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Hu B, Ma X, Fu P, Sun Q, Tang W, Sun H, Yang Z, Yu M, Zhou J, Fan J, Xu Y. miRNA-mRNA Regulatory Network and Factors Associated with Prediction of Prognosis in Hepatocellular Carcinoma. GENOMICS PROTEOMICS & BIOINFORMATICS 2021; 19:913-925. [PMID: 33741523 PMCID: PMC9402792 DOI: 10.1016/j.gpb.2021.03.001] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/28/2018] [Revised: 01/02/2019] [Accepted: 02/15/2019] [Indexed: 12/22/2022]
Abstract
The aim of this study was to identify novel gene and miRNA biomarkers of risk and prognostic factors for hepatocarcinogenesis using methods in systems biology. Differentially expressed genes (DEGs), microRNAs (miRNAs), and long non-coding RNA (lncRNAs) were compared between hepatocellular carcinoma (HCC) tumour tissue and normal liver tissues in the Cancer Genome Atlas (TCGA) database. Subsequently, the prognosis-associated gene co-expression network, mRNA-miRNA, and mRNA-miRNA-lncRNA regulatory networks were constructed to identify biomarkers of risk for HCC through Cox survival analysis. Seven prognosis-associated gene co-expression modules were obtained by analyzing these DEGs. An expression module including 120 genes significantly correlated with HCC patient survival. Combined with patient survival data, several mRNAs and miRNAs, including CHST4, SLC22A8, STC2, hsa-miR-326, and hsa-miR-21 were identified from the network to predict HCC patient prognosis. Clinical significance was investigated using tissue microarray analysis of samples from 258 patients with HCC. Functional annotation of hsa-miR-326 and hsa-miR-21-5p indicated specific associations with several cancer-related pathways. The present study provides a bioinformatics method for biomarker screening, which led to the identification of an integrated mRNA-miRNA-lncRNA regulatory network and their co-expression in relation to predicting HCC patient survival.
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Affiliation(s)
- Bo Hu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai 200032, China
| | - Xiaolu Ma
- Laboratory Medicine Department, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai 200032, China
| | - Peiyao Fu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai 200032, China
| | - Qiman Sun
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai 200032, China
| | - Weiguo Tang
- Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, Shanghai 201199, China
| | - Haixiang Sun
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai 200032, China
| | - Zhangfu Yang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai 200032, China
| | - Mincheng Yu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai 200032, China
| | - Jian Zhou
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai 200032, China; State Key Laboratory of Genetic Engineering, Fudan University, Shanghai 200032, China; Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China
| | - Jia Fan
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai 200032, China; State Key Laboratory of Genetic Engineering, Fudan University, Shanghai 200032, China; Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China
| | - Yang Xu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai 200032, China.
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Badawy AAG, El-Hindawi A, Hammam O, Moussa M, Gabal S, Said N. Impact of epidermal growth factor receptor and transforming growth factor-α on hepatitis C virus-induced hepatocarcinogenesis. APMIS 2015; 123:823-31. [DOI: 10.1111/apm.12431] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2015] [Accepted: 07/10/2015] [Indexed: 12/11/2022]
Affiliation(s)
| | | | - Olfat Hammam
- Department of Pathology; Theodor Bilharz Research Institute; Imbaba Egypt
| | - Mona Moussa
- Department of Pathology; Theodor Bilharz Research Institute; Imbaba Egypt
| | - Samia Gabal
- Faculty of Medicine; Cairo University; Giza Egypt
| | - Noha Said
- Department of Pathology; Theodor Bilharz Research Institute; Imbaba Egypt
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Grusch M, Drucker C, Peter-Vörösmarty B, Erlach N, Lackner A, Losert A, Macheiner D, Schneider WJ, Hermann M, Groome NP, Parzefall W, Berger W, Grasl-Kraupp B, Schulte-Hermann R. Deregulation of the activin/follistatin system in hepatocarcinogenesis. J Hepatol 2006; 45:673-80. [PMID: 16935389 DOI: 10.1016/j.jhep.2006.06.014] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2006] [Revised: 05/23/2006] [Accepted: 06/27/2006] [Indexed: 12/04/2022]
Abstract
