High-Level Expression of Notch1 Increased the Risk of Metastasis in T1 Stage Clear Cell Renal Cell Carcinoma

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.

Elevated Expression of Notch1 Is Associated With Metastasis of Human Malignancies

“…Our findings are consistent with previous studies demonstrating that elevated Notch1 may contribute to PCa metastases, 16 HCC metastases, 17 and RCC metastases. 18 To our knowledge, this is the first study evaluating and comparing the protein expression levels of Notch1 between human primary and metastatic malignancies from the same tissue origin in multiple cancers simultaneously using IHC staining. Therefore, as a novel approach, our experimental method enables a better comparison of relative expression levels of Notch1 for primary and metastatic malignancies from different organs/ tissues.…”

“…17 Furthermore, high-level expression of Notch1 signaling is associated with the metastasis of T1-stage clear-cell renal cell carcinoma (RCC) by stimulating the proliferation and migration of tumor cells. 18 Some literature reports also suggest that Notch signaling may participate in cancer metastasis by modulating EMT, tumor angiogenesis, and anoikis resistance of tumor cells. [19][20][21] In the present study, we used immunohistochemical analysis to compare Notch1 protein expression levels between primary and metastatic malignancies from the same origin in 12 different cancers and demonstrate the elevated expression of Notch1 in some metastatic tumors.…”

Elevated S100A6 (calcyclin) enhances tumorigenesis and suppresses CXCL14-induced apoptosis in clear cell renal cell carcinoma

“…These methods were described previously [36] and detailed elucidated in Supplementary Data. The primers used in the PCR analysis were presented in Table S1.…”

Notch1 Predicts Recurrence and Survival of Patients With Clear-cell Renal Cell Carcinoma After Surgical Resection

“…Finally, on the basis of the results of multivariate analysis, we constructed a nomogram. Previous studies revealed that Notch signaling pathway played an important role in RCC, [21][22][23][24][25] acute kidney injury, 26 and kidney failure. 27 Sj€ olund et al demonstrated that higher levels of Notch1 expression were detected in ccRCC compared with normal kidney, and inhibition of Notch signaling attenuated the growth of ccRCC cells both in vivo and in vitro.…”

“…27 Sj€ olund et al demonstrated that higher levels of Notch1 expression were detected in ccRCC compared with normal kidney, and inhibition of Notch signaling attenuated the growth of ccRCC cells both in vivo and in vitro. 21 Ai et al 25 found that high expression of Notch signaling increased the risk of metastasis in T1 stage of ccRCC by stimulating the proliferation and migration of tumor cells. Our previous study demonstrated Notch1 activation can promote RCC growth via PI3K/Akt signaling, 12 and we also found that the expression level of Jagged1, a Notch ligand, was an independent predictor of poor survival in patients with ccRCC.…”