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

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