182

JAG1

jagged 1;JAG1;jagged 1

protein jagged-1

20p12.1-p11.23

protein-coding

We report a paracrine effect whereby endothelial cells (ECs) promote the cancer stem cell (CSC) phenotype of human colorectal cancer (CRC) cells. We showed that, without direct cell-cell contact, ECs secrete factors that promoted the CSC phenotype in CRC cells via Notch activation. In human CRC specimens, CD133 and Notch intracellular domain-positive CRC cells colocalized in perivascular regions. An EC-derived, soluble form of Jagged-1, via ADAM17 proteolytic activity, led to Notch activation in CRC cells in a paracrine manner; these effects were blocked by immunodepletion of Jagged-1 in EC-conditioned medium or blockade of ADAM17 activity. Collectively, ECs play an active role in promoting Notch signaling and the CSC phenotype by secreting soluble Jagged-1.

Recent studies suggest that NOTCH signaling can promote epithelial-mesenchymal transitions and augment signaling through AKT, an important growth and survival pathway in epithelial cells and prostate cancer in particular. Here we show that JAGGED1, a NOTCH receptor ligand, is significantly more highly expressed in metastatic prostate cancer as compared with localized prostate cancer or benign prostatic tissues, based on immunohistochemical analysis of JAGGED1 expression in human tumor samples from 154 men. Furthermore, high JAGGED1 expression in a subset of clinically localized tumors was significantly associated with recurrence, independent of other clinical parameters. These findings support a model in which dysregulation of JAGGED1 protein levels plays a role in prostate cancer progression and metastasis and suggest that JAGGED1 may be a useful marker in distinguishing indolent and aggressive prostate cancers.

BACKGROUND: Involvement of Notch signaling in several tumors is well known, but its role in tongue squamous cell carcinoma remains poorly characterized. The purpose of this study was to evaluate the roles of Notch signaling in the oncogenesis of tongue carcinoma. MATERIALS AND METHODS: tumor specimens and adjacent non-neoplastic tongue tissues from 74 patients with tongue carcinoma and human tongue carcinoma cell line Tca8113 were examined using immunohistochemistry and RT-PCR to determine the expressions of Notch1, Notch3, Jagged1, and Jagged2. RESULTS: The mRNA expressions of Notch1, Notch3, Jagged1, and Jagged2 were detected in Tca8113, tongue carcinoma, and adjacent non-neoplastic tongue tissues. The expression levels of mRNAs in tongue carcinoma were higher than those in adjacent non-neoplastic tongue tissues (P < 0.05). Immunohistochemical examination showed that the Notch signal molecules were expressed in Tca8113, tongue carcinoma, and adjacent non-neoplastic tongue tissues. The expression rates of Notch1 and Notch3 protein in tongue carcinoma were higher than those in adjacent non-neoplastic tongue tissues (chi(2) = 6.10, P = 0.013; chi(2) = 3.94, P = 0.047). Notch1 and jagged1 were significantly more highly expressed in lymph node metastasis-positive tongue carcinoma (chi(2) = 6.108, P = 0.013; chi(2) = 7.354, P = 0.025). In addition, expressions of Notch3 and Jagged2 were highly correlated in tongue carcinoma tissues (chi(2) = 42.130, P < 0.001). CONCLUSIONS: expressions of Notch receptors and ligands in tongue carcinoma and adjacent non-neoplastic tongue tissues suggest that Notch signaling may control cell differentiation and proliferation of carcinoma cells. The disorder of Notch signaling may be a mechanism of the tongue carcinoma development.