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Deregulation of secreted frizzled-related proteins is associated with aberrant β-catenin activation in the carcinogenesis of oral submucous fibrosis

Authors Zhou S, Chen L, Mashrah M, Zhu Y, Liu J, Yang X, He Z, Wang L, Xiang T, Yao Z, Guo F, Yang W, Zhang CP

Received 30 June 2015

Accepted for publication 1 September 2015

Published 14 October 2015 Volume 2015:8 Pages 2923—2931

DOI https://doi.org/10.2147/OTT.S91460

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Ram Prasad

Peer reviewer comments 2

Editor who approved publication: Prof. Dr. Geoffrey Pietersz


Shanghui Zhou,1 Ling Chen,2 Mubarak Mashrah,1 Yun Zhu,1 Jiannan Liu,1 Xi Yang,1 Zhijing He,3 Lizhen Wang,4 Tingxiu Xiang,2 Zhigang Yao,5 Feng Guo,6 Wenjun Yang,1 Chenping Zhang1

1Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 2Molecular Oncology and Epigenetics Laboratory, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 3Department of Oral and Maxillofacial Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 4Department of Oral Pathology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 5Department of Oral Pathology, Xiangya Stomatological Hospital, 6Department of Oral and Maxillofacial Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China

Abstract: Secreted frizzled-related proteins (SFRPs), the first identified Wnt antagonists, have been well recognized as tumor suppressors in multiple human cancers through suppressing the Wnt/β-catenin pathway. To better elucidate the mechanisms of SFRPs involved in the carcinogenesis of oral submucous fibrosis (OSF), one of the precancerous lesions of oral squamous cell carcinoma (OSCC), we investigated expression and localization of SFRP1, SFRP5, and β-catenin in normal oral epithelium, OSF, and OSCC tissues. We found that SFRP1 and SFRP5 were readily expressed in normal oral mucous tissues but gradually decreased in OSF early, moderately advanced, and advanced tissues and rarely expressed in OSCC tissues. We found the changes of SFRP1 localization and SFRP5 localization from nucleus to cytoplasm in the carcinogenesis of OSF. There is a significant association among reduced SFRP1, SFRP5, and cytoplasmic/nuclear β-catenin expression, which is correlated with higher tumor grade and stage of OSCC. We further found that SFRP1 and SFRP5 were frequently methylated in OSCC cases with betel quid chewing habit but not in normal oral mucous and different stages of OSF tissues, suggesting that methylation of SFRP1 and SFRP5 is tumor specific in the carcinogenesis of OSF. Taken together, our data demonstrated that reduced SFRP1 and SFRP5 by promoter methylation could lead to cytoplasmic/nuclear accumulation of β-catenin and tumor progression. The changes of SFRPs and β-catenin localization, as well as SFRPs’ methylation, could be useful predictors or biomarkers of OSF malignant progression and prognosis.

Keywords: Wnt antagonist, methylation, tumor suppressor gene, Wnt signaling, OSF, OSCC

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