BRAF^V600E And RET/PTC Promote Proliferation And Migration Of Papillary Thyroid Carcinoma By Regulating Nuclear Factor-?B

Background:Thyroid carcinoma(TC)is one of the common malignant tumors clinically,and papillary thyroid carcinoma(PTC)is one kind with the highest incidence in TC.In the past few decades,the incidence of TC increased gradually.Therefore,it is necessary to find the effectively therapeutic method to treat and prevent from TC.RAF is the critical role in mitogen-activated protein kinase(MAPK)signaling pathway,BRAF is one of RAF.The carcinogenicity of BRAF came from the point mutation in the domain encoding kinase.For example,thymine at the 1799th place changes into adenine(T1799A),resulting in valine turns into glutamate(V600E),as the most common mutation,which influences the activation of kinase domain or P loop,and then promotes the continuous activation of BRAF kinase.Many previous reports both showed the higher BRAF mutation in PTC.Approximately 45%of PTC patients were with BRAF mutation,and most of them were BRAFV600E.Although many researches focused on the relationship between BRAFV600E and PTC metastasis,the persuasiveness was still weak for the limitation on sample size and technology.Therefore,the correlation of BRAF mutation with PTC metastasis is still unclear for lacking of convincing proof.RET rearrangement could induce the connection between the 3' terminal of RET and 5 different genes' 5' terminal,and then form the fusion protein.Until now,there are at least 11 kinds of RET/PTC rearrangement,and the RET/PTC1 and RET/PTC3 are with more attentions.However,fewer investigations are focused on the relationship between RET/PTC and PTC metastasis.Part I Association of BRAFV600E or RET/PTC with NF-?B,lymphatic metastasis and inflammatory factors in Inner MongolianClinical data and tumor samples were collected from 50 PTC patients with recurrence and 10 thyroid adenoma(TA)patients,who received diagnosis and hospitalized in endocrinology department of Inner Mongolia People's Hospital from January of 2016 to January of 2017.BRAFV600E,RET/PTC,NF-?B activity and serum inflammatory factors' level were detected.the effects of NF-?B on PTC regulated by BRAFV600E or RET/PTC,lymphatic metastasis and inflammation were analyzed.Results:BRAFV600E,RET/PTC and BRAFV600Ecombined with RET/PTC only appeared in recurrent PTC patients but not in TA patients.Female PTC patients were more than male,while male TA patients were more than female.Female PTC patients were with higher positive BRAFF600E rate,while male PTC patients were with higher positive RET/PTC rate.PTC patients with BRAFV600E or RET/PTC were younger than those with BRAFV600E combined with RET/PTC.The age of PTC patients was positive correlated with positive BRAFV600E,RET/PTC and BRAFV600E combined with RET/PTC.Recurrent time of PTC patients with BRAFV600E was longer than those with BRAFV600E combined with RET/PTC.Lymphatic metastasis rate of PTC patients with BRAFV600E was lower than those with RET/PTC or those with BRAFV600E combined with RET/PTC,showing as the positive correlation between lymphatic metastasis rate of PTC patients and positive RET/PTC or BRAFV600E combined with RET/PTC.Positive NF-?B in PTC patients was higher than that in TA patients.The older or the longer recurrent time of PTC patients,the higher lymphatic metastasis rate.The longer recurrent time of PTC patients,the higher positive NF-?B rate.No matter before or after surgery,the levels of inflammatory factors of PTC patients was higher than that of TA patients.Part ? BRAFV600E and RET/PTC promote proliferation,migration and inflammatory factors' expression of papillary thyroid carcinoma by regulating nuclear factor-?BWe used BCPAP(BRAFv600F/v600E),TPC-1(BRAFWT/WT),PCCL3 and PTC3-5(RET/PTC)cell lines to study NF-?B activity,in order to investigate the effects of BRAFV600E or RET/PTC on NF-?B activity,proliferation and migration.Results:BRAFV600E and RET/PTC could both promote BRAF and RET expressions in thyroid cells,which was related NF-?B activity.BRAFV600E and RET/PTC could both promoted the expression of phosphorylation of p100/p52,p65,IKK?/? and I?B?,as well as activating NF-?B and promoting p65 nuclear translocation.Meanwhile,the promoting effect of BRAFV600E on p65 nuclear translocation was more obvious than that of RET/PTC.BRAFV600E and RET/PTC could both promote proliferation and migration of thyroid cell by regulating NF-?B activity.