BACKGROUND/AIMS Activins A and E negatively regulate hepatic cell number by inhibiting cell replication and inducing apoptosis. Follistatin and follistatin-like 3 bind activins and antagonise their biological activities. Aim of our study was to investigate, whether activins and follistatins may play a role in hepatocarcinogenesis. METHODS Expression levels of follistatin, follistatin-like 3, and activin subunits beta(A) as well as beta(E) were investigated in chemically induced rat and human liver tumours by real-time PCR and immunohistochemistry. In addition, the effects of follistatin and activin A on DNA synthesis of normal as well as preneoplastic hepatocytes and hepatoma cells were analysed. RESULTS Follistatin was overexpressed while both activin subunits were downregulated in the majority of rat and human liver tumours. Follistatin-like 3 expression was low in normal but enhanced in malignant rat liver. In human normal liver, in contrast, it was abundantly expressed but downregulated in liver cancer. Administration of follistatin to normal and preneoplastic hepatocytes stimulated DNA synthesis preferentially in preneoplastic rat hepatocytes, whereas activin A repressed it. CONCLUSIONS The balanced expression of follistatins and activins becomes deregulated during hepatocarcinogenesis. The sensitivity of preneoplastic hepatocytes to activin signals suggests the activin/follistatin system as promising target for therapeutic intervention.
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Affiliation(s)
- Michael Grusch
- Department of Medicine I, Division: Institute of Cancer Research, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria.
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4
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Pontisso P, Calabrese F, Benvegnù L, Lise M, Belluco C, Ruvoletto MG, Marino M, Valente M, Nitti D, Gatta A, Fassina G. Overexpression of squamous cell carcinoma antigen variants in hepatocellular carcinoma. Br J Cancer 2004; 90:833-7. [PMID: 14970861 PMCID: PMC2410161 DOI: 10.1038/sj.bjc.6601543] [Citation(s) in RCA: 97] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Pathogenetic mechanisms of hepatocellular carcinoma (HCC) are still unclear and new tools for diagnostic and therapeutic purposes are ongoing. We have assessed whether squamous cell carcinoma antigen (SCCA), a serpin overexpressed in neoplastic cells of epithelial origin, is also expressed in liver cancer. Squamous cell carcinoma antigen was evaluated by immunohistochemistry in 65 HCCs of different aetiology and in 20 normal livers. Proliferative activity was assessed using MIB-1 antibody. In 18 surgical samples, tumour and nontumour liver tissue was available for SCCA cDNA amplification and sequencing. Squamous cell carcinoma antigen was detected in 55 out of 65 (85%) tumour specimens, but in none of the 20 controls. In the majority of the cases, the positive signal was found in the cytoplasm of more than 50% of the hepatocytes. Low or undetectable SCCA (score⩽1) was associated to lower MIB-1 labelling index, compared to cases with SCCA score ⩾2 (mean±s.d.: 2%±2.4 vs 7.5%±10.3, P<0.05). Squamous cell carcinoma antigen mRNA could be directly sequenced in 14 out of 18 liver tumours but in none of the corresponding nontumour samples. From sequence alignment, a novel SCCA1 variant (G351 to A) was identified in five cases, while SCCA1 was revealed in six cases and SCCA2 in three cases. In conclusion, SCCA variants are overexpressed in HCC, independently of tumour aetiology. A novel SCCA1 variant has been identified in one third of liver tumours.
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Affiliation(s)
- P Pontisso
- Department of Clinical and Experimental Medicine, Via Giustiniani, 2 35123, Padova, Italy.
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Liu LX, Liu ZH, Jiang HC, Qi SY, Zhang WH, Zhu AL, Wang XQ, Wu M. Overexpression of Akt-1 gene in human hepatocellular carcinoma. Chin J Cancer Res 2002. [DOI: 10.1007/s11670-002-0036-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022] Open
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Liu LX, Jiang HC, Liu ZH, Zhou J, Zhang WH, Zhu AL, Wang XQ, Wu M. Intergrin gene expression profiles of humanhepatocellular carcinoma. World J Gastroenterol 2002; 8:631-7. [PMID: 12174369 PMCID: PMC4656311 DOI: 10.3748/wjg.v8.i4.631] [Citation(s) in RCA: 38] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate gene expression profiles of intergrin genes in hepatocellular carcinoma (HCC) through the usage of Atlas Human Cancer Array membranes, semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) and Northern blot.
