Elevated Tyrosine Kinase HCK Expression in Renal Cell Carcinomas
Liwei Jia, Karl Dykema, Celina Villa, Chunyan Luan, Fan Lin, Bin T Teh, Ximing J Yang. Northwestern University Feinberg School of Medicine, Chicago, IL; Van Andel Research Institute, Grand Rapids, MI; Geisinger Health System, Danville, PA
Background: Targeted therapy with tyrosine kinase inhibitors (mostly against vascular endothelial growth factor receptor) has demonstrated efficacy in the treatment of patients with renal cell carcinoma. However, the majority of patients eventually develop drug resistance after a median of 6-11 months of the treatment. Therefore, there is a need to identify new tyrosine kinase targets for potent inhibiting agents. Hematopoietic Cell Kinase (HCK) is a member of the Src tyrosine kinase family and one of promising targets of chemotherapy for renal cell carcinoma patients. Studies on HCK in renal cell carcinoma are very limited in literature. To evaluate its potential for targeted therapy, we studied HCK expression by gene expression microarrays and immunohistochemistry in a large cohort of renal cell carcinomas.
Design: Gene expression microarray data containing 72 renal neoplasms, including 37 clear cell renal cell carcinomas (CCRCCs) and 35 papillary renal cell carcinomas (PRCCs), were evaluated from our previously established database and mRNA levels of 103 tyrosine kinases were assessed. To confirm the mRNA expression, immunohistochemistry was carried out using a mouse monoclonal antibody specific for HCK in 136 cases, including 90 CCRCCs and 46 PRCCs with 1.5-mm punchers using a Beecher tissue microarray (TMA) instrument. Staining intensity was graded as negative, weakly positive, moderately positive and strongly positive in renal neoplasms. Moderately positive staining and strongly positive staining of HCK are considered as elevated protein expression.
Results: In our gene expression microarrays, 13 of 103 tyrosine kinases in CCRCCs were significantly upregulated at mRNA levels, whereas only 6 tyrosine kinases showed a marked increase at mRNA levels in PRCCs compared to the corresponding normal renal tissues. Among these elevated tyrosine kinases, the mRNA level of HCK was elevated in 89% of CCRCCs (33 of 37) and 66% of PRCCs (23 of 35). Immunohistochemistry revealed HCK protein expression was increased in 90% of CCRCCs (81 of 90) and 91% of PRCCs (42 of 46) in comparison to normal renal tissues.
Conclusions: In our study, we found the upregulation of HCK in the majority of clear cell renal cell carcinomas and papillary renal cell carcinomas by mRNA and IHC expression. HCK is a valuable potential target for tyrosine kinase inhibitor-based therapy for renal cell carcinomas.
Category: Genitourinary (including renal tumors)
Tuesday, March 5, 2013 9:30 AM
Poster Session III # 83, Tuesday Morning