer is derived from a large body of evidence, although the GHR signaling pathway involved in the prognosis of hepatocellular carcinoma (HCC) in patients with hepatitis C virus (HCV)-related HCC, remains unclear. We aimed to explore the expression of GHR and analyze its association with clinicopathologic features and prognosis of patients with chronic hepatitis C and HCC. Methods: The expression of GHR mRNA was investigated by quantitative real-time polymerase chain reaction in paired tumors and adjacent non-tumorous (ANT) liver tissues of 200 patients with chronic hepatitis C and HCC. Western blotting and immunofluorescence assays using the HCV-infected Huh7.5.1 cell model was performed. Results: GHR mRNA was significantly lower in HCV-HCC tissues than in corresponding ANT liver tissues. GHR mRNA and protein levels also decreased in the HCV-infected Huh7.5.1 cell model. Notably, lower GHR expression was associated with age of >60 years (P=0.0111) and worse clinicopathologic characteristics, including alpha-fetoprotein >100 ng/mL (P=0.0403), cirrhosis (P=0.0075), vascular invasion (P=0.0052), pathological stage II–IV (P=0.0002), and albumin ≤4.0 g/dL (P=0.0055), which were linked with poor prognosis of HCC. Most importantly, the high incidence of recurrence and poor survival rates in patients with a low ratio of tumor/ANT GHR (≤0.1) were observed, indicating that low expression levels of GHR had great risk for development of HCC in patients with chronic hepatitis C. Conclusions: Our study demonstrates a significant down-regulation of GHR expression as a new unfavorable independent prognostic factor in patients with chronic hepatitis C and HCC.
Abstract
Background/Aims: Growth hormone (GH) is the main regulator of somatic growth, metabolism, and gender dimorphism in the liver. GH receptor (GHR) signaling in cancer is derived from a large body of evidence, although the GHR signaling pathway involved in the prognosis of hepatocellular carcinoma (HCC) in patients with hepatitis C virus (HCV)-related HCC, remains unclear. We aimed to explore the expression of GHR and analyze its association with clinicopathologic features and prognosis of patients with chronic hepatitis C and HCC. Methods: The expression of GHR mRNA was investigated by quantitative real-time polymerase chain reaction in paired tumors and adjacent non-tumorous (ANT) liver tissues of 200 patients with chronic hepatitis C and HCC. Western blotting and immunofluorescence assays using the HCV-infected Huh7.5.1 cell model was performed. Results: GHR mRNA was significantly lower in HCV-HCC tissues than in corresponding ANT liver tissues. GHR mRNA and protein levels also decreased in the HCV-infected Huh7.5.1 cell model. Notably, lower GHR expression was associated with age of >60 years (P=0.0111) and worse clinicopathologic characteristics, including alpha-fetoprotein >100 ng/mL (P=0.0403), cirrhosis (P=0.0075), vascular invasion (P=0.0052), pathological stage II–IV (P=0.0002), and albumin ≤4.0 g/dL (P=0.0055), which were linked with poor prognosis of HCC. Most importantly, the high incidence of recurrence and poor survival rates in patients with a low ratio of tumor/ANT GHR (≤0.1) were observed, indicating that low expression levels of GHR had great risk for development of HCC in patients with chronic hepatitis C. Conclusions: Our study demonstrates a significant down-regulation of GHR expression as a new unfavorable independent prognostic factor in patients with chronic hepatitis C and HCC.
