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Sorcin silencing inhibits epithelial-to-mesenchymal transition and suppresses breast cancer metastasis in vivo

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Abstract

Sorcin, a 22-kDa calcium-binding protein, renders cancer cells resistant to chemotherapeutic agents, thus playing an important role in multidrug resistance. As there is a clear association between drug resistance and an aggressive phenotype, we asked whether sorcin affects also the motility, invasion, and stem cell characteristics of cancer cells. We have used both RNA interference (transient and stable expression of hairpins) and a lentiviral expression vector to experimentally modulate sorcin expression in a variety of cells. We demonstrate that sorcin depletion in MDA-MB-231 breast cancer cells reduces the pool of CD44+/CD24− and ALDH1high cancer stem cells (CSCs) as well as mammosphere-forming capacity. We also observe that sorcin regulates epithelial-mesenchymal transition and CSCs partly through E-cadherin and vascular endothelial growth factor expression. This leads to the acquisition of an epithelial-like phenotype, attenuating epithelial-mesenchymal transition and suppression of metastases in nude mice. The sorcin-depleted phenotype can also be reproduced in lung adenocarcinoma A549 cells and lung fibrosarcoma HT1080 cells. In addition, overexpression of sorcin in MCF7 cells, which have low endogenous sorcin expression levels, increases their migration and invasion in vitro. This offers the rationale for the development of therapeutic strategies down-regulating sorcin expression for the treatment of cancer.

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Acknowledgments

YH acknowledges support from the China Scholarship Council to visit Imperial College London. We thank S. Raguz (Medical Research Council, UK) for her advice on lentiviral expression. This work was supported by Grants from Natural Science Foundation of China (Grant numbers 30873091, 30971291, and 81170512); Natural Science Foundation of Tianjin (Grant number. 05YFGZGX02800); and National Science and Technology Major Project (Grant number 2012ZX09102301-015).

Conflict of interest

The authors declare no conflict of interest. The experiments described in the manuscript comply with the current laws of the countries in which they were performed.

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Authors and Affiliations

  1. State Key Laboratory of Experimental Hematology, Department of Pharmacy, Institute of Hematology & Hospital of Blood Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China

    Yunhui Hu, Shuangjing Li, Ming Yang, Cihui Yan, Dongmei Fan, Yuan Zhou, Yanjun Zhang & Dongsheng Xiong

  2. Division of Cancer, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London, W12 0NN, UK

    Yunhui Hu & Ernesto Yagüe

  3. Department of Breast Cancer, China Tianjin Breast Cancer Prevention, Treatment and Research Center, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300020, China

    Yunhui Hu

  4. Liaocheng People’s Hospital, Liaocheng, 252000, Shandong, China

    Shuangjing Li

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  1. Yunhui Hu
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  2. Shuangjing Li
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  3. Ming Yang
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Correspondence to Ernesto Yagüe or Dongsheng Xiong.

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Yunhui Hu and Shuangjing Li contributed equally to this work.

Senior corresponding authors, Ernesto Yagüe and Dongsheng Xiong contributed equally.

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Hu, Y., Li, S., Yang, M. et al. Sorcin silencing inhibits epithelial-to-mesenchymal transition and suppresses breast cancer metastasis in vivo. Breast Cancer Res Treat 143, 287–299 (2014). https://doi.org/10.1007/s10549-013-2809-2

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