Binyong Liang1, Yi Zhou2, Manning Qian3, Meng Xu4, Jingxiao Wang5, Yi Zhang6, Xinhua Song7, Haichuan Wang8, Shumei Lin9, Chuanli Ren10, Satdarshan P Monga11, Bruce Wang12, Matthias Evert13, Yifa Chen14, Xiaoping Chen14, Zhiyong Huang15, Diego F Calvisi16, Xin Chen17. 1. Hepatic Surgery Center, Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, San Francisco, CA, USA. 2. Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, San Francisco, CA, USA; Department of Infectious Diseases, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China. 3. Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, San Francisco, CA, USA; College of Clinical Medicine, Yangzhou University, Yangzhou, China. 4. Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, San Francisco, CA, USA; Department of Gastroenterology, The Second Hospital of Xi'an Jiaotong University, Xi'an, China. 5. Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, San Francisco, CA, USA; School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China. 6. Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, San Francisco, CA, USA; Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China. 7. Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, San Francisco, CA, USA. 8. Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, San Francisco, CA, USA; Liver Transplantation Division, Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China; Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China. 9. Department of Infectious Diseases, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China. 10. Department of Laboratory Medicine, Clinical Medical College of Yangzhou University, Yangzhou, China. 11. Department of Pathology and Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA. 12. Department of Medicine and Liver Center, University of California San Francisco, San Francisco, CA, USA. 13. Institute of Pathology, University of Regensburg, Regensburg, Germany. 14. Hepatic Surgery Center, Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. 15. Hepatic Surgery Center, Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: zyhuang126@126.com. 16. Institute of Pathology, University of Regensburg, Regensburg, Germany. Electronic address: diego.calvisi@klinik.uni-regensburg.de. 17. Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, San Francisco, CA, USA. Electronic address: xin.chen@ucsf.edu.
Abstract
BACKGROUND & AIMS: Gain of function (GOF) mutations in the CTNNB1 gene are one of the most frequent genetic events in hepatocellular carcinoma (HCC). T-box transcription factor 3 (TBX3) is a liver-specific target of the Wnt/β-catenin pathway and thought to be an oncogene mediating activated β-catenin-driven HCC formation. METHODS: We evaluated the expression pattern of TBX3 in human HCC specimens. Tbx3 was conditionally knocked out in murine HCC models by hydrodynamic tail vein injection of Cre together with c-Met and ΔN90-β-catenin (c-Met/β-catenin) in Tbx3flox/flox mice. TBX3 was overexpressed in human HCC cell lines to investigate the functions of TBX3 in vitro. RESULTS: A bimodal expression pattern of TBX3 in human HCC samples was detected: high expression of TBX3 in GOF CTNNB1 HCC and downregulation of TBX3 in non-CTNNB1 mutant tumors. High expression of TBX3 was associated with increased differentiation and decreased expression signatures of tumor growth. Using Tbx3flox/flox mice, we found that ablation of Tbx3 significantly accelerates c-Met/β-catenin-driven HCC formation. Moreover, Tbx3(-) HCC demonstrated increased YAP/TAZ activity. The accelerated tumor growth induced by loss of TBX3 in c-Met/β-catenin mouse HCC was successfully prevented by overexpression of LATS2, which inhibited YAP/TAZ activity. In human HCC cell lines, overexpression of TBX3 inhibited HCC cell growth as well as YAP/TAZ activation. A negative correlation between TBX3 and YAP/TAZ target genes was observed in human HCC samples. Mechanistically, phospholipase D1 (PLD1), a known positive regulator of YAP/TAZ, was identified as a novel transcriptional target repressed by TBX3. CONCLUSION: Our study suggests that TBX3 is induced by GOF CTNNB1 mutants and suppresses HCC growth by inactivating PLD1, thus leading to the inhibition of YAP/TAZ oncogenes. LAY SUMMARY: TBX3 is a liver-specific target of the Wnt/β-catenin pathway and thought to be an oncogene in promoting liver cancer development. Herein, we demonstrate that TBX3 is in fact a tumor suppressor gene that restricts liver tumor growth. Strategies which increase TBX3 expression and/or activities may be effective for HCC treatment.
