Renal cell carcinoma (RCC) is the most lethal genitourinary cancer; more than one-fourth of patients have metastasis at its presentation. Patients undergoing radical nephrectomy frequently relapse with metastasis; the median survival for metastatic patients is only 8 months and 5-year survival rate less than 10%. Therefore, investigating the underlying mechanisms of RCC metastasis is needed for the improvement in therapeutic applications. It had been suggested the kidney regeneration process after acute kidney injury (AKI) presented similar features as the renal tubular cell malignancy. The extracellular matrix protein, nephronectin (NPNT) was expressed on the regenerating renal proximal tubular cells (RPTEC) after AKI. Embryos lacking a functional NPNT gene display server defects in the kidney development. However, little is known for its role in RPTEC and RCC. In our preliminary data, we had found NPNT were down-regulated in the RCC cell lines and clinical specimens. Silencing NPNT in RPTEC cell line, HK-2 cell, altered epithelial cell morphology into spindlelike shape and loss cell-cell contact junctions, these phenomena mimic to epithelial-to-mesenchymal transition process in the progression of cancer. Tight junctions (TJs) are a component of the epithelial junctional complex enables epithelial cells to create cellular sheets that separate compartments with different compositions, the formation of TJs may represent the status of epithelial cell differentiation. It is of note that tumor cells frequently show abnormal TJ function, decreased differentiation and cell polarity. Through cDNA microarray analysis, we had found NPNT was participated in pathways in cancer, cell adhesion molecules, transcriptional misregulation in cancer, ECM-receptor interaction. In addition, claudin (CLDN) 1, 2, 16 and occludin were all suppressed in NPNT silencing cell, while CLDN4 was up-regulated. These evidences supported NPNT may promote RPTEC cellular TJ formation, and by increasing intracellular junction formation, cell migration ability may be suppressed. Therefore, in the current proposal, we will firstly evaluate the underlying mechanisms of NPNT in regulating RPTEC TJ formation, thereafter; we will further study whether NPNT can inhibit RCC cell motility and metastasis in a spontaneous metastatic RCC mouse model. Understanding the role of NPNT in regulating intracellular junctions may largely increase our knowledge in the mechanisms of RCC metastasis.
|Effective start/end date||8/1/17 → 7/31/18|