Jian Chen1, Sobia Zaidi2, Shuyun Rao2, Jiun-Sheng Chen1, Liem Phan3, Patrizia Farci4, Xiaoping Su5, Kirti Shetty6, Jon White7, Fausto Zamboni8, Xifeng Wu9, Asif Rashid10, Nagarajan Pattabiraman11, Raja Mazumder11, Anelia Horvath11, Ray-Chang Wu12, Shulin Li13, Cuiying Xiao14, Chu-Xia Deng15, David A Wheeler16, Bibhuti Mishra17, Rehan Akbani5, Lopa Mishra18. 1. Departments of Gastroenterology, Hepatology, and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas. 2. Center for Translational Medicine, Department of Surgery, George Washington University, Washington, DC. 3. Departments of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. 4. Hepatic Pathogenesis Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland. 5. Departments of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas. 6. Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, Maryland. 7. Institute of Clinical Research, Veterans Affairs Medical Center, Washington, DC. 8. Department of General Surgery, Liver and Pancreas Transplantation, Brotzu Hospital, Cagliari, Italy. 9. Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas. 10. Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas. 11. Department of Biochemistry and Molecular Medicine, McCormick Genomic and Proteomic Center, George Washington University, Washington, DC. 12. Department of Biochemistry and Molecular Biology, George Washington University, Washington, DC. 13. Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas. 14. Genetics of Development and Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD. 15. Center for Translational Medicine, Department of Surgery, George Washington University, Washington, DC; Faculty of Health Sciences, University of Macau, Macau SAR, China. 16. Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas. 17. Center for Translational Medicine, Department of Surgery, George Washington University, Washington, DC; Institute of Clinical Research, Veterans Affairs Medical Center, Washington, DC. 18. Center for Translational Medicine, Department of Surgery, George Washington University, Washington, DC; Institute of Clinical Research, Veterans Affairs Medical Center, Washington, DC. Electronic address: lopamishra2@gmail.com.
Abstract
BACKGROUND & AIMS: Development of hepatocellular carcinoma (HCC) is associated with alterations in the transforming growth factor-beta (TGF-β) signaling pathway, which regulates liver inflammation and can have tumor suppressor or promoter activities. Little is known about the roles of specific members of this pathway at specific of HCC development. We took an integrated approach to identify and validate the effects of changes in this pathway in HCC and identify therapeutic targets. METHODS: We performed transcriptome analyses for a total of 488 HCCs that include data from The Cancer Genome Atlas. We also screened 301 HCCs reported in the Catalogue of Somatic Mutations in Cancer and 202 from Cancer Genome Atlas for mutations in genome sequences. We expressed mutant forms of spectrin beta, non-erythrocytic 1 (SPTBN1) in HepG2, SNU398, and SNU475 cells and measured phosphorylation, nuclear translocation, and transcriptional activity of SMAD family member 3 (SMAD3). RESULTS: We found somatic mutations in at least 1 gene whose product is a member of TGF-β signaling pathway in 38% of HCC samples. SPTBN1 was mutated in the largest proportion of samples (12 of 202, 6%). Unsupervised clustering of transcriptome data identified a group of HCCs with activation of the TGF-β signaling pathway (increased transcription of genes in the pathway) and a group of HCCs with inactivation of TGF-β signaling (reduced expression of genes in this pathway). Patients with tumors with inactivation of TGF-β signaling had shorter survival times than patients with tumors with activation of TGF-β signaling (P = .0129). Patterns of TGF-β signaling correlated with activation of the DNA damage response and sirtuin signaling pathways. HepG2, SNU398, and SNU475 cells that expressed the D1089Y mutant or with knockdown of SPTBN1 had increased sensitivity to DNA crosslinking agents and reduced survival compared with cells that expressed normal SPTBN1 (controls). CONCLUSIONS: In genome and transcriptome analyses of HCC samples, we found mutations in genes in the TGF-β signaling pathway in almost 40% of samples. These correlated with changes in expression of genes in the pathways; up-regulation of genes in this pathway would contribute to inflammation and fibrosis, whereas down-regulation would indicate loss of TGF-β tumor suppressor activity. Our findings indicate that therapeutic agents for HCCs can be effective, based on genetic features of the TGF-β pathway; agents that block TGF-β should be used only in patients with specific types of HCCs.
