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Carcinogenesis Advance Access published online on September 16, 2008
Carcinogenesis, doi:10.1093/carcin/bgn215
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Tumor suppressor effect of follistatin-like 1 in ovarian and endometrial carcinogenesis – a differential expression and functional analysis

Queeny K.Y. CHAN1, Hextan Y.S. Ngan2, Philip P.C. Ip1, Vincent W.S. Liu2, W.C. Xue1 and Annie N.Y. Cheung1

1 Department of Pathology, The University of Hong Kong
2 Department of Obstetrics & Gynecology, The University of Hong Kong

Author for correspondence and requests for reprints: Annie N.Y. Cheung, MD., FRCPath., Department of Pathology, the University of Hong Kong, Queen Mary Hospital, Pokfulam Road, Hong Kong, China. Telephone: (852) 2855 4876 Fax: (852) 2872 5197, Email: anycheun{at}hkucc.hku.hk

Endometrial and ovarian cancers are the most common and the most lethal gynecologic malignancies worldwide, respectively. By performing differential expression analysis using annealing control primerTM-based reverse transcription-polymerase chain reaction (RT-PCR) on pooled cDNA from 45 endometrial and 36 ovarian cancers and their non-tumor samples, reduced expression of the follistatin-like 1 (FSTL1) was identified. Down-regulation of FSTL1 was further confirmed on individual samples and cell lines by quantitative real-time RT-PCR and western blotting. For in vitro functional study, full length cDNA of FSTL1 was cloned and transiently transfected into the ovarian cancer cell line Ovca420 and endometrial cancer cell line AN3CA. MTT assay and cell count demonstrated significantly slower proliferation rate. By TUNEL and flow cytometric analysis, higher apoptotic activity and a remarkable increase in sub-G1 cell population was observed in transfected cells, suggesting that FSTL1 induced apoptosis in cancer cells. Subsequent mRNA and protein expression analysis on downstream apoptotic molecules revealed up-regulation and/or activation of FAS, FASLG, TRADD, Caspase-3, Caspase-7 and PARP by FSTL1 transfection, suggesting that FSTL1-induced apoptosis may be initiated mainly by FAS/FASLG death receptor-ligand binding. Cell migration and invasion assays demonstrated a remarkably lower cell migration and invasion capability in FSTL1-transfected cells in relation to down-regulation of MMP-2. Our findings suggested a tumor suppressor role of FSTL1 may be important in ovarian and endometrial carcinogenesis.

Key Words: follistatin-like 1 • ovarian • endometrial

Received May 5, 2008; revised September 6, 2008; accepted September 7, 2008.


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