Smad inhibitor induces CSC differentiation for effective chemosensitization in cyclin D1- and TGF-β/Smad-regulated liver cancer stem cell-like cells
| Autor: | Randy Yat Choi Poon, Sitian Yang, Wei Xia, Lin Chen, Tan To Cheung, Chung Mau Lo, Xiao Qi Wang, Albert C. Y. Chan, George S.W. Tsao |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Male cancer stem cells Carcinoma Hepatocellular Population cyclin D1 Antineoplastic Agents Apoptosis SMAD Mice SCID Smad2 Protein 03 medical and health sciences Mice Cyclin D1 Chemosensitization Cancer stem cell Transforming Growth Factor beta medicine Biomarkers Tumor Tumor Cells Cultured Animals Humans Smad2/3/Smad4 education Cyclin Cell Proliferation Smad4 Protein education.field_of_study business.industry Liver Neoplasms Smad inhibitor Cell Differentiation medicine.disease Prognosis Xenograft Model Antitumor Assays chemosensitization 030104 developmental biology Oncology Drug Resistance Neoplasm Immunology Cancer research Neoplastic Stem Cells Stem cell Liver cancer business Signal Transduction Research Paper |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | // Wei Xia 1 , Chung Mau Lo 1 , Randy Y.C. Poon 2 , Tan To Cheung 1 , Albert C.Y. Chan 1 , Lin Chen 1 , Sitian Yang 1 , George S.W. Tsao 3 and Xiao Qi Wang 1, 4 1 Department of Surgery, The University of Hong Kong, Hong Kong, China 2 Division of Life Science, Center for Cancer Research, and State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Hong Kong, China 3 School of Biomedical Sciences, The University of Hong Kong, Hong Kong, China 4 State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, China Correspondence to: Xiao Qi Wang, email: xqwang@hku.hk George S.W. Tsao, email: gswtsao@hku.hk Keywords: cyclin D1, Smad2/3/Smad4, cancer stem cells, Smad inhibitor, chemosensitization Received: November 02, 2016 Accepted: March 09, 2017 Published: March 21, 2017 ABSTRACT Understanding cancer stem cell (CSC) maintenance pathways is critical for the development of CSC-targeting therapy. Here, we investigated the functional role of the cyclin D1-dependent activation of Smad2/3 and Smad4 in hepatocellular carcinoma (HCC) CSCs and in HCC primary tumors. Cyclin D1 sphere-derived xenograft tumor models were employed to evaluate the therapeutic effects of a Smad inhibitor in combination with chemotherapy. Cyclin D1 overexpression confers stemness properties by enhancing single sphere formation, enhancing the CD90+ and EpCAM+ population, increasing stemness gene expression, and increasing chemoresistance. Cyclin D1 interacts with and activates Smad2/3 and Smad4 to result in cyclin D1-Smad2/3-Smad4 signaling-regulated liver CSC self-renewal. The cyclin D1-dependent activation of Smad2/3 and Smad4 is also found in HCC patients and predicts disease progression. A Smad inhibitor impaired cyclin D1-Smad-mediated self-renewal, resulting in the chemosensitization. Thus, pretreatment with a Smad inhibitor followed by chemotherapy not only successfully suppressed tumor growth but also eliminated 57% of the tumors in a cyclin D1 sphere-derived xenograft model. Together, The cyclin D1-mediated activation of Smad2/3 and Smad4 is an important regulatory mechanism in liver CSC self-renewal and stemness. Accordingly, a Smad inhibitor induced CSC differentiation and consequently significant chemosensitization, which could be an effective strategy to target CSCs. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|