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A novel signaling pathway regulates colon cancer angiogenesis through Norrin.

ABSTRACT: Norrin binds to the frizzled-4 receptor, stimulating canonical Wnt signaling. We investigate here the role of colorectal cancer (CRC) produced Norrin in endothelial cell growth, motility, and blood vessel formation, as well as the expression of the Norrin signaling pathway components in the CRC tumor microenvironment. Norrin conditioned medium produced by CRC cell line CaCO2 transfected with Norrin expression construct increased endothelial cell motility. Blocking Norrin signaling reduced endothelial cell motility, branch point number (1/mm(2)), and the network length (mm/mm(2)) during in vitro angiogenesis. Colorectal tumors express Norrin protein. Endothelial cells in the colorectal tumor microenvironment contain all of the components of the Norrin signaling pathway needed to respond to Norrin protein. This study presents data that Norrin may play a role in the regulation of angiogenesis in the colorectal cancer tumor microenvironment.

SUBMITTER: Planutis K

PROVIDER: S-EPMC4088094 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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A novel signaling pathway regulates colon cancer angiogenesis through Norrin.

Planutis Kestutis K Planutiene Marina M Holcombe Randall F RF

Scientific reports 20140709

Norrin binds to the frizzled-4 receptor, stimulating canonical Wnt signaling. We investigate here the role of colorectal cancer (CRC) produced Norrin in endothelial cell growth, motility, and blood vessel formation, as well as the expression of the Norrin signaling pathway components in the CRC tumor microenvironment. Norrin conditioned medium produced by CRC cell line CaCO2 transfected with Norrin expression construct increased endothelial cell motility. Blocking Norrin signaling reduced endoth ...[more]

PMID: 25005225

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Project description:BackgroundAbnormal expression of ribosomal proteins has an important regulatory effect on the progression of cancer. RPL5 is involved in the progression of various malignancies, however, the role of RPL5 in colon cancer remains is still unclear.MethodsData from TCGA and GTEx databases were used to analyze the RPL5 expression in pan-cancer. The expression level of RPL5 in clinical colon cancer tissue samples and human colon cancer cell lines was detected by western blotting; siRNA targeting RPL5 was designed, and its interference efficiency was verified by western blotting and RT-qPCR; CCK8 assay, clone formation assay, cell cycle assay, and cell scratch assay were used to observe the effect of RPL5 on colon cancer cell proliferation and migration; the changes of proteins related to MAPK/ERK signaling pathway were also detected using western blotting.ResultsThe expression level of RPL5 in colon cancer tissues and cell lines was significantly higher than that in adjacent tissues and NCM460 cells, respectively, and its expression level was higher in HCT116 cells and RKO cells. Knockdown of RPL5 significantly inhibited the proliferation and migration of HCT16 and RKO cells, and arrested the cell cycle in G0/G1 phase. Mechanistic studies revealed that the expression of p-MEK1/2, p-ERK, c-Myc were down-regulated, and the expression of FOXO3 was up-regulated after down-regulation of RPL5, ERK activator (TBHQ) could partially reverse the above-mentioned effects caused by siRPL5. Moreover, TBHQ could partially reverse the inhibitory effect of siRPL5 on the proliferation and migration of colon cancer cells. Collectively, RPL5 promoted colon cell proliferation and migration, at least in part, by activating the MAPK/ERK signaling pathway.ConclusionRPL5 promoted colon cell proliferation and migration, at least in part, by activating the MAPK/ERK signaling pathway, which may serve as a novel therapeutic target for cancers in which MAPK/ERK signaling is a dominant feature.

Project description:BackgroundVascular endothelial growth factor receptor-2 (VEGFR-2) signaling is an obligate requirement for normal development and pathological angiogenesis such as cancer and age-related macular degeneration. Although autophosphorylation of tyrosine 1173 (Y1173) of VEGFR-2 is considered a focal point for its angiogenic signal relay, however, the mechanism of phosphorylation of Y1173, signaling proteins that are recruited to this residue and their role in angiogenesis is not fully understood.Methodology/principal findingsIn this study we demonstrate that c-Src kinase directly through its Src homology 2 (SH2) domain and indirectly via c-Cbl binds to phospho-Y1057 of VEGFR-2. Activation of c-Src kinase by a positive feedback mechanism phosphorylates VEGFR-2 at multi-docking site, Y1173. c-Src also catalyzes tyrosine phosphorylation of IQGAP1 and acts as an adaptor to bridge IQGAP1 to VEGFR-2. In turn, IQGAP1 activates b-Raf and mediates proliferation of endothelial cells. Silencing expression of IQGAP1 and b-Raf revealed that their activity is essential for VEGF to stimulate angiogenesis in an in vivo angiogenesis model of chicken chorioallantoic membrane (CAM).Conclusions/significanceAngiogenesis contributes to the pathology of numerous human diseases ranging from cancer to age-related macular degeneration. Determining molecular mechanism of tyrosine phosphorylation of VEGFR-2 and identification of molecules that are relaying its angiogenic signaling may identify novel targets for therapeutic intervention against angiogenesis-associated diseases. Our study shows that recruitment and activation of c-Src by VEGFR-2 plays a pivotal role in relaying angiogenic signaling of VEGFR-2; it phosphorylates VEGFR-2 at Y1173, facilitates association and activation of IQGAP1 and other signaling proteins to VEGFR-2. IQGAP1-dependent signaling, in part, is critically required for endothelial cell proliferation, a key step in angiogenesis. Thus, Y1057 of VEGFR-2 serves to regulate VEGFR-2 function in a combinatorial manner by supporting both diversity of recruitment of angiogenic signaling proteins to VEGFR-2, and its ability to promote angiogenesis.

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A novel signaling pathway regulates colon cancer angiogenesis through Norrin.

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A novel signaling pathway regulates colon cancer angiogenesis through Norrin.

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