Anaplastic thyroid carcinoma (ATC) represents an undifferentiated, aggressive and highly metastatic form of thyroid cancer with high mortality. GAB1, through direct interaction with the kinase PI3K and phosphatase SHP2, is tightly involved in the activation of oncogenic signals; however, the role of GAB1 in ATC remains unclear. GAB1 was significantly increased in ATC, accompanied with AKT activation. Cell proliferation, migration and invasion were impaired or enhanced by GAB1 knockdown in ATC cells or overexpression in PTC cells. Moreover, GAB1 knockdown in ATC cells inhibited and overexpression in PTC cells promoted the growth of thyroid cancer in nude mice. GAB1 mutation disrupting the interaction between GAB1 and PI3K failed to restore cell migration and invasion in GAB1-knockdown ATC cells. RNA sequencing data showed GAB1-knockdown partially reprogramed gene expression in ATC cells back to that in normal thyroid cells. MDR1 was transcriptionally regulated by GAB1, which was mediated by AKT. MDR1 was upregulated in ATC cells and MDR1 knockdown in ATC cells decreased migration and invasion. In addition, MDR1 overexpression restored cell migration and invasion and lung metastasis of GAB1-knockdown ATC cells. Collectively, GAB1 is upregulated in ATC to promote AKT activation and cellular migration and invasion through regulating MDR1 expression.
Keywords: AKT; Anaplastic thyroid cancer; GAB1; MDR1; Migration.
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