Abstract 4625: Tumor expression of PIM kinases in renal cell carcinoma and the association with disease progression

Abstract

Abstract Hypoxia-inducible factor (HIF) plays an important role in the tumorigenesis of renal cell carcinoma (RCC). Mutational inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene, which is the most frequent molecular event, has been implicated in HIF overexpression. Recent studies found that PIM kinases increase HIF expression in cancer. The PIM Kinases are a family of highly conserved serine/threonine kinases consisting of three isoforms (PIM1, PIM2, and PIM3). PIM kinases play multiple roles in promoting cell proliferation and survival and preventing apoptosis. The expression and the potential function of PIM kinases in RCC remain unclear. Thus, we examined the expression patterns and the clinical significance of the three individual PIM kinases in RCC. PIM expression was examined by immunohistochemical staining tumor tissue and adjacent non-tumor tissue samples from 218 patients with clear cell RCC (ccRCC), including 60 patients with metastatic ccRCC. The expression of each PIM kinase in primary and metastatic ccRCC tissues comparing with adjacent normal tissues was analyzed with variables including tumor stage, grade and survival. Effect of PIM kinase on cell growth in ACHN and 786-O RCC cell lines was examined by individual PIM knockdown with specific siRNA followed by in vitro proliferation assay. Effect of PIM kinase on RCC cell motility was examined by siRNA followed by in vitro Matrigel-based invasion assay. Expression of PIM1, PIM2 and PIM3 was detected in the majority of ccRCC samples (185, 85%), but localization of isoforms differed. PIM1 expression was higher in the nucleus than in cytoplasm, while the reverse was true for PIM 2 and 3. PIM2 and PIM3 expression was higher in cytoplasm than in the nucleus. Higher expression of PIM1 and PIM2 in tumor tissues was significantly associated with metastasis. Nuclear PIM2 was associated with poorly differentiated ccRCC cells. ccRCC patients with increased nuclear PIM2 expression had significantly poorer survival compared with patients with low nuclear PIM2. siRNA-PIM2, but not siRNA-PIM1 and siRNA-PIM3, significantly reduced proliferation of ACHN and 786-O cells. Further, knockdown of PIM2 by siRNA reduced the ability of cell invasion in 786-O cells. In conclusion, PIM kinases, especially PIM2, are associated with ccRCC progression, indicating that PIM kinases may serve as potential markers for metastatic ccRCC. Targeting PIM kinases may have a therapeutic potential in ccRCC. This work was supported by NIH/NCI grant CA067267, CA085142 (Johnson, CS) and National Cancer Institute (NCI) grant P30 CA016056 involving the use of Roswell Park Cancer Institute's Bioinformatics, Pathology Resource Network, Genomics, and Clinical Data Network Shared Resources. Citation Format: Wei Luo, Yingyu Ma, Eduardo Cortes, Angela Omilian, Wiam Bshara, Gissou Azabdaftari, Brittany Bunch, Candace Johnson, Donald Trump. Tumor expression of PIM kinases in renal cell carcinoma and the association with disease progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4625.