Study On The Role Of ErbB3 In Cell Proliferation,Migration,Invasion And Sunitinib Resistance In Renal Cell Carcinoma And Its Underlying Molecular Mechanism

The reported worldwide incidence and mortality of renal cell carcinoma(RCC)have increased in recent years.Among all subfamilies of RTKs,the ErbB family members consisting of the epidermal growth factor receptor EGFR(ErbBl),HER2(ErbB2),HER3(ErbB3),and HER4(ErbB4)play important role in regulating cell growth/proliferation and diff-erentiation.As a key member of ErbB family,ErbB3 has been shown to involve in initiation and development of a variety of human cancers as well as resistance to chemotherapy and/or target therapy.However,whether ErbB3 may play any possible role in development of renal cell carcinoma remains unclear.In our current study,lentiviral system was used to introduce overexpression and/or specific knockdown expression of ErbB3 following by phenotype analysis.Tumor xenograft model was also established to evaluate the growth of tumor and in vivo efficacy of sunitinib.We found that while overexpression of ErbB3 in renal cell carcinoma cells significantly promoted proliferation,clonogenic formation and growth of xenograft tumor,migration and invasion,specific knockdown expression of ErbB3 inhibited those aforementioned phenotypes in RCC cells on the contrary.Meanwhile,the expression level of ErbB3 was shown to correlate with sensitivity of sunitinib in RCC cells both in vitro and in vivo.Mechanistic study revealed that altered expression of ErbB3 mainly resulted in changes of downstream Akt and MAPK signalings,which in turn influenced the malignant progression of RCC.Taken together,our results indicated that abnormal expression of ErbB3 palys important role in initiation and development of RCC as well as resistance to sunitinib.Thus,ErbB3 and key components in its downstream signalings may serve as candidate targets for development of new target therapy strategy against RCC in the near future.