| 摘要: | Thyroid hormone status has long been implicated in cancer development. Here I investigated the role of T4 in APC wild type/mutant colorectal cancer cell lines HCT 116, HT-29, and SW480, as well as the primary cultures of cancer cells derived from colorectal cancer patients. Cell proliferation was evaluated with standard assay and proliferation marker expression. β-catenin activation was examined according to nuclear β-catenin accumulation and β-catenin target gene expression. Meanwhile, possible mechanisms regarding the phosphorylation status of β-catenin pathway components, the association between β-catenin and its destruction complex, as well as the expression profile of β-catenin upstream regulators under T4 influence were initially inspected. The results showed that T4 increased colorectal cancer cell proliferation while cell number/viability, as well as the transcriptions of proliferative genes PCNA, CCND1 and c-Myc were elevated by T4 in both established cell lines and primary cells. Moreover, T4 induced nuclear β-catenin accumulation, as well as the levels of cyclin D1, c-Myc, β-catenin itself, and a newly-presented target HMGA2 within cells, whereas T3 might exert discrete function. The T4-mediated gene expression could be averted by the knockdown of β-catenin. Furthermore, the resulting activation of β-catenin might engage both Wnt-dependent and Wnt-independent signalling, which possibly initiated by the crosstalk between integrin αvβ3 and IGF-1R. The expression of oncogenes including TRβ and HIF1α were also enhanced due to T4 exposure. Last of all, these T4 behaviours in colorectal cancer could be, at least in part, deterred by T4 analogue tetrac. These data suggested that T4 promotes β-catenin activation/cell proliferation in colorectal cancer and might play additional parts in tumour progression. This indicates that the complex networks of thyroid hormones and an applicable therapeutic strategy in colorectal cancer require further exploration. |
