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SALL4 is a new target in endometrial cancer

Oncogene volume 34, pages 63–72 (2015)Cite this article

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Abstract

Aggressive cancers and embryonic stem (ES) cells share a common gene expression signature. Identifying the key factors/pathway(s) within this ES signature responsible for the aggressiveness of cancers can lead to a potential cure. In this study, we find that SALL4, a gene involved in the maintenance of ES cell self-renewal, is aberrantly expressed in 47.7% of primary human endometrial cancer samples. It is not expressed in normal or hyperplastic endometrial. More importantly, SALL4 expression is positively correlated with worse patient survival and aggressive features such as metastasis in endometrial carcinoma. Further functional studies have shown that loss of SALL4 inhibits endometrial cancer cell growth in vitro and tumorigenicity in vivo, as a result of inhibition of cell proliferation and increased apoptosis. In addition, downregulation of SALL4 significantly impedes the migration and invasion properties of endometrial cancer cells in vitro and their metastatic potential in vivo. Furthermore, manipulation of SALL4 expression can affect drug sensitivity of endometrial cancer cells to carboplatin. Moreover, we show that SALL4 specifically binds to the c-Myc promoter region in endometrial cancer cells. While downregulation of SALL4 leads to a decreased expression of c-Myc at both protein and mRNA levels, ectopic SALL4 overexpression causes increased c-Myc protein and mRNA expression, indicating that c-Myc is one of the SALL4 downstream targets in endometrial tumorigenesis. In summary, we are the first to demonstrate that SALL4 has functional role(s) in metastasis and drug resistance in aggressive endometrial cancer. As a consequence of its functional roles in cancer cell and absence in normal tissue, SALL4 is a potential novel therapeutic target for the high-risk endometrial cancer patient population.

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Acknowledgements

This work was supported in part through NIH grants PO1DK080665, NIH RO1HL092437, and PO1HL095489 (to LC). We also thank Nicole Tenen and Joline Lim in assisting with the preparation of the manuscript and Xi Tian in helping with mouse work.

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Authors and Affiliations

  1. Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    A Li, Y Jiao, F Wang, C Gao, P Tang & L Chai

  2. Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, Singapore, Singapore

    K J Yong, S Srivastava, H Yang & D G Tenen

  3. Department of Clinical Laboratory, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China

    F Wang

  4. Department of Pathology, National University Health System and National University of Singapore, Singapore, Singapore

    B Yan & G S D Lim

  5. Harvard Stem Cell Institute, Center for Life Science, Boston, MA, USA

    D G Tenen

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  1. A Li
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Correspondence to L Chai.

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Li, A., Jiao, Y., Yong, K. et al. SALL4 is a new target in endometrial cancer. Oncogene 34, 63–72 (2015). https://doi.org/10.1038/onc.2013.529

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