Ya-Wen Lin1, Chun-Ming Tsao, Pei-Ning Yu, Yu-Lueng Shih, Chia-Hsin Lin, Ming-De Yan. 1. Department and Graduate Institute of Microbiology and Immunology, National Defense Medical Center, Taipei, Taiwan, ROC; Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan, ROC. Electronic address: ndmc.yawen@msa.hinet.net.
Abstract
OBJECTIVE: Abnormal activation of the Wnt/β-catenin signaling pathway is common in human cancers, including cervical cancer. Many papers have shown that SRY (sex-determining region Y)-box (SOX) family genes serve as either tumor suppressor genes (TSGs) or oncogenes by regulating the Wnt signaling pathway in different cancers. We have demonstrated recently that epigenetic silencing of SOX1 gene occurs frequently in cervical cancer. However, the possible role of SOX1 in cervical cancer remains unclear. This study aimed to explore whether SOX1 functions as a TSG in cervical cancer. METHODS: We established a constitutive and an inducible system that overexpressed SOX1 and monitored its function by in vitro experiments. To confirm SOX1 function, we manipulated SOX1 using an inducible expression approach in cell lines. The effect of SOX1 on tumorigenesis was also analyzed in animal models. RESULTS: Overexpression of SOX1 inhibited cell proliferation, anchorage independency, and invasion in vitro. SOX1 suppressed tumor growth in nonobese diabetic/severe combined immunodeficiency mice. After induction of SOX1 by doxycycline (DOX), SOX1 inhibited cell growth and invasion in the inducible system. Repression of SOX1 by withdrawal of DOX partially reversed the malignant phenotype in cervical cells. SOX1 inhibited TCF-dependent transcriptional activity and the Wnt target genes. SOX1 also repressed the invasive phenotype by regulating the expression of invasion-related genes. CONCLUSIONS: Taken together, these data suggest that SOX1 can function as a tumor suppressor partly by interfering with Wnt/β-catenin signaling in cervical cancer.
OBJECTIVE: Abnormal activation of the Wnt/β-catenin signaling pathway is common in humancancers, including cervical cancer. Many papers have shown that SRY (sex-determining region Y)-box (SOX) family genes serve as either tumor suppressor genes (TSGs) or oncogenes by regulating the Wnt signaling pathway in different cancers. We have demonstrated recently that epigenetic silencing of SOX1 gene occurs frequently in cervical cancer. However, the possible role of SOX1 in cervical cancer remains unclear. This study aimed to explore whether SOX1 functions as a TSG in cervical cancer. METHODS: We established a constitutive and an inducible system that overexpressed SOX1 and monitored its function by in vitro experiments. To confirm SOX1 function, we manipulated SOX1 using an inducible expression approach in cell lines. The effect of SOX1 on tumorigenesis was also analyzed in animal models. RESULTS: Overexpression of SOX1 inhibited cell proliferation, anchorage independency, and invasion in vitro. SOX1 suppressed tumor growth in nonobese diabetic/severe combined immunodeficiencymice. After induction of SOX1 by doxycycline (DOX), SOX1 inhibited cell growth and invasion in the inducible system. Repression of SOX1 by withdrawal of DOX partially reversed the malignant phenotype in cervical cells. SOX1 inhibited TCF-dependent transcriptional activity and the Wnt target genes. SOX1 also repressed the invasive phenotype by regulating the expression of invasion-related genes. CONCLUSIONS: Taken together, these data suggest that SOX1 can function as a tumor suppressor partly by interfering with Wnt/β-catenin signaling in cervical cancer.