2. Academic Validation
  3. SIPA1 enhances SMAD2/3 expression to maintain stem cell features in breast cancer cells

SIPA1 enhances SMAD2/3 expression to maintain stem cell features in breast cancer cells

  • Stem Cell Res. 2020 Dec;49:102099. doi: 10.1016/j.scr.2020.102099.
Ning Wang 1,  Jun Weng 1,  Jing Xia 1,  Yangjin Zhu 1,  Qiongrong Chen 2,  Die Hu 1,  Xue Zhang 3,  Rui Sun 4,  Jueping Feng 4,  Nagahiro Minato 5,  Yiping Gong 6,  Li Su 7
Affiliations

Affiliations

  • 1 Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China.
  • 2 Department of Pathology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China.
  • 3 Department of Breast Surgery, Renmin Hospital of Wuhan University, Wuhan University, Wuhan 430060, China.
  • 4 Department of Oncology, Puai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430034, China.
  • 5 Department of Immunology and Cell Biology, Graduate School of Medicine, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan.
  • 6 Department of Breast Surgery, Renmin Hospital of Wuhan University, Wuhan University, Wuhan 430060, China; Department of Breast Surgery, Hubei Cancer Hospital, Wuhan 430079, China. Electronic address: gyp@medmail.com.cn.
  • 7 Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China. Electronic address: lisu@hust.edu.cn.
PMID: 33296812 DOI: 10.1016/j.scr.2020.102099
Abstract

SIPA1, a GTPase activating protein that negatively regulates Ras-related protein (Rap), is a potential modulator of tumor metastasis and recurrence. In this study, we first showed that SIPA1 facilitated the stemness features of breast Cancer cells, such as of tumorsphere formation capability and the expression of stemness marker CD44. In addition, SIPA1 promoted the expression of four stemness-associated transcription factors through increasing the expression of SMAD2 and SMAD3 in vitro and in vivo. The stemness features were abolished by blocking the phosphorylation of SMAD3 with its specific inhibitor SIS3. Furthermore, SIPA1 decreased the breast Cancer cell sensitivity to chemotherapy drugs. This effect was, however, competitively reversed by blocking the SMAD3 phosphorylation by SIS3 treatment in breast Cancer cells. Taken together, SIPA1 promotes and sustains the stemness of breast Cancer cells and their resistance to chemotherapy by increasing the expression of SMAD2 and SMAD3, and blocking SMAD3 phosphorylation could suppress the Cancer cell stemness and increase the sensitivity to chemotherapy in breast Cancer cells expressing a high level of SIPA1.

Keywords

Breast cancer; CD44; Cancer stem cell; SIPA1; SMADs.

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