MicroRNA-200 family governs ovarian inclusion cyst formation and mode of ovarian cancer spread

• Published in: Oncogene Vol. 39; no. 20; pp. 4045 - 4060
• Main Authors: Choi, Pui-Wah, So, Wai Wing, Yang, Junzheng, Liu, Shubai, Tong, Ka Kui, Kwan, Kin Ming, Kwok, Jamie S.-L., Tsui, Stephen K. W., Ng, Shu-Kay, Hales, Karen H., Hales, Dale B., Welch, William R., Crum, Christopher P., Fong, Wing-Ping, Berkowitz, Ross S., Ng, Shu-Wing
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 14-05-2020; Nature Publishing Group
• Subjects: 14/19; 14/32; 38; 42/109; 42/89; 631/67; 631/67/1517; 82/51; 82/80; 96/106; 96/95; Apoptosis; Biotechnology industry; Bone morphogenetic proteins; Cancer; Carcinogenesis; Carcinogenesis - genetics; Carcinogenesis - metabolism; Carcinogenesis - pathology; Cell activation; Cell Biology; Cell culture; Cysts; Development and progression; E-cadherin; Epidemiology; Estrogen; Estrogens; Female; Gene expression; Gene Expression Regulation, Neoplastic; Genes; Human Genetics; Humans; Hypoxia; Internal Medicine; Medicine; Medicine & Public Health; Mesenchyme; MicroRNA; MicroRNAs; MicroRNAs - biosynthesis; MicroRNAs - genetics; miRNA; Myosin; Oncology; Oncology, Experimental; Ovarian cancer; Ovarian Cysts - genetics; Ovarian Cysts - metabolism; Ovarian Cysts - pathology; Ovarian Neoplasms - genetics; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Ovulation; Phosphorylation; RNA, Neoplasm - biosynthesis; RNA, Neoplasm - genetics; Scientific equipment and supplies industry; Stem cells; Transforming growth factors; California; United States; Massachusetts; China
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-020-1264-x

Epidemiologic and histopathologic findings and the laying hen model support the long-standing incessant ovulation hypothesis and cortical inclusion cyst involvement in sporadic ovarian cancer development. MicroRNA-200 (miR-200) family is highly expressed in ovarian cancer. Herewith, we show that ovarian surface epithelial (OSE) cells with ectopic miR-200 expression formed stabilized cysts in three-dimensional (3D) organotypic culture with E-cadherin fragment expression and steroid hormone pathway activation, whereas ovarian cancer 3D cultures with miR-200 knockdown showed elevated TGF-β expression, mitotic spindle disorientation, increased lumenization, disruption of ROCK-mediated myosin II phosphorylation, and SRC signaling, which led to histotype-dependent loss of collective movement in tumor spread. Gene expression profiling revealed that epithelial–mesenchymal transition and hypoxia were the top enriched gene sets regulated by miR-200 in both OSE and ovarian cancer cells. The molecular changes uncovered by the in vitro studies were verified in both human and laying hen ovarian cysts and tumor specimens. As miR-200 is also essential for ovulation, our results of estrogen pathway activation in miR-200-expressing OSE cells add another intriguing link between incessant ovulation and ovarian carcinogenesis.