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.