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PKN3 is the major regulator of angiogenesis and tumor metastasis in mice.

ABSTRACT: PKN, a conserved family member related to PKC, was the first protein kinase identified as a target of the small GTPase Rho. PKN is involved in various functions including cytoskeletal arrangement and cell adhesion. Furthermore, the enrichment of PKN3 mRNA in some cancer cell lines as well as its requirement in malignant prostate cell growth suggested its involvement in oncogenesis. Despite intensive research efforts, physiological as well as pathological roles of PKN3 in vivo remain elusive. Here, we generated mice with a targeted deletion of PKN3. The PKN3 knockout (KO) mice are viable and develop normally. However, the absence of PKN3 had an impact on angiogenesis as evidenced by marked suppressions of micro-vessel sprouting in ex vivo aortic ring assay and in vivo corneal pocket assay. Furthermore, the PKN3 KO mice exhibited an impaired lung metastasis of melanoma cells when administered from the tail vein. Importantly, PKN3 knock-down by small interfering RNA (siRNA) induced a glycosylation defect of cell-surface glycoproteins, including ICAM-1, integrin ?1 and integrin ?5 in HUVECs. Our data provide the first in vivo genetic demonstration that PKN3 plays critical roles in angiogenesis and tumor metastasis, and that defective maturation of cell surface glycoproteins might underlie these phenotypes.

SUBMITTER: Mukai H

PROVIDER: S-EPMC4705536 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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PKN3 is the major regulator of angiogenesis and tumor metastasis in mice.

Mukai Hideyuki H Muramatsu Aiko A Mashud Rana R Kubouchi Koji K Tsujimoto Sho S Hongu Tsunaki T Kanaho Yasunori Y Tsubaki Masanobu M Nishida Shozo S Shioi Go G Danno Sally S Mehruba Mona M Satoh Ryosuke R Sugiura Reiko R

Scientific reports 20160108

PKN, a conserved family member related to PKC, was the first protein kinase identified as a target of the small GTPase Rho. PKN is involved in various functions including cytoskeletal arrangement and cell adhesion. Furthermore, the enrichment of PKN3 mRNA in some cancer cell lines as well as its requirement in malignant prostate cell growth suggested its involvement in oncogenesis. Despite intensive research efforts, physiological as well as pathological roles of PKN3 in vivo remain elusive. Her ...[more]

PMID: 26742562

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Project description:ADAM12, (ADisintegrin and metalloproteinase domain-containing protein 12), is upregulated in epithelial cancers and contributes to increased tumor proliferation, metastasis, and endocrine resistance. However, its role in tumor angiogenesis is unknown. Here, we report that ADAM12 is upregulated in the vessels of aggressive breast tumors and exerts key regulatory functions. ADAM12 significantly increases bFGF-mediated angiogenesis in vivo and ADAM12 levels are upregulated in tumors that have undergone a switch to the angiogenic phenotype. Importantly, ADAM12-overexpressing breast tumors display a higher microvessel density (MVD). Our goal was to identify the mechanisms by which tumor-associated ADAM12 promotes angiogenesis. ADAM12 expression in breast tumor cells correlated with a significant upregulation of proangiogenic factors such as VEGF and MMP-9 and downregulation of antiangiogenic factors such as Thrombospondin-1 (THBS1/TSP1) and Tissue Inhibitor of Metalloproteinases-2 (TIMP-2). Co-culture with ADAM12-expressing tumor cells promoted endothelial cell (EC) recruitment and capillary tube formation. Conversely, downregulation of endogenous ADAM12 in breast cancer cell lines resulted in reduction of pro-angiogenic factors and EC recruitment. These ADAM12-mediated effects are driven by the activation of EGFR, STAT3 and Akt signaling. Blockade of EGFR/STAT3 or silencing of ADAM12 reversed the proangiogenic tumor phenotype, significantly downregulated pro-angiogenic mitogens and reduced EC recruitment. In human breast cancer tissues, ADAM12 expression was significantly positively correlated with pro-angiogenic factors including VEGF and MMP-9 but negatively associated with TSP1.Implications: These novel findings suggest that ADAM12 regulates EC function and facilitates a proangiogenic microenvironment in a STAT3-dependent manner. A combined approach of targeting ADAM12 and STAT3 signaling in breast cancer may represent a promising strategy to inhibit tumor neovascularization. Mol Cancer Res; 15(11); 1608-22. ©2017 AACR.

Dataset Information

PKN3 is the major regulator of angiogenesis and tumor metastasis in mice.

Publications

PKN3 is the major regulator of angiogenesis and tumor metastasis in mice.

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