SOX1 suppresses cell growth and invasion in cervical cancer.
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.
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.
Ya-Wen
YW
Lin
Chun-Ming
CM
Tsao
Pei-Ning
PN
Yu
Yu-Lueng
YL
Shih
Chia-Hsin
CH
Lin
Ming-De
MD
Yan
D000818:Animals; D015703:Antigens, CD; D015820:Cadherins / Q000378:metabolism; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000378:metabolism; D004318:Doxycycline / Q000494:pharmacology; D005260:Female; D005822:Genetic Vectors; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D010957:Plasmids; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D002583:Uterine Cervical Neoplasms / Q000378:metabolism*; D060449:Wnt Signaling Pathway
D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; C490906:SOX1 protein, human; D055748:SOXB1 Transcription Factors; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D019938:Cyclin D1; D004318:Doxycycline
Cervical cancer; SOX1 gene; Wnt/β-catenin signaling pathway