The tumor suppressor LKB1 antagonizes WNT signaling pathway through modulating GSK3[beta] activity in cell growth of esophageal carcinoma

• Published in: Tumor biology 2014-02, Vol.35 (2), p.995
• Main Authors: Liu, Kai, Luo, Yue, Tian, Hui, Yu, Kai-zhong, He, Jin-xian, Shen, Wei-yu
• Format: Article
• Language: English
• Subjects: Cellular biology; Esophageal cancer; Gene expression
• ISSN: 1010-4283; 1423-0380
• DOI: 10.1007/s13277-013-1133-0

The tumor suppressor LKB1 gene encodes a serine-threonine kinase that regulates cell proliferation and polarity. Inactivation of LKB1 by mutations in LKB1 or loss of its expression is highly correlated with lung, ovarian, and pancreatic cancers, and WNT/[beta]-catenin pathway is also known to be involved in many human malignancies. However, the relationship between LKB1 and WNT signaling pathway in esophageal carcinoma remains unknown. The expression of LKB1 in 62 cases of esophageal cancer patients was determined by quantitative real-time PCR. It was found that LKB1 mRNA level was significantly lower than the adjacent normal epithelium and that the LKB1 downregulation was correlating with TNM stages. Moreover, the expression of WNT target genes such as Cyclin D1, C-MYC, MMP2, and FZD2 was significantly upregulated in esophageal cancer tissues. LKB1 overexpression in TE10 cells inhibited TOPFlash luciferase reporter activity and WNT target gene expression even in the presence of WNT3A. Conversely, LKB1 knockdown enhanced WNT signaling activity in esophageal cancer cells. It was also found that LKB1 antagonized WNT signaling pathway through interaction with GSK3[beta] to downregulate [beta]-catenin expression level. Functional investigation revealed that LKB1 suppressed the promotion effects of WNT3A on the cell growth of TE10 cells. The LKB1 functions in regulating cell growth and WNT target genes expression were impaired by GSK3[beta] inhibition, suggesting that LKB1 antagonized WNT-induced cell proliferation through enhancement of GSK3[beta] activity. Together, the interaction between LKB1 and GSK3[beta] upregulates GSK3[beta] activity to suppress WNT-induced cell proliferation in esophageal carcinoma cells. Loss of LKB1 expression may result in the deregulation of WNT/[beta]-catenin pathway to promote malignant progression of esophageal cancer.[PUBLICATION ABSTRACT]