METHODS: Hybridization of cDNA array membrane was performed with α32P-labeled cDNA probes synthesized from RNA isolated from hepatocellular carcinoma and adjacent non-cirrhotic liver. AtlasImage, which is a software specific to array, was used to analyze the result. RT-PCR of 24 pairs specimen and Northern blot of 4 pairs specimen were used to confirm the expression pattern of some intergrin genes identified by Atlas arrays hybridization.
RESULTS: Among 588 genes spotted in membrane, 17 genes were related to intergrin. Four genes were up-regulated, such as intergrin alpha8, beta1, beta7 and beta8 in HCC. Whereas there were no genes down-regulated in HCC. RT-PCR and Northern blot analysis of intergrin beta1 gene gave results consistent with cDNA array findings.
CONCLUSION: Investigation of these intergrin genes should help to disclose the molecular mechanism of the cell adhesion, invasive and metastasis of HCC. A few genes are reported to have changed in HCC for the first time. The quick and high-throughout method of profiling gene expression by cDNA array provides us overview of key factors that may involved in HCC, and may find the clue of the study of HCC metastasis and molecular targets of anti-metastasis therapy. The precise relationship between the altered genes and HCC is a matter of further investigation.
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Affiliation(s)
- Lian-Xin Liu
- National Laboratory of Molecular Oncology, Cancer Institute, Chinese Academy of Medical Science Peking Union Medical College, Panjiayuan, Chaoyang District, Beijing 100021, China
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Lim SO, Park SJ, Kim W, Park SG, Kim HJ, Kim YI, Sohn TS, Noh JH, Jung G. Proteome analysis of hepatocellular carcinoma. Biochem Biophys Res Commun 2002; 291:1031-7. [PMID: 11866469 DOI: 10.1006/bbrc.2002.6547] [Citation(s) in RCA: 148] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Development of hepatocellular carcinoma (HCC) is a complex process involving multiple changes in gene expression and usually occurs in the presence of liver cirrhosis. In this research, we observed proteome alterations of three tissue types isolated from livers of HCC patients: normal, cirrhotic, and tumorous tissue. Proteome alterations were observed using two-dimensional polyacrylamide gel electrophoresis and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Comparing the tissue types with each other, a significant change in expression level was found in 21 proteins. Of these proteins, sarcosine dehydrogenase, liver carboxylesterase, peptidyl-prolyl isomerase A, and lamin B1 are considered novel HCC marker candidates. In particular, lamin B1 may be considered as a marker for cirrhosis, because its expression level changes considerably in cirrhotic tissue compared with normal tissue. The proteins revealed in this experiment can be used in the future for studies pertaining to hepatocarcinogenesis, or as diagnostic markers and therapeutic targets for HCC.
