Klotho Inhibits Proliferation in a RET Fusion Model of Papillary Thyroid Cancer by Regulating the Wnt/β-Catenin Pathway

Cancer Manag Res. 2021 Jun 17;13:4791-4802. doi: 10.2147/CMAR.S295086. eCollection 2021.

ABSTRACT

PURPOSE: We aimed to investigate the mechanisms of action on Klotho that underlie cancer development in RET fusion models of human papillary thyroid cancer (PTC).

MATERIALS AND METHODS: Normal Nthy-ori 3-1 thyroid cells and two PTC cell lines (BHP10-3 and TPC-1), which were used as RET fusion models of PTC, were used to study Klotho. Klotho expression was analyzed by Western blotting. Klotho overexpression cell lines were constructed using the two types of PTC cells. Cell proliferation and apoptosis were assessed. Western blotting was used to detect the expression of proteins in the Wnt/β-catenin pathway. In addition, an activator and an inhibitor of the Wnt/β-catenin pathway were used to confirm that Klotho regulates the pathway in PTC cells. Mice were used to analyze the in vivo effect of Klotho on tumor growth and the Wnt/β-catenin pathway.

RESULTS: In BHP10-3 and TPC-1 cells, Klotho expression was low. After Klotho overexpression, the cell proliferation was significantly suppressed and apoptosis was significantly increased (p<0.05). Wnt1, β-catenin, and CyclinD1 expression were also significantly decreased after Klotho overexpression (p<0.05). Administration of the Wnt/β-catenin pathway activator attenuated the effect of Klotho overexpression (p<0.05). In vivo, the tumor growth was suppressed, and apoptosis of the cancer cells in the tumors were increased after Klotho overexpression. However, injection of the Wnt/β-catenin pathway activator attenuated the effects of Klotho overexpression.

CONCLUSION: Klotho inhibits cell proliferation in RET fusion models of PTC by inhibiting the Wnt/β-catenin pathway, providing a potential target for developing treatment for PTC.

PMID:34168498 | PMC:PMC8216664 | DOI:10.2147/CMAR.S295086