MAEL expression links epithelial-mesenchymal transition and stem cell properties in colorectal cancer Qingguo Li 1,2 *, Ping Wei 2,3 *, Ben Huang 1,2 *, Ye Xu 1,2 , Xinxiang Li 1,2 , Yaqi Li 1,2 , Sanjun Cai 1,2 and Dawei Li 1,2 1 Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China 2 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China 3 Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai 200032, China MAEL plays a central role during spermatogenesis by repressing transposable elements and preventing their mobilisation, however, its role on cancers is unclear. In this study, MAEL expression was analysed in a tissue microarray containing 185 samples of primary colon cancer tumor samples and human colon cancer cell lines. The effect of MAEL on cell proliferation, tumorigenesis, metastasis and drug resistance was examined in vitro and in vivo. Immunoprecipitation assay, confocal immu- nofluorescent analysis and luciferase assay were used for mechanism study. As results, MAEL was significantly upregulated in colon cancer patient tissue samples, and elevated MAEL protein levels positively correlated with overall survival and disease free survival of colon cancer patients. Using in vitro and in vivo models, we demonstrated that MAEL expression was correlat- ed with cell proliferation, invasion and drug resistance of colon cancer cells by inducing epithelial-mesenchymal transition and stemness characteristics. Mechanistically, our study demonstrated that MAEL interacts with Snail and inhibit E-cadherin promoter activity. Collectively, MAEL is an oncogene that plays an important role in the development and progression of colon cancer, which may be a novel potential therapeutic target for colon cancer. Colorectal cancer (CRC) is the third most commonly diag- nosed cancer and the second leading cause of cancer death in men and women combined in the United States. The Ameri- can Cancer Society estimates 139,970 people will be diag- nosed in 2015 and 50,710 will die from colon cancer in the United States. 1 In China, the incidence of CRC has been increasing in recent years as living conditions improve and eating habits change. Fortunately, evidences have shown that the mortality rate of CRC has decreased in Asian countries, possibly due to the early screening and detection, as well as the use of more advanced surgical and systemic modalities. 2 However, a considerable proportion of CRC patients develop recurrence or metastasis within 5 years after surgical treat- ment. 3 To increase the efficacy of CRC therapy, it is impor- tant to identify candidate genes that are essential in cancer cell proliferation and metastasis, which would facilitate tumor detection and recurrence at high sensitivity and specificity rates. The Maelstrom gene (MAEL) was originally identified in Drosophila, and functions in oocyte polarity. 4 In mouse mod- els, the MAEL is only expressed in the male germ line and also is a component of nuage. 5 The human MAEL protein contains a high mobility group domain in its N-terminal seg- ment that is known to mediate DNA binding and a novel MAEL-specific domain in the C-terminal segment. 6 It plays a central role during spermatogenesis by repressing transpos- able elements and preventing their mobilisation, which is essential for the germline integrity. 7 In normal condition, expression of MAEL can only be detected in the testis, whereas its abnormal expression has been observed in various cancer tissues and cell lines. 8–11 However, its role on cancers is rather controversial. MAEL have a repressive effect on cell invasiveness in epithelial ovarian cancer, 11 whereas, it acts as an oncogene and plays an important role in the development and progression of hepatocellular carcinoma. 9 Xiao et al. Key words: MAEL, colorectal cancer, epithelial-mesenchymal transi- tion, stemness Abbreviations: CRC: colorectal cancer; DFS: disease free survival; EMT: epithelial-mesenchymal transition; MAEL: Maelstrom gene; OS: overall survival; TMA: tissue microarray Additional Supporting Information may be found in the online version of this article. *Q.L., P.W. and B.H. contributed equally to this work Conflict of Interest: We declare that we have no conflicts of interest. Grant sponsor: National Science Foundation of China; Grant numbers: 81372646 and 81101586; Grant sponsor: National Key Basic Research Program of China; Grant number: 2014CBA02002 DOI: 10.1002/ijc.30388 History: Received 23 Feb 2016; Accepted 10 Aug 2016; Online 18 Aug 2016 Correspondence to: Dawei Li, MD, PhD, Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University.No.270 Dong’an Road, Xuhui District, Shanghai 20032, China, Tel.: 86-021- 64175590, E-mail: davidleehero@126.com or Sanjun Cai, MD, PhD, Department of Colorectal Surgery, Fudan University Shanghai Can- cer Center, Department of Oncology, Shanghai Medical College, Fudan University.No.270 Dong’an Road, Xuhui District, Shanghai 20032, China, Tel.: 86-021-64175590, E-mail: caisanjun_sh@163.com Cancer Genetics and Epigenetics Int. J. Cancer: 139, 2502–2511 (2016) V C 2016 UICC International Journal of Cancer IJC