Abstract
BackgroundAlthough metastasis of clear cell renal cell carcinoma (ccRCC) is basically observed in late stage tumors, T1 stage metastasis of ccRCC can also be found with no definite molecular cause resulting inappropriate selection of surgery method and poor prognosis. Notch signaling is a conserved, widely expressed signal pathway that mediates various cellular processes in normal development and tumorigenesis. This study aims to explore the potential role and mechanism of Notch signaling in the metastasis of T1 stage ccRCC.Methodology/Principal FindingsThe expression of Notch1 and Jagged1 were analyzed in tumor tissues and matched normal adjacent tissues obtained from 51 ccRCC patients. Compared to non-tumor tissues, Notch1 and Jagged1 expression was significantly elevated both in mRNA and protein levels in tumors. Tissue samples of localized and metastatic tumors were divided into three groups based on their tumor stages and the relative mRNA expression of Notch1 and Jagged1 were analyzed. Compared to localized tumors, Notch1 expression was significantly elevated in metastatic tumors in T1 stage while Jagged1 expression was not statistically different between localized and metastatic tumors of all stages. The average size of metastatic tumors was significantly larger than localized tumors in T1 stage ccRCC and the elevated expression of Notch1 was significantly positive correlated with the tumor diameter. The functional significance of Notch signaling was studied by transfection of 786-O, Caki-1 and HKC cell lines with full-length expression plasmids of Notch1 and Jagged1. Compared to the corresponding controls, all cell lines demonstrated significant promotion in cell proliferation and migration while cell cycle remained unaffected.Conclusions/SignificanceHigh-level expression of Notch signaling increased the risk of metastasis in T1 stage ccRCC by stimulating the proliferation and migration of tumor cells, which may be helpful for the selection of suitable operation method and prognosis of ccRCC.
Highlights
Renal cell carcinoma (RCC) is the second leading cause of death among urologic tumors, accounting for 2% of adult malignancies and the most common histologic subtype is clear cell renal cell carcinoma [1]
We found out that Notch1 and Jagged1 expression was significantly elevated in both localized and metastatic tumor tissues compared to non-tumor tissues
Notch1 expression was higher in metastatic tumors but Jagged1 expression was lower compared to localized tumors indicating that the receptor and ligand of Notch signaling may function differently in the metastasis of clear cell renal cell carcinoma (ccRCC) (Figure 1A)
Summary
Renal cell carcinoma (RCC) is the second leading cause of death among urologic tumors, accounting for 2% of adult malignancies and the most common histologic subtype is clear cell renal cell carcinoma (ccRCC) [1]. Aside from the imaging evidence, there is no definite molecular targets that can be used to identify the metastatic liability of ccRCC which may help the doctors to determine the suitable operation method in surgery. The Notch proteins comprise a conserved, widely expressed family of cell-surface receptors that mediate various cellular processes including differentiation, proliferation, and apoptosis via direct cell-cell interactions [4]. Metastasis of clear cell renal cell carcinoma (ccRCC) is basically observed in late stage tumors, T1 stage metastasis of ccRCC can be found with no definite molecular cause resulting inappropriate selection of surgery method and poor prognosis. Notch signaling is a conserved, widely expressed signal pathway that mediates various cellular processes in normal development and tumorigenesis. This study aims to explore the potential role and mechanism of Notch signaling in the metastasis of T1 stage ccRCC
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