참고문헌 (49)
- Global Burden Of Hepatitis C Working Group, "Global burden of disease (GBD) for hepatitis C", J Clin Pharmacol, 44, pp.20~29 (2004)
- Perz JF, "The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide", J Hepatol, 45, pp.529~538 (2006)
- Torre LA, "Global cancer statistics, 2012", CA Cancer J Clin, 65, pp.87~108 (2015)
- Bertuccio P, "Global trends and predictions in hepatocellular carcinoma mortality", J Hepatol, 67, pp.302~309 (2017)
- Hoshida Y, "Pathogenesis and prevention of hepatitis C virus-induced hepatocellular carcinoma", J Hepatol, 61(1 Suppl), pp.S79~S90 (2014)
- Fattovich G, "Hepatocellular carcinoma in cirrhosis: incidence and risk factors", Gastroenterology, 127(5 Suppl 1), pp.S35~S50 (2004)
- Yu ML, "A simple noninvasive index for predicting long-term outcome of chronic hepatitis C after interferon-based therapy", Hepatology, 44, pp.1086~1097 (2006)
- Lin CW, "Heavy alcohol consumption increases the incidence of hepatocellular carcinoma in hepatitis B virus-related cirrhosis", J Hepatol, 58, pp.730~735 (2013)
- Huang CF, "Genetics variants and serum levels of MHC class I chain-related A in predicting hepatocellular carcinoma development in chronic hepatitis C patients post antiviral treatment", EBioMedicine, 15, pp.81~89 (2017)
- Yu MC, "Environmental factors and risk for hepatocellular carcinoma", Gastroenterology, 127(5 Suppl 1), pp.S72~S78 (2004)
- Yu ML, "Time-degenerative factors and the risk of hepatocellular carcinoma after antiviral therapy among hepatitis C virus patients: a model for prioritization of treatment", Clin Cancer Res, 23, pp.1690~1697 (2017)
- Huang CF, "Baseline gamma-glutamyl transferase levels strongly correlate with hepatocellular carcinoma development in non-cirrhotic patients with successful hepatitis C virus eradication", J Hepatol, 61, pp.67~74 (2014)
- Huang CF, "Pretreatment glucose status determines HCC development in HCV patients with mild liver disease after curative antiviral therapy", Medicine (Baltimore), 95, pp.e4157~ (2016)
- Branda M, "Signal transduction cascades and hepatitis B and C related hepatocellular carcinoma", Hepatology, 43, pp.891~902 (2006)
- Lu WP, "Hepatectomy for hepatocellular carcinoma in the era of liver transplantation", World J Gastroenterol, 20, pp.9237~9244 (2014)
- Roayaie S, "Resection of hepatocellular cancer ≤2 cm: results from two Western centers", Hepatology, 57, pp.1426~1435 (2013)
- Dai CY, "Impact of tumor size on the prognosis of hepatocellular carcinoma in patients who underwent liver resection", J Chin Med Assoc, 81, pp.155~163 (2018)
- Ko S, "Liver fibrosis increases the risk of intrahepatic recurrence after hepatectomy for hepatocellular carcinoma", Br J Surg, 89, pp.57~62 (2002)
- Bruix J, "American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma: an update", Hepatology, 53, pp.2011~2053 (2011)
- Imamura H, "Risk factors contributing to early and late phase intrahepatic recurrence of hepatocellular carcinoma after hepatectomy", J Hepatol, 38, pp.200~207 (2003)
- Yeh ML, "The prognostic factors between different viral etiologies among advanced hepatocellular carcinoma patients receiving sorafenib treatment", Kaohsiung J Med Sci, 35, pp.624~632 (2019)
- Kaibori M, "Positive status of alpha-fetoprotein and des-gamma-carboxy prothrombin: important prognostic factor for recurrent hepatocellular carcinoma", World J Surg, 28, pp.702~707 (2004)
- Lin ZY, "Primary cultures of aspiration residual specimens predict outcomes of hepatocellular carcinoma patients receiving curative treatment", Kaohsiung J Med Sci, 36, pp.750~756 (2020)
- Baik M, "Growth hormone-STAT5 regulation of growth, hepatocellular carcinoma, and liver metabolism", Ann N Y Acad Sci, 1229, pp.29~37 (2011)
- Boutin JM, "Cloning and expression of the rat prolactin receptor, a member of the growth hormone", prolactin receptor gene family, 1988, pp.53, 69~77