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Affiliation(s)
- Seung Oe Lim
- School of Biological Sciences, Seoul National University, Seoul 151-747, Korea
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Chung YH, Kim JA, Song BC, Lee GC, Koh MS, Lee YS, Lee SG, Suh DJ. Expression of transforming growth factor-alpha mRNA in livers of patients with chronic viral hepatitis and hepatocellular carcinoma. Cancer 2000; 89:977-82. [PMID: 10964327 DOI: 10.1002/1097-0142(20000901)89:5<977::aid-cncr6>3.0.co;2-i] [Citation(s) in RCA: 42] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Transforming growth factor-alpha (TGFalpha) is an important autocrine growth factor of hepatocytes. The authors evaluated the roles of TGFalpha in chronic viral hepatitis (CVH) and hepatocellular carcinoma (HCC). METHODS The authors measured the amounts of TGFalpha mRNA in liver tissues from 18 patients with HCC, 31 patients with CVH, and 7 normal controls. " Hot-start" reverse transcription-polymerase chain reaction (RT-PCR) using oligo-dT and specific primers detected TGFalpha mRNA in total cellular RNA extracted from liver tissues. The levels of TGFalpha mRNA were determined by the end point titers of serial, two-fold dilutions of cDNA. The amounts of hepatitis B virus RNA (HBV-RNA) in livers of patients with chronic hepatitis B also were measured by Northern blot hybridization. RESULTS TGFalpha mRNA levels were extremely higher in patients with HCC compared with patients with CVH and normal controls, and the levels in patients with CVH also were elevated compared with normal controls. The levels of TGFalpha mRNA were overexpressed in the underlying livers of patients with HCC compared with patients with CVH, although they were lower than those found in HCC tissues. The levels of TGFalpha mRNA were higher in samples from patients with chronic hepatitis B than in samples from patients with chronic hepatitis C. The levels of TGFalpha mRNA were not correlated with serum alanine aminotransferase or HBV-RNA levels in liver tissues in patients with chronic hepatitis B. However, the expression of TGFalpha mRNA tended to be higher in the livers of patients with raised serum alpha-fetoprotein levels. CONCLUSIONS The overexpression of TGFalpha mRNA in the liver seems to be associated with the regeneration of hepatocytes rather than hepatic necrosis or viral replication. Also, it may be related closely to the development or progression of HCC, especially in the livers of patients with chronic hepatitis B.
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Affiliation(s)
- Y H Chung
- Department of Internal Medicine, University of Ulsan College of Medicine, Seoul, Korea
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9
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Harada K, Shiota G, Kawasaki H. Transforming growth factor-alpha and epidermal growth factor receptor in chronic liver disease and hepatocellular carcinoma. LIVER 1999; 19:318-25. [PMID: 10459631 DOI: 10.1111/j.1478-3231.1999.tb00056.x] [Citation(s) in RCA: 80] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
AIMS/BACKGROUND Transforming growth factor-alpha (TGF-alpha) is a potent mitogen of normal and neoplastic hepatocytes. In addition, TGF-alpha has been reported to play a pivotal role in hepatocarcinogenesis. To evaluate the significance of TGF-alpha in chronic liver diseases and hepatocellular carcinoma, we examined serum TGF-alpha, and expression of TGF-alpha, epidermal growth factor receptor (EGFR) and proliferating cell nuclear antigen (PCNA) mRNA in liver tissues. METHODS Thirty-five patients with chronic hepatitis (CH), 33 with liver cirrhosis (LC), 55 with hepatocellular carcinoma (HCC) and 53 normal controls (C) were enrolled in this study. Serum TGF-alpha levels were measured by an enzyme-linked immunosorbent assay. Expression of TGF-alpha, EGFR, PCNA and beta-actin mRNA in liver tissues were examined by reverse transcription polymerase chain reaction. RESULTS Serum TGF-alpha levels in C, CH, LC and HCC were 5.6+/-2.1, 33.2+/-8.3, 404.0+/-173.0 and 100.3+/-39.2 pg/ml, respectively. Serum TGF-alpha level in LC was higher than in other diseases (p<0.01, compared to CH, HCC and C, respectively). Serum TGF-alpha levels exhibited a significant positive correlation with total bilirubin, ICGR15 and Pugh score (p<0.01, p<0.01 and p<0.05, respectively), and increased in parallel with severity of disease according to Child classification. Although the ratios of TGF-alpha, EGFR and PCNA mRNA to beta-actin mRNA were not significantly different among the diseases, the TGF-alpha/beta-actin ratio correlated with EGFR/beta-actin and PCNA/beta-actin ratios (p<0.001 and p<0.0001, respectively), and EGFR/beta-actin ratio was related to PCNA/beta-actin ratio in all patients, especially with HCC. CONCLUSION The results of the present study suggest that serum TGF-alpha levels are closely related to severity of liver dysfunction, and that hepatic expression of TGF-alpha and EGFR correlates with proliferation of normal and neoplastic hepatocytes.
