Study On The Effects And Mechanisms Of GAB1 In The Malignant Progression Of Anaplastic Thyroid Cancer

Aims : Anaplastic thyroid cancer(ATC)is one of the most deadly cancers in humans.Currently,rare therapies are available to cure or to prolong the survival of patients with ATC.The mechanisms of its development and high aggressiveness are still far from clarified.As essential docking proteins,GRB2-associated binding proteins(GABs)are implicated in many cancer-related signaling pathways.Recent studies have found that their abnormal expression and regulation of oncoproteins played a role in malignant progression of many cancers,including low-risk papillary thyroid cancer However,role of GABs in ATC is unclear.This study aims to investigate the effect and corresponding mechanism of GAB1,an important member of GABs family,in ATC malignant progression.Materials and Methods: In vitro,expression of GABs was compared among papillary,anaplastic and normal thyroid cell lines at protein and mRNA levels.After gene overexpression or knock-down,the effects of differential protein on proliferation,migration and invasion of PTC and ATC were studied,respectively.In vivo,we studied the role of differential GAB protein in tumor malignant progression through subcutaneous and orthotropic ATC transplantation models.Results: GAB1 expression in ATC was significantly higher than that of PTC and normal thyroid cells,while there were no differences in GAB2 expression.Thus we focused on the role of GAB1 in ATC.Overexpression of GAB1 in PTC could significantly promote cell migration and invasion,and GAB1/SHP2 and GAB1/PI3 K pathways were implicated in them.After knocking down GAB1 with siRNA and lenti-virus in ATC,cell migration and invasion were both inhibited.Overexpression of GAB1 in PTC and knocking down it in ATC did not affect the proliferation of tumor cells,which might be related to the continuous enhancement of downstream Erk signaling induced by gene mutations(For instance,BRAF)in the cell lines.GAB1 knockdown in ATC significantly inhibited tumor growth in both subcutaneously and orthotopically transplanted tumor models.Moreover,both tumor weight and tumor volume were positively correlated with GAB1 expression level.Conclusions: The abnormal overexpression of GAB1 may promote the migration,invasion and the in vivo malignant growth of transplanted ATC tumors through GAB1/SHP2 and GAB1/PI3 K pathways.Our results suggest the important role of GAB1 in the malignant progression of ATC and its potential as a new anti-tumor target.