Upregulation of FLT1 activates the TGF-β1/Smad3 pathway to promote iodide resistance in thyroid cancer.

BACKGROUND: The identification of new therapeutic targets for patients with radioiodide resistance differentiated thyroid cancer (DTC) may help improve the prognosis for I131-resistant DTC patients.

OBJECTIVES: To investigate the potential molecular mechanism of FLT-1 in DTC.

METHODS: RNA sequencing data for thyroid cancer in the Cancer Genome. The genes of the tumor samples subjected to I131 radiotherapy were analyzed using the edgeR package. An FLT1-overexpressing plasmid was constructed and a lentivirus was transfected into BHT101 cells. The proliferation, migration, colony formation, invasion and apoptosis were detected by CCK-8 assay, plate cloning, Transwell assay and flow cytometry, respectively. The protein expression of FLT1, NIS, TGF-β1, Smad3, and P-Smad3 was detected using WB. The localization of FOXP3, TGFβ-R1, and p-Smad3 in BHT101 cells was determined with immunofluorescence. A model of subcutaneous tumor formation in BALB/C mice was established to observe the effect of FLT1 on tumor growth.

RESULTS: The expression of FLT1 was increased in thyroid cancer cells not treated with I131. The proliferation, colony formation, migration and invasion of FLT1-overexpressing BHT101 cells were significantly increased. The protein expression of TGFβ1 and p-Smad3 in FLT1-overexpressing thyroid cancer cells was significantly increased, while SMAD3 was not significantly changed. The expression of NIS decreased due to the upregulation of FLT1. FOXP3, TGF-βR1, and p-Smad3 were colocalized in FLT1-overexpressing BHT101 cells. In vivo, tumor volume and tumor weight increased with increasing FLT1 expression.

CONCLUSION: The upregulation of FLT1 can activate the TGF-β1/Smad3 pathway, downregulate the expression of NIS and enhance the function of thyroid cancer cells.