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Affiliation(s)
- K Harada
- Second Department of Internal Medicine, Tottori University School of Medicine, Yonago, Japan
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Nalesnik MA, Lee RG, Carr BI. Transforming growth factor alpha (TGFalpha) in hepatocellular carcinomas and adjacent hepatic parenchyma. Hum Pathol 1998; 29:228-34. [PMID: 9496824 DOI: 10.1016/s0046-8177(98)90040-5] [Citation(s) in RCA: 20] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
We examined stage T1 to T4 hepatocellular carcinomas (HCC) to determine whether transforming growth factor alpha (TGFalpha) presence differed between early- and late-stage HCC and between tumors with low and high proliferative rates. Paraffin sections from 36 HCC were evaluated for TGFalpha and the proliferation markers Kiel 67 antigen (Ki67) or proliferating cell nuclear antigen (PCNA) by immunoperoxidase staining. In 12 cases, double staining for TGFalpha and Ki67 was also performed. Eighty-one percent of tumors and 94% of adjacent liver sections contained TGFalpha. A trend toward inverse correlation was seen between the percentage of TGFalpha-positive tumor cells and the proliferative rate as determined by Ki67 staining. No clear correlation of TGFalpha to either tumor stage or percentage of PCNA-positive cells was seen. This study confirms the presence of TGFalpha in the majority of early- and late-stage HCC. Positivity within tumor tissue is consistent with autocrine or paracrine stimulation. A trend toward inverse correlation between TGFalpha-producing cells and the number of cycling cells suggests that rapidly proliferating tumors may consume this growth factor at an accelerated rate. Alternatively, other hepatic mitogens may have more functional significance in these latter tumors. Finally, the presence of TGFalpha in peritumoral hepatocytes suggests these cells as potential sources of paracrine stimulation for HCC.
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Affiliation(s)
- M A Nalesnik
- Division of Transplantation Pathology, University of Pittsburgh Medical Center, PA 15213, USA
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Kira S, Nakanishi T, Suemori S, Kitamoto M, Watanabe Y, Kajiyama G. Expression of transforming growth factor alpha and epidermal growth factor receptor in human hepatocellular carcinoma. LIVER 1997; 17:177-82. [PMID: 9298487 DOI: 10.1111/j.1600-0676.1997.tb00803.x] [Citation(s) in RCA: 79] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Transforming growth factor alpha (TGF-alpha) is thought to be involved in liver regeneration, cellular proliferation, and hepatocarcinogenesis. We have looked at the relationship between TGF-alpha and it's receptor, and have attempted to relate the expression of TGF-alpha and it's receptor to the differentiation of hepatocellular carcinoma (HCC) on serial sections of HCC. We examined immunohistochemically the expression of the TGF-alpha and of epidermal growth factor receptor (EGFR) proteins in the same area of 53 nodules (< 5 cm in diameter) of HCC obtained from patients. Immunoreactive proteins were visualized by using a biotin-streptoavidin system (LSAB Kil, Dako). TGF-alpha was strongly expressed in 29 of 53 (54.7%) nodules. Specimens strongly positive for TGF-alpha were found mainly in well-differentiated HCC, while specimens positive for EGFR were found mainly in poorly differentiated HCC (p < 0.05). In the tissues that stained weakly positive for TGF-alpha, the expression of EGFR differed significantly, according to the degree of HCC histologic differentiation (p < 0.05). These results led us to speculate that the expression of TGF-alpha and EGFR might be related to the pattern of histologic differentiation of HCC.
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Affiliation(s)
- S Kira
- First Department of Internal Medicine, Hiroshima University School of Medicine, Japan
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Tsai JF, Chuang LY, Jeng JE, Yang ML, Chang WY, Hsieh MY, Lin ZY, Tsai JH. Clinical relevance of transforming growth factor-beta 1 in the urine of patients with hepatocellular carcinoma. Medicine (Baltimore) 1997; 76:213-26. [PMID: 9193456 DOI: 10.1097/00005792-199705000-00007] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
To assess the clinical relevance of transforming growth factor-beta 1 (TGF-beta 1) in the urine of patients with hepatocellular carcinoma (HCC), TGF-beta 1 was measured, by radioimmunoassay, in 140 patients with HCC, 50 cirrhotic patients, 30 patients with chronic active hepatitis, and 50 healthy controls. The results indicate that there were significantly increased urinary TGF-beta 1 levels in patients with HCC. Raised TGF-beta 1 levels were associated, in a dose-related fashion, with increased risk for development of HCC (odds ratio, 1.05, 95% confidence interval, 1.03-1.07). HCC patients with raised TGF-beta 1 levels had shorter survival than those with normal TGF-beta 1 levels (p = 0.038). TGF-beta 1 levels decreased after successful anticancer therapy (p < 0.0001). There was an inverse correlation between TGF-beta 1 and serum alpha-fetoprotein (AFP) (r = -0.199, p < 0.04). Receiver operating characteristics (ROC) curve analysis indicated that parallel determination of TGF-beta 1 and AFP significantly increased the sensitivity and diagnostic accuracy, with a high specificity. In conclusion, raised urinary TGF-beta 1 was associated with HCC development. It is a predictor of poor prognosis, and a tumor marker for diagnosis and therapeutic follow-up of HCC.
