Quercetin upregulates TLE4 to block the Wnt/β-catenin signaling pathway and inhibit cell migration and invasion of cervical cancer cells.

METHODS

Using established TLE4-overexpression and CRISPR-Cas9-knockout cervical cancer cell lines and nude mouse tumorigenesis models, we verified the biological function and regulatory mechanism of TLE4 in cervical cancer.

RESULTS

Quercetin treatment upregulated the expression of TLE4 in HeLa cells. Compared with normal cervical tissues from clinical specimens, the expression of TLE4 in the nucleus of cervical cancer tissues was significantly downregulated. Transwell assays showed that the migration and invasion of C-33A TLE4-overexpression cells were significantly suppressed, accompanied by an upregulation of the expression of E-cadherin and a downregulation of the expression of N-cadherin, Vimentin, and Snail. Conversely, the migration and invasion of Ca Ski TLE4-knockout cells were significantly enhanced, and the expressions of these EMT-related markers showed the opposite trend. Meanwhile, the in vivo xenograft experiment revealed that the Ca Ski TLE4-knockout group exhibited faster tumor growth compared with the wild-type group. Furthermore, we examined the role of TLE4 in the Wnt/β-catenin signaling pathway. In C-33A TLE4-overexpression cells, β-catenin, TCF-1, TCF-4, CyclinD1, c-Myc, and MMP-7 were decreased, p-β-catenin expression was increased, whereas in Ca Ski TLE4-knockout cells, the expression trends of these factors were opposite. After treating TLE4-knockout Ca Ski cells with quercetin, the enhanced migration and invasion capabilities induced by TLE4 knockout were effectively reversed.

CONCLUSION

Quercetin targets and upregulates the expression of TLE4, which inhibits the migration and invasion of cervical cancer cells by blocking the Wnt/β-catenin signaling pathway, thereby providing theoretical and experimental evidence for quercetin therapy in cervical cancer.