BACKGROUND & AIMS: Development of hepatocellular carcinoma (HCC) is associated with alterations in the transforming growth factor-beta (TGF-β) signaling pathway, which regulates liver inflammation and can have tumor suppressor or promoter activities. Little is known about the roles of specific members of this pathway at specific of HCC development. We took an integrated approach to identify and validate the effects of changes in this pathway in HCC and identify therapeutic targets. METHODS: We performed transcriptome analyses for a total of 488 HCCs that include data from The Cancer Genome Atlas. We also screened 301 HCCs reported in the Catalogue of Somatic Mutations in Cancer and 202 from Cancer Genome Atlas for mutations in genome sequences. We expressed mutant forms of spectrin beta, non-erythrocytic 1 (SPTBN1) in HepG2, SNU398, and SNU475 cells and measured phosphorylation, nuclear translocation, and transcriptional activity of SMAD family member 3 (SMAD3). RESULTS: We found somatic mutations in at least 1 gene whose product is a member of TGF-β signaling pathway in 38% of HCC samples. SPTBN1 was mutated in the largest proportion of samples (12 of 202, 6%). Unsupervised clustering of transcriptome data identified a group of HCCs with activation of the TGF-β signaling pathway (increased transcription of genes in the pathway) and a group of HCCs with inactivation of TGF-β signaling (reduced expression of genes in this pathway). Patients with tumors with inactivation of TGF-β signaling had shorter survival times than patients with tumors with activation of TGF-β signaling (P = .0129). Patterns of TGF-β signaling correlated with activation of the DNA damage response and sirtuin signaling pathways. HepG2, SNU398, and SNU475 cells that expressed the D1089Y mutant or with knockdown of SPTBN1 had increased sensitivity to DNA crosslinking agents and reduced survival compared with cells that expressed normal SPTBN1 (controls). CONCLUSIONS: In genome and transcriptome analyses of HCC samples, we found mutations in genes in the TGF-β signaling pathway in almost 40% of samples. These correlated with changes in expression of genes in the pathways; up-regulation of genes in this pathway would contribute to inflammation and fibrosis, whereas down-regulation would indicate loss of TGF-β tumor suppressor activity. Our findings indicate that therapeutic agents for HCCs can be effective, based on genetic features of the TGF-β pathway; agents that block TGF-β should be used only in patients with specific types of HCCs.
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Authors: Shelli M Morris; Ji Yeon Baek; Amanda Koszarek; Samornmas Kanngurn; Sue E Knoblaugh; William M Grady Journal: Hepatology Date: 2011-12-06 Impact factor: 17.425
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Authors: Mark Yarchoan; Parul Agarwal; Augusto Villanueva; Shuyun Rao; Laura A Dawson; Josep M Llovet; Richard S Finn; John D Groopman; Hashem B El-Serag; Satdarshan P Monga; Xin Wei Wang; Michael Karin; Robert E Schwartz; Kenneth K Tanabe; Lewis R Roberts; Preethi H Gunaratne; Allan Tsung; Kimberly A Brown; Theodore S Lawrence; Riad Salem; Amit G Singal; Amy K Kim; Atoosa Rabiee; Linda Resar; Yujin Hoshida; Aiwu Ruth He; Kalpana Ghoshal; Patrick B Ryan; Elizabeth M Jaffee; Chandan Guha; Lopa Mishra; C Norman Coleman; Mansoor M Ahmed Journal: Cancer Res Date: 2019-09-01 Impact factor: 12.701