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Affiliation(s)
- J F Tsai
- Department of Internal Medicine, Kaohsiung Medical College, Taiwan
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Moser GJ, Wolf DC, Goldsworthy TL. Quantitative relationship between transforming growth factor-alpha and hepatic focal phenotype and progression in female mouse liver. Toxicol Pathol 1997; 25:275-83. [PMID: 9210259 DOI: 10.1177/019262339702500305] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Modulations in the positive hepatocyte growth factor, transforming growth factor-alpha (TGF-alpha) and its receptor epidermal growth factor receptor (EGFR), occur in rat and human liver tumors. The purpose of this study was to determine if TGF-alpha and EGFR are altered in basophilic and acidophilic preneoplastic and neoplastic liver lesions generated in DEN-initiated mice exposed to a variety of hepatocarcinogens. Female B6C3F1 mice were initiated with N-nitrosodiethylamine (DEN) and treated with hepatocarcinogenic concentrations of unleaded gasoline vapor (2,000 ppm), methyl tertiary butyl ether vapor (7,814 ppm), phenobarbital (500 ppm, diet), or chlordane (25 ppm, diet). Hepatic foci and tumors were identified and evaluated immunohistochemically with antibodies for TGF-alpha and EGFR. In all treatment groups, basophilic hepatic foci were negative for TGF-alpha immunoreactivity (554/564, 98%). In contrast, regardless of treatment, acidophilic hepatic foci were immunoreactive for TGF-alpha (107/108, 99%). There was no significant difference in mean hepatic labeling index as measured by the incorporation of 5-bromo-2'-deoxyuridine between foci immunoreactive and nonimmunoreactive for TGF-alpha. The incidence of immunoreactivity for TGF-alpha increased in hepatocellular tumors that were predominantly of the basophilic phenotype. Of basophilic hepatocellular adenomas, 16/81 (20%) were immunoreactive for TGF-alpha, while 17/29 (59%) of hepatocellular carcinomas stained positive for TGF-alpha. A similar increased incidence of EGFR immunoreactivity was found in basophilic hepatocellular adenomas (17/67, 25%) and carcinomas (19/28, 68%) relative to basophilic foci (11/367, 3%), suggesting an autocrine mechanism for the development of mouse liver tumors. The increased incidence of TGF-alpha immunoreactivity in basophilic liver tumors suggests that TGF-alpha is a marker of tumor progression in mouse liver. Furthermore, TGF-alpha modulations were dependent on phenotype rather than treatment, indicating inherent differences in the expression of TGF-alpha in basophilic and acidophilic hepatic lesions.
