HIF-1α Promotes The Invasion And Metastasis Of Thyroid Cancer

Objective To investigate the effect of hypoxia-inducible factor-1α oninvasion and metastasis of undifferentiated thyroid carcinoma and papillarythyroid carcinoma, and the involved possible molecular mechanism.Methods When treated with hypoxia (5%O2) for0h,2h,4h,8h,12h,the morphology of undifferentiated thyroid carcinoma FRO cells wasobserved under microscope, and the protein expression levels of HIF-1α,Snail, E-cadherin, Vimentin and MMP2in treated cells were detected byWestern blotting. FRO cells were divided into five groups: normoxia group,the YC-1+normoxia group, hypoxia group, the YC-1+hypoxia group，andthe normoxia+CoCl2group. HIF-1α, Snail, and EMT-associated proteinexpression of the above five groups were detected by Western blotting. Thecell migration ability and invasion potential in the five groups weremeasured by transwell chamber. Immunohistochemistry was used toanalyze the expression of HIF-1α, Snail, E-cadherin and MMP2in83patients samples of papillary thyroid carcinoma without any radiotherapyor chemotherapy. The expression levels of HIF-1α, Snail, E-cadherin and MMP2in papillary thyroid carcinoma NPA cells were detected by Westernblotting after hypoxia (5%O2) treatment for12h.Results When treated with hypoxia (5%O2) for0h,2h,4h,8h,12h,FRO cells, morphology changed gradually from epithelial to mesenchymalphenotype, the protein expression levels of HIF-1α, Snail、Vimentin andMMP2increased gradually, and epithelial cells characteristic proteinE-cadherin expression decreased gradually. Moreover, the proteinexpression levels of these molecules in FRO cells treated with hypoxia for12h were significantly different relative to normoxia group (P<0.01).Comparing to normoxia group, the protein expression levels of HIF-1α,Snail, Vimentin and MMP2were significantly increased in hypoxia groupor normoxia+CoCl2group (P<0.05). However, E-cadherin expression wasdecreased (P<0.05). The cell count of migration and invasion in hypoxiagroup or the normoxia+CoCl2group was higher than that in normoxiagroup (P<0.01). In papillary thyroid carcinoma tissues, the expression ratesof HIF-1α, Snail, E-cadherin and MMP2were71.08%（59/83）,66.27%（55/83）and44.58%（37/83）. The expressions of HIF-1α, Snail,E-cadherin and MMP2were significantly correlated with TNM stage andlymph node metastasis (P<0.05), and not correlated with tumor diameterand patient age. The expression of HIF-1α was positively correlated withthat of Snail (r=0.276P<0.05), and the expression of Snail wassignificantly negatively correlated with that of E-cadherin (r=-0.431P<0.01) in papillary thyroid carcinoma. The expressions of HIF-1α and Snail havepositive correlation with that of MMP2(r=0.368P<0.01; r=0.220P<0.05).HIF-1α, Snail, and MMP2protein expression of papillary thyroid carcinomaNPA cells increased gradually with the treatment of hypoxia, and theexpression levels of these molecules in hypoxia group were significantlydifferent relative to normoxia group (P<0.01). However, epithelial cellscharacteristic protein E-cadherin expression decreased with the treatmentof hypoxia (P<0.05).Conclusion HIF-1α promotes the invasion and migration ofundifferentiated thyroid carcinoma FRO cells and papillary thyroidcarcinoma NPA cells by up-regulating Snail, Vimentin and MMP2expression, and by down-regulating E-cadherin expression. Theexpressions of HIF-1α, Snail, E-cadherin and MMP2might be used asmarkers for monitoring the invasion, metastasis and progression of thyroidcancer.