Medical School, Nankai University, Tianjin, People's Republic of China.
PLoS One. 2012;7(4):e35022. doi: 10.1371/journal.pone.0035022. Epub 2012 Apr 10.
Although 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 FINDINGS: The 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/SIGNIFICANCE: High-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.
虽然透明细胞肾细胞癌（ccRCC）的转移基本上发生在晚期肿瘤中，但 T1 期 ccRCC 的转移也可以发现，没有明确的分子原因导致手术方法选择不当和预后不良。Notch 信号通路是一种保守的、广泛表达的信号通路，在正常发育和肿瘤发生过程中介导各种细胞过程。本研究旨在探讨 Notch 信号通路在 T1 期 ccRCC 转移中的潜在作用和机制。
方法/主要发现：分析了 51 例 ccRCC 患者肿瘤组织和配对正常相邻组织中 Notch1 和 Jagged1 的表达。与非肿瘤组织相比，肿瘤组织中 Notch1 和 Jagged1 的 mRNA 和蛋白水平均显著升高。根据肿瘤分期，将局限性和转移性肿瘤的组织样本分为三组，并分析 Notch1 和 Jagged1 的相对 mRNA 表达。与局限性肿瘤相比，T1 期转移性肿瘤中 Notch1 的表达显著升高，而 Jagged1 的表达在各期局限性和转移性肿瘤之间无统计学差异。T1 期 ccRCC 中转移性肿瘤的平均大小明显大于局限性肿瘤，Notch1 的高表达与肿瘤直径呈显著正相关。通过转染全长表达质粒 Notch1 和 Jagged1，研究了 Notch 信号的功能意义。与相应对照相比，所有细胞系均表现出显著促进细胞增殖和迁移，而细胞周期不受影响。
结论/意义：Notch 信号的高表达通过刺激肿瘤细胞的增殖和迁移增加了 T1 期 ccRCC 转移的风险，这可能有助于选择合适的手术方法和预测 ccRCC 的预后。
