Smad inhibitor induces CSC differentiation for effective chemosensitization in cyclin D1- and TGF-β/Smad-regulated liver cancer stem cell-like cells
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Wei Xia1, Chung Mau Lo1, Randy Y.C. Poon2, Tan To Cheung1, Albert C.Y. Chan1, Lin Chen1, Sitian Yang1, George S.W. Tsao3 and Xiao Qi Wang1,4
1Department of Surgery, The University of Hong Kong, Hong Kong, China
2Division 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
3School of Biomedical Sciences, The University of Hong Kong, Hong Kong, China
4State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, China
Xiao Qi Wang, email: firstname.lastname@example.org
George S.W. Tsao, email: email@example.com
Keywords: cyclin D1, Smad2/3/Smad4, cancer stem cells, Smad inhibitor, chemosensitization
Received: November 02, 2016 Accepted: March 09, 2017 Published: March 21, 2017
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.
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