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MESH Headings
- Adenoma, Liver Cell/chemically induced
- Adenoma, Liver Cell/chemistry
- Adenoma, Liver Cell/pathology
- Animals
- Carcinoma, Hepatocellular/chemically induced
- Carcinoma, Hepatocellular/chemistry
- Carcinoma, Hepatocellular/pathology
- Chlordan/toxicity
- Crosses, Genetic
- Diethylnitrosamine/toxicity
- Disease Progression
- ErbB Receptors/analysis
- Female
- Gasoline/toxicity
- Liver Neoplasms, Experimental/chemically induced
- Liver Neoplasms, Experimental/chemistry
- Liver Neoplasms, Experimental/pathology
- Male
- Methyl Ethers/toxicity
- Mice
- Mice, Inbred C3H
- Mice, Inbred C57BL
- Mitotic Index/drug effects
- Phenobarbital/toxicity
- Phenotype
- Precancerous Conditions/chemically induced
- Precancerous Conditions/chemistry
- Precancerous Conditions/pathology
- Solvents/toxicity
- Transforming Growth Factor alpha/analysis
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Affiliation(s)
- G J Moser
- Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina 27709, USA
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14
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Burr AW, Toole K, Mathew J, Hines JE, Chapman C, Burt AD. Transforming growth factor-alpha expression is altered during experimental hepatocarcinogenesis. J Pathol 1996; 179:276-82. [PMID: 8774483 DOI: 10.1002/(sici)1096-9896(199607)179:3<276::aid-path573>3.0.co;2-u] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
In order to characterize the role of transforming growth factor-alpha (TGF alpha) during hepatocarcinogenesis, liver tissue was examined at 10, 16, and 19 weeks following initial 10-week diethylnitrosamine (50 mg l-1 drinking water) exposure in female Wistar rats. Liver tissue protein extracts were electrophoresed and transferred to nitrocellulose filters. Levels of tissue-derived TGF alpha and epidermal growth factor receptor (EGFr) were assessed using an anti-TGF alpha monoclonal antibody (Ab-1) and an anti-EGFr polyclonal antibody (AB-4), coupled with scanning densitometric quantification. Immunolocalization of TGF alpha was performed in Bouin's-fixed, paraffin-embedded liver tissue sections. The distribution and intensity of TGF alpha immunoreactivity varied according to the degree of dysplasia, severely dysplastic cells being strongly immunoreactive. At week 10, mild hepatocyte dysplasia and perivenular inflammation were evident, together with a corresponding increase in perivenular TGF alpha immunoreactivity. By week 16, foci of moderate to severe dysplasia were observed; at this stage, there was a decrease in perivenular immunoreactivity but a further increase in overall liver tissue TGF alpha levels. Some 'altered foci' and dysplastic nodules showed intense immunoreactivity for TGF alpha. At these time points, immunodetectable liver EGFr was found to decrease significantly in comparison with normal control tissue. TGF alpha immunoreactivity was observed in fully developed carcinomas at week 19, although some tumours were negative by immunohistochemistry. The up-regulation of immunodetectable TGF alpha and the concomitant down-regulation of EGFr demonstrated positive (P < 0.01) and negative (P < 0.001) correlations, respectively, with hepatocyte proliferation indices. These findings suggest that the TGF alpha/EGFr ligand receptor system may be important during tumour promotion and in the stimulation of continued proliferation in hepatocellular carcinomas.
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Affiliation(s)
- A W Burr
- Division of Pathology, School of Pathological Sciences, Royal Victoria Infirmary, University of Newcastle upon Tyne, U.K
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Morimitsu Y, Hsia CC, Kojiro M, Tabor E. Nodules of less-differentiated tumor within or adjacent to hepatocellular carcinoma: relative expression of transforming growth factor-alpha and its receptor in the different areas of tumor. Hum Pathol 1995; 26:1126-32. [PMID: 7557946 DOI: 10.1016/0046-8177(95)90275-9] [Citation(s) in RCA: 55] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Expression of transforming growth factor-alpha (TGF-alpha) and its receptor, the epidermal growth factor receptor (EGFR), in hepatocellular carcinomas (HCCs) and adjacent nontumorous livers from 25 Japanese patients were examined using immunoperoxidase staining of paraffin-embedded sections. TGF-alpha was detected in 24 of 25 (96%) HCCs and 23 of 24 (96%) available adjacent nontumorous livers. EGFR was detected in 16 of 25 (64%) HCCs and 17 of 24 (71%) adjacent nontumorous livers. TGF-alpha and EGFR were not detected by immunohistochemical staining in normal livers. Fifteen of 25 HCCs contained an apparent area of a second tumor (two of the 15 also contained a third tumor) that had a less-differentiated histological grade developing within or adjacent to the first tumor. In those cases, staining in the less-differentiated area of tumor was usually less intense than in the more highly differentiated area (80% of cases for TGF-alpha; 91% for EGFR). These data confirm that increased expression of TGF-alpha and EGFR occur frequently in human HCC. Furthermore, the detection of greater staining in more highly differentiated portions of the tumors suggests that increased expression of TGF-alpha and EGFR may be events of the early stages of human hepatocarcinogenesis.