BACKGROUND & AIMS: Gain of function (GOF) mutations in the CTNNB1 gene are one of the most frequent genetic events in hepatocellular carcinoma (HCC). T-box transcription factor 3 (TBX3) is a liver-specific target of the Wnt/β-catenin pathway and thought to be an oncogene mediating activated β-catenin-driven HCC formation. METHODS: We evaluated the expression pattern of TBX3 in human HCC specimens. Tbx3 was conditionally knocked out in murine HCC models by hydrodynamic tail vein injection of Cre together with c-Met and ΔN90-β-catenin (c-Met/β-catenin) in Tbx3flox/flox mice. TBX3 was overexpressed in human HCC cell lines to investigate the functions of TBX3 in vitro. RESULTS: A bimodal expression pattern of TBX3 in human HCC samples was detected: high expression of TBX3 in GOF CTNNB1 HCC and downregulation of TBX3 in non-CTNNB1 mutant tumors. High expression of TBX3 was associated with increased differentiation and decreased expression signatures of tumor growth. Using Tbx3flox/flox mice, we found that ablation of Tbx3 significantly accelerates c-Met/β-catenin-driven HCC formation. Moreover, Tbx3(-) HCC demonstrated increased YAP/TAZ activity. The accelerated tumor growth induced by loss of TBX3 in c-Met/β-catenin mouse HCC was successfully prevented by overexpression of LATS2, which inhibited YAP/TAZ activity. In human HCC cell lines, overexpression of TBX3 inhibited HCC cell growth as well as YAP/TAZ activation. A negative correlation between TBX3 and YAP/TAZ target genes was observed in human HCC samples. Mechanistically, phospholipase D1 (PLD1), a known positive regulator of YAP/TAZ, was identified as a novel transcriptional target repressed by TBX3. CONCLUSION: Our study suggests that TBX3 is induced by GOF CTNNB1 mutants and suppresses HCC growth by inactivating PLD1, thus leading to the inhibition of YAP/TAZ oncogenes. LAY SUMMARY: TBX3 is a liver-specific target of the Wnt/β-catenin pathway and thought to be an oncogene in promoting liver cancer development. Herein, we demonstrate that TBX3 is in fact a tumor suppressor gene that restricts liver tumor growth. Strategies which increase TBX3 expression and/or activities may be effective for HCC treatment.
Authors: Richard S Finn; Shukui Qin; Masafumi Ikeda; Peter R Galle; Michel Ducreux; Tae-You Kim; Masatoshi Kudo; Valeriy Breder; Philippe Merle; Ahmed O Kaseb; Daneng Li; Wendy Verret; Derek-Zhen Xu; Sairy Hernandez; Juan Liu; Chen Huang; Sohail Mulla; Yulei Wang; Ho Yeong Lim; Andrew X Zhu; Ann-Lii Cheng Journal: N Engl J Med Date: 2020-05-14 Impact factor: 91.245
Authors: Sofia M E Weiler; Federico Pinna; Thomas Wolf; Teresa Lutz; Aman Geldiyev; Carsten Sticht; Maria Knaub; Stefan Thomann; Michaela Bissinger; Shan Wan; Stephanie Rössler; Diana Becker; Norbert Gretz; Hauke Lang; Frank Bergmann; Vladimir Ustiyan; Tatiana V Kalin; Stephan Singer; Ju-Seog Lee; Jens U Marquardt; Peter Schirmacher; Vladimir V Kalinichenko; Kai Breuhahn Journal: Gastroenterology Date: 2017-02-27 Impact factor: 22.682
Authors: Michelle Z Xu; Tzy-Jyun Yao; Nikki P Y Lee; Irene O L Ng; Yuk-Tat Chan; Lars Zender; Scott W Lowe; Ronnie T P Poon; John M Luk Journal: Cancer Date: 2009-10-01 Impact factor: 6.860