Loss of calponin h1 confers anoikis resistance and tumor progression in the development of high-grade serous carcinoma originating from the fallopian tube epithelium
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Kai-Hung Wang1,2, Sung-Chao Chu3 and Tang-Yuan Chu1,2,4
1Department of Research, Center for Prevention of Gynecological Cancer, Buddhist Tzu Chi General Hospital, Hualien, Taiwan
2Institute of Medical Sciences, Tzu Chi University, Hualien, Taiwan
3Department of Hematology and Oncology, Buddhist Tzu Chi General Hospital, Hualien, Taiwan
4Department of Obstetrics and Gynecology, Buddhist Tzu Chi General Hospital, Hualien, Taiwan
Tang-Yuan Chu, email: [email protected]
Keywords: fallopian tube epithelium, high-grade serous carcinoma (HGSC), ovarian cancer, Calponin h1 (CNN1), anoikis
Received: September 02, 2016 Accepted: May 08, 2017 Published: May 19, 2017
Increasing evidence indicates that ovarian high-grade serous carcinoma (HGSC) originates from the fallopian tube epithelium and metastasizes to the ovary as the secondary site. A working hypothesis is that detached tubal HGSC cells survive anoikis and implant on the ovary. In this study, we found that downregulation of calponin h1 (CNN1) is necessary for the anoikis survival and cell transformation. CNN1 was progressively downregulated in cells and tissues representing different stages of HGSC development from fallopian tube epithelium (FTE). Knock down of CNN1 in immortalized human FTE cells conferred gains of resistance to anoikis and transformation phenotypes including anchorage independent growth (AIG) and xenograft tumorigenesis in NSG mice. Conversely, overexpression of CNN1 in RAS-transformed FTE cells resulted in an almost complete loss of AIG and tumorigenesis. Besides, there was a dramatic change of cell morphology from a polygonal, raised appearance to a round and flattened one. Increase in cell adhesion to laminin and collagen, and reduction in cell motility, anoikis resistance and invasiveness were also observed. A microarray analysis revealed upregulation of genes involved in cytoskeleton stabilization and signal transduction, and downregulation of genes involved in cytokine and chemokine activities. The study disclosed multiple tumor suppressor roles of CNN1 in the development of HGSC from the fallopian tube, and loss of CNN1 expression is crucial for its metastasis to a new site.
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