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Affiliation(s)
- Y Morimitsu
- Biological Carcinogenesis Program, National Cancer Institute, Bethesda, MD 20892, USA
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16
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Aubrecht J, Hirsch-Ernst KI, Becker-Rabbenstein V, Kahl GF, Taniguchi H, Höhne MW. Induction of cytochrome P-4502B1-related mouse cytochrome P-450 and regulation of its expression by epidermal growth factor/transforming growth factor alpha in primary hepatocyte culture. Biochem Pharmacol 1995; 50:781-5. [PMID: 7575638 DOI: 10.1016/0006-2952(95)00200-j] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Phenobarbital-dependent induction of mouse cytochrome P-450 (Cyp) orthologous to rat CYP2B1 and its modulation by hepatotrophic growth factors were examined in primary hepatocyte cultures. Compared to rat hepatocytes, induction in mouse hepatocytes was more rapid and effective. Ligands of the EGF receptor, epidermal growth factor, and transforming growth factor alpha inhibited induction on the basis of protein expression and CYP2B-associated 7-pentoxyresorufin-O-depentylase activity. Furthermore, EGF led to repression of accumulation of corresponding mRNA under phenobarbital, an effect not blocked by inhibition of protein synthesis under cycloheximide. Ligands of the EGF receptor may contribute towards the decrease in hepatic CYP expression observed during (pre)neoplastic development and regeneration.
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Affiliation(s)
- J Aubrecht
- Institute of Pharmacology and Toxicology, University of Göttingen, Germany
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17
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Affiliation(s)
- V Desmet
- Laboratory of Histo- and Cytochemistry, University Hospital St. Rafael, University of Leuven, Belgium
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18
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Park BC, Huh MH, Seo JH. Differential expression of transforming growth factor alpha and insulin-like growth factor II in chronic active hepatitis B, cirrhosis and hepatocellular carcinoma. J Hepatol 1995; 22:286-94. [PMID: 7608479 DOI: 10.1016/0168-8278(95)80281-9] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
In the present study we investigated the expression of transforming growth factor alpha and insulin-like growth factor II to explain the role of these growth factors in the development of hepatocellular carcinoma from chronic active hepatitis B and cirrhosis. The expression of transforming growth factor alpha and insulin-like growth factor II was tested in 38 tissue samples from patients with chronic active hepatitis B, 32 cirrhosis and 31 hepatocellular carcinoma, by immunohistochemical staining using monoclonal anti-transforming growth factor alpha and anti-insulin-like growth factor II. All patients were seropositive for HBsAg. Transforming growth factor alpha was expressed in 26 (68.4%) of 38 chronic active hepatitis B, 18 (56.3%) of 32 cirrhosis and 16 (51.6%) of 31 hepatocellular carcinoma tissue samples. Transforming growth factor alpha was found in the periportal hepatocytes of chronic active hepatitis B and in regenerating hepatocytes of cirrhotic nodules. In hepatocellular carcinoma tissues, transforming growth factor alpha-containing tumor cells were evenly distributed within the tumor tissues but focal distribution limited to a part of tumor tissues was also observed. The expression of insulin-like growth factor II was observed in 30 (93.8%) of 32 cirrhosis and all the 31 hepatocellular carcinoma tissue samples tested, but not in chronic active hepatitis B samples. Insulin-like growth factor II was expressed in most hepatocytes of regenerating nodules and in tumorous as well as non-tumorous hepatocytes of hepatocellular carcinoma tissues.(ABSTRACT TRUNCATED AT 250 WORDS)
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Affiliation(s)
- B C Park
- Department of Internal Medicine, Kosin University School of Medicine, Busan, Korea
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19
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Affiliation(s)
- A D Burt
- Department of Pathology, Royal Victoria Infirmary, Newcastle upon Tyne, UK
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