Signals of ERBB3 and other receptor tyrosine kinases in hepatocellular carcinogenesis and therapies

Receptor tyrosine kinases (RTKs) play critical roles regulation of cell growth, and deregulation of these signals is implicated in most forms of human malignancies. A wealth of data has demonstrated the etiological role of EGFR/ERBB members in human cancer development. EGFR- and HER2-targeted therapies have been effective in many cancers. In the ERBB family, ERBB3 is unique for the functional defect of its tyrosine kinase domain, so that its roles in oncogenesis and anti-cancer therapy have been neglected. Recently ERBB3 was found to be essential for oncogenesis in lung cancer with EGFR mutation and breast cancers with HER2 gene amplification, and to play a pivotal role in resistance to targeted therapies in these patients. We have reported the overexpression of ERBB3 in HCC (Pan et al. BMC Genomics 2006). Recently, we further found a strong association of ERBB3 overexpression with male gender, chronic hepatitis B, high recurrence, and poor prognosis. However, neither the role of ERBB members nor that of other RTKs in hepatocellular carcinogenesis remains elusive. The aims of this study are to systematically elucidate the roles of ERBB members along with other RTKs in the hepatocellular carcinogenesis with special emphasis on ERBB3, to elucidate their intracellular signaling, and to evaluate potential roles in future development of anti-HCC therapy. The following objectives are to be accomplished: 1. To systematically evaluate the roles ERBB family genes along with other RTKs expressed in HCC cells in the oncogenesis of HCC including downstream elicited signaling pathways and tumorigenicity. 2. To elucidate the mechanisms and oncogenic role of ERBB3 in HCC: Mechanisms of overexpression and constitutive activation of ERBB3 in HCC will be elucidated. In addition, diversified and compensatory signaling among different RTKs in HCC cells will be investigated, so as to clarify roles of different RTKs in hepatocellular carcinogenesis. 3. To investigate the mechanisms leading to primary and acquired resistance to EGFR-/HER2-targeted therapies in HCC and the roles of ERBB3 and other receptor tyrosine kinase(s) in emerging resistance. 4. To study the molecular basis for the association between ERBB3 overexpression and male gender and chronic hepatitis B, particularly the roles of HBV X antigen and androgen receptors in modulation of ERBB3 expression. In our pilot studies, we have established a panel of HCC cells with different features of ERBB3 activation. This cell model allows us to manipulate ERBB3 activities in vitro as well ex vivo, so that we can investigate the related molecular mechanisms and their biological consequences. Through this study, we expect to have a relative comprehensive view of roles of human RTKs in hepatocellular carcinogenesis. We particularly focus on ERBB3 because of its pivotal roles in ERBB signaling. We expect that our studies will contribute to future development of better therapies for HCC.

Project ID:PG10112-0091
External Project ID:NHRI-EX102-10013BI