Abstract 3529: KIM-1 is a novel therapeutic target in renal cell carcinoma

Abstract

Abstract Background. Renal cell carcinoma (RCC) is characterized by lack of early warning signs, diverse clinical manifestations, absence of a reliable diagnostic and predictive biomarker, and resistance to targeted therapy. Given the high incidence and worse prognosis, novel approaches for diagnosis, management and treatment of RCC are urgently needed. Kidney Injury Molecule-1 (KIM-1) is not expressed in normal kidney tissues but markedly up-regulated in dedifferentiated proximal tubular epithelial cells following renal injury. We demonstrated KIM-1 is expressed ubiquitoulsy by both primary and metastatic lesions of clear cell and papillary renal cell carcinoma, while barely detectable in other subtypes of RCC. The ectodomain of KIM-1 molecule cleaves by matrix metaloproteinases and sheds into surround milieu. In the present study, we investigated the role of KIM-1 in the pathogenesis of RCC. Methods. KIM-1 is stably transfected in immortalized tubular epithelial cells (LLC-PK1, gain-of-function) and KIM-1 was knockdown in RCC cell lines (loss-of-function) using lentiviral apporach and interoggated KIM-1 function in carcinogenesis. Results. Heterologous expression of KIM-1 increased cell proliferation, induced anchorage indepdent growth, increased migration and invasion potential, and increased the secreation of tumor promoting fractors, including TGF beta and IL-6 in immortalized tubular epithelial cells (PK1-KIM-1); while depletion of KIM-1 in RCC cells leads to cell cycle arrest at G1 phase and senescence. Recently, we and others have demonstrated that KIM-1 is a phosphatildyl serine receptor and the expression of KIM-1 converts a normal epithelial cell into a “semi professional phagocyte” and facilitates the removal of apoptotic and necrotic cells by recognizing phosphotidyl serine (PS) on their cell surface. Our data suggests that during this process, tumor epithelial cells undergo reprogramming and secrete and activate cytokines involved in cell survival and angiogenesis programs. Conclusions. The present study demonstrates that KIM-1-expression promotes tumorigenesis primarily by two distinct mechanisms: i) by directly conferring oncogenic properties to renal epithelial cells; ii) by resulting in production of a variety of chemokines and cytokines that support tumor progression and angiogenesis. We believe that our findings can significantly contribute to the development of novel therapeutic apporaches and in the advancement of management strategies in renal cell carcinoma and help reduce associated mortality and morbidity. Citation Format: Venkata S. Sabbisetti. KIM-1 is a novel therapeutic target in renal cell carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3529. doi:10.1158/1538-7445.AM2014-3529