Zhibin Liao1,2, Lin Chen1,2, Xuewu Zhang1,2, Hongwei Zhang1,2, Xiaolong Tan1,2, Keshuai Dong1,2, Xun Lu1,2, He Zhu1,2, Qiumeng Liu1,2, Zhanguo Zhang1,2, Zeyang Ding1,2, Wei Dong1,2, Peng Zhu1,2, Liang Chu1,2, Huifang Liang1,2, Pran K Datta3,4, Bixiang Zhang1,2,5,6,7, Xiaoping Chen1,2,5,6,7. 1. Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. 2. Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China. 3. Division of Hematology and Oncology, Department of Medicine, UAB Comprehensive Cancer Center, Birmingham, AL. 4. Birmingham Veterans Affairs Medical Center, Birmingham, AL. 5. Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, China. 6. Key Laboratory of Organ Transplantation, National Health Commission, Wuhan, China. 7. Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China.
Abstract
BACKGROUND AND AIMS: Transforming growth factor beta (TGF-β) suppresses early stages of tumorigenesis, but contributes to the migration and metastasis of cancer cells. However, the role of TGF-β signaling in invasive prometastatic hepatocellular carcinoma (HCC) is poorly understood. In this study, we investigated the roles of canonical TGF-β/mothers against decapentaplegic homolog 3 (SMAD3) signaling and identified downstream effectors on HCC migration and metastasis. APPROACH AND RESULTS: By using in vitro trans-well migration and invasion assays and in vivo metastasis models, we demonstrated that SMAD3 and protein tyrosine phosphatase receptor epsilon (PTPRε) promote migration, invasion, and metastasis of HCC cells in vitro and in vivo. Further mechanistic studies revealed that, following TGF-β stimulation, SMAD3 binds directly to PTPRε promoters to activate its expression. PTPRε interacts with TGFBR1/SMAD3 and facilitates recruitment of SMAD3 to TGFBR1, resulting in a sustained SMAD3 activation status. The tyrosine phosphatase activity of PTPRε is important for binding with TGFBR1, recruitment and activation of SMAD3, and its prometastatic role in vitro. A positive correlation between pSMAD3/SMAD3 and PTPRε expression was determined in HCC samples, and high expression of SMAD3 or PTPRε was associated with poor prognosis of patients with HCC. CONCLUSIONS: PTPRε positive feedback regulates TGF-β/SMAD3 signaling to promote HCC metastasis.
BACKGROUND AND AIMS: Transforming growth factor beta (TGF-β) suppresses early stages of tumorigenesis, but contributes to the migration and metastasis of cancer cells. However, the role of TGF-β signaling in invasive prometastatic hepatocellular carcinoma (HCC) is poorly understood. In this study, we investigated the roles of canonical TGF-β/mothers against decapentaplegic homolog 3 (SMAD3) signaling and identified downstream effectors on HCC migration and metastasis. APPROACH AND RESULTS: By using in vitro trans-well migration and invasion assays and in vivo metastasis models, we demonstrated that SMAD3 and protein tyrosine phosphatase receptor epsilon (PTPRε) promote migration, invasion, and metastasis of HCC cells in vitro and in vivo. Further mechanistic studies revealed that, following TGF-β stimulation, SMAD3 binds directly to PTPRε promoters to activate its expression. PTPRε interacts with TGFBR1/SMAD3 and facilitates recruitment of SMAD3 to TGFBR1, resulting in a sustained SMAD3 activation status. The tyrosine phosphatase activity of PTPRε is important for binding with TGFBR1, recruitment and activation of SMAD3, and its prometastatic role in vitro. A positive correlation between pSMAD3/SMAD3 and PTPRε expression was determined in HCC samples, and high expression of SMAD3 or PTPRε was associated with poor prognosis of patients with HCC. CONCLUSIONS: PTPRε positive feedback regulates TGF-β/SMAD3 signaling to promote HCC metastasis.
Authors: Qian Yun Ge; Jin Chen; Gan Xun Li; Xiao Long Tan; Jia Song; Deng Ning; Jie Mo; Peng Cheng Du; Qiu Meng Liu; Hui Fang Liang; Ze Yang Ding; Xue Wu Zhang; Bi Xiang Zhang Journal: Clin Transl Med Date: 2021-11