- Husman B, "Characterization and subcellular distribution of somatogenic receptor in rat liver", Endocrinology, 116, pp.2605~2611 (1985)
- Davey HW, "STAT5b is required for GH-induced liver Igf-I gene expression", Endocrinology, 142, pp.3836~3841 (2001)
- Waxman DJ, "Growth hormone regulation of sex-dependent liver gene expression", Mol Endocrinol, 20, pp.2613~2629 (2006)
- Dehkhoda F, "The growth hormone receptor: mechanism of receptor activation, cell signaling, and physiological aspects", Front Endocrinol (Lausanne), 9, pp.35~ (2018)
- Lee TK, "Signal transducers and activators of transcription 5b activation enhances hepatocellular carcinoma aggressiveness through induction of epithelialmesenchymal transition", Cancer Res, 66, pp.9948~9956 (2006)
- Yu JH, "The transcription factors signal transducer and activator of transcription 5A (STAT5A) and STAT5B negatively regulate cell proliferation through the activation of cyclin-dependent kinase inhibitor 2b (Cdkn2b) and Cdkn1a expression", Hepatology, 52, pp.1808~1818 (2010)
- Mueller KM, "Impairment of hepatic growth hormone and glucocorticoid receptor signaling causes steatosis and hepatocellular carcinoma in mice", Hepatology, 54, pp.1398~1409 (2011)
- Donaghy A, "Growth hormone, insulinlike growth factor-1, and insulinlike growth factor binding proteins 1 and 3 in chronic liver disease", Hepatology, 21, pp.680~688 (1995)
- Chang TC, "Absence of growth-hormone receptor in hepatocellular carcinoma and cirrhotic liver", Hepatology, 11, pp.123~126 (1990)
- Brunet-Dunand SE, "Autocrine human growth hormone promotes tumor angiogenesis in mammary carcinoma", Endocrinology, 150, pp.1341~1352 (2009)
- Conway-Campbell BL, "Nuclear targeting of the growth hormone receptor results in dysregulation of cell proliferation and tumorigenesis", Proc Natl Acad Sci U S A, 104, pp.13331~13336 (2007)
- Basu R, "Targeting growth hormone receptor in human melanoma cells attenuates tumor progression and epithelial mesenchymal transition via suppression of multiple oncogenic pathways", Oncotarget, 8, pp.21579~21598 (2017)
- Ramadevi Subramani, "Growth hormone receptor inhibition decreases the growth and metastasis of pancreatic ductal adenocarcinoma", Experimental and Molecular Medicine, 46, pp.1~11 (2014), 생화학분자생물학회
- García-Caballero T, "Increased expression of growth hormone and prolactin receptors in hepatocellular carcinomas", Endocrine, 12, pp.265~271 (2000)
- Carotti S, "Impairment of GH", IGF-1 axis in the liver of patients with HCV-related chronic hepatitis, 2018, pp.50, 145~151
- Goossens N, "Hepatitis C virus-induced hepatocellular carcinoma", Clin Mol Hepatol, 21, pp.105~114 (2015)
- Nguyen H, "Hepatitis C virus core protein expression leads to biphasic regulation of the p21cdk inhibitor and modulation of hepatocyte cell cycle", Virology, 312, pp.245~253 (2003)
- Hassan M, "Activation of RB", E2F signaling pathway is required for the modulation of hepatitis C virus core protein-induced cell growth in liver and non-liver cells, 2004, pp.16, 1375~1385
- Massagué J, "G1 cell-cycle control and cancer", Nature, 432, pp.298~306 (2004)
- Brooks AJ, "The growth hormone receptor: mechanism of activation and clinical implications", Nat Rev Endocrinol, 6, pp.515~525 (2010)
- Chhabra Y, "Role of the growth hormoneIGF-1 axis in cancer", Expert Rev Endocrinol Metab, 6, pp.71~84 (2011)
- Huang JF, "The tertiary prevention of hepatocellular carcinoma in chronic hepatitis C patients", J Gastroenterol Hepatol, 30, pp.1768~1774 (2015)
- Chishima S, "The relationship between the growth hormone", insulin-like growth factor system and the histological features of nonalcoholic fatty liver disease, 2017, pp.56, 473~480
- Wittekind C, "TNM-System 2010", Onkologe, 16, pp.175~180 (2010)
