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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >VHL loss in renal cell carcinoma leads to up-regulation of CUB domain-containing protein 1 to stimulate PKCδ-driven migration
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VHL loss in renal cell carcinoma leads to up-regulation of CUB domain-containing protein 1 to stimulate PKCδ-driven migration

机译：肾细胞癌中VHL的丧失导致含有CUB结构域的蛋白1上调以刺激PKCδ驱动的迁移

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摘要

A common genetic mutation found in clear cell renal cell carcinoma (CC-RCC) is the loss of the von Hippel-Lindau (VHL) gene, which results in stabilization of hypoxia-inducible factors (HIFs), and contributes to cancer progression and metastasis. CUB-domain-containing protein 1 (CDCP1) was shown to promote metastasis in scirrhous and lung adenocarcinomas as well as in prostate cancer. In this study, we established a molecular mechanism linking VHL loss to induction of the CDCP1 gene through the HIF-1/2 pathway in renal cancer. Also, we report that Fyn, which forms a complex with CDCP1 and mediates its signaling to PKCS, is a HIF-1 target gene. Mechanistically, we found that CDCP1 specifically regulates phosphorylation of PKCS, but not of focal adhesion kinase or Crk-associated substrate. Signal transduc-tion from CDCP1 to PKCS leads to its activation, increasing migration of CC-RCC. Furthermore, patient survival can be stratified by CDCP1 expression at the cell surface of the tumor. Taken together, our data indicates that CDCP1 protein might serve as a therapeutic target for CC-RCC.
机译：在透明细胞肾细胞癌（CC-RCC）中发现的常见基因突变是von Hippel-Lindau（VHL）基因的丢失，这导致了缺氧诱导因子（HIFs）的稳定，并有助于癌症的发展和转移。含CUB结构域的蛋白1（CDCP1）已显示出可促进肝硬化和肺腺癌以及前列腺癌的转移。在这项研究中，我们建立了一种通过HIF-1 / 2途径在肾癌中将VHL丢失与CDCP1基因诱导联系起来的分子机制。同样，我们报告Fyn，它与CDCP1形成复合物并介导其向PKCS的信号传导，是HIF-1靶基因。从机理上讲，我们发现CDCP1特异性调节PKCS的磷酸化，但不调控粘着斑激酶或Crk相关底物的磷酸化。从CDCP1到PKCS的信号转导导致其激活，增加了CC-RCC的迁移。此外，可以通过肿瘤细胞表面的CDCP1表达来对患者的生存进行分层。综上所述，我们的数据表明CDCP1蛋白可能充当CC-RCC的治疗靶标。

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    Olga V. Razorenova; Elizabeth C. Finger; Renata Colavitti; Sophia B. Chernikova; Alexander D. Boiko; Charles K. F. Chan; Adam Krieg; Barbara Bedogni; Edward LaGory; Irving L. Weissman; Marianne Broome-Powell; Amato J. Giaccia;

  • 作者单位

    Department of Radiation Oncology, Center for Clinical Sciences Research, Stanford University School of Medicihe, Stanford, CA 94305;

    Department of Radiation Oncology, Center for Clinical Sciences Research, Stanford University School of Medicihe, Stanford, CA 94305;

    Department of Radiation Oncology, Center for Clinical Sciences Research, Stanford University School of Medicihe, Stanford, CA 94305;

    Department of Radiation Oncology, Center for Clinical Sciences Research, Stanford University School of Medicihe, Stanford, CA 94305;

    lnstitute for Stem Cell Biology and Regenerative Medicine, Stanford Cancer Center, and Ludwig Center at Stanford, Stanford, CA 94305;

    lnstitute for Stem Cell Biology and Regenerative Medicine, Stanford Cancer Center, and Ludwig Center at Stanford, Stanford, CA 94305;

    Department of Radiation Oncology, Center for Clinical Sciences Research, Stanford University School of Medicihe, Stanford, CA 94305;

    Department of Biochemistry, Case Western Reserve University, Cleveland, OH 44106;

    Department of Radiation Oncology, Center for Clinical Sciences Research, Stanford University School of Medicihe, Stanford, CA 94305;

    Department of Radiation Oncology, Center for Clinical Sciences Research, Stanford University School of Medicihe, Stanford, CA 94305;

    Department of Radiation Oncology, Center for Clinical Sciences Research, Stanford University School of Medicihe, Stanford, CA 94305;

    Department of Radiation Oncology, Center for Clinical Sciences Research, Stanford University School of Medicihe, Stanford, CA 94305;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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