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PKC sigma facilitates lymphatic metastatic spread of prostate cancer cells in a mice xenograft model
Umeå University, Faculty of Medicine, Department of Medical Biosciences.
Umeå University, Faculty of Medicine, Department of Medical Biosciences.
Umeå University, Faculty of Medicine, Department of Medical Biosciences.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
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2019 (English)In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 38, no 22, p. 4215-4231Article in journal (Refereed) Published
Abstract [en]

Prostate cancer disseminates primarily into the adjacent lymph nodes, which is related to a poor outcome. Atypical protein kinase C ζ (PKCζ) is highly expressed in aggressive prostate cancer and correlates with Gleason score, clinical stage, and poor prognosis. Here, we report the molecular mechanisms of PKCζ in lymphatic metastasis during prostate cancer progression. Using zinc-finger nuclease technology or PKCζ shRNA lentiviral particles, and orthotopic mouse xenografts, we show that PKCζ-knockout or knockdown from aggressive prostate cancer (PC3 and PC3U) cells, decreasesd tumor growth and lymphatic metastasis in vivo. Intriguingly, PKCζ-knockout or knockdown impaired the activation of AKT, ERK, and NF-κB signaling in prostate cancer cells, thereby impairing the expression of lymphangiogenic factors and macrophage recruitment, resulting in aberrant lymphangiogenesis. Moreover, PKCζ regulated the expression of hyaluronan synthase enzymes, which is important for hyaluronan-mediated lymphatic drainage and tumor dissemination. Thus, PKCζ plays a crucial oncogenic role in the lymphatic metastasis of prostate cancer and is predicted to be a novel therapeutic target for prostate cancer.

Place, publisher, year, edition, pages
Nature Publishing Group, 2019. Vol. 38, no 22, p. 4215-4231
National Category
Cancer and Oncology
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URN: urn:nbn:se:umu:diva-160292DOI: 10.1038/s41388-019-0722-9ISI: 000469339100002PubMedID: 30705401OAI: oai:DiVA.org:umu-160292DiVA, id: diva2:1326018
Funder
Science for Life Laboratory - a national resource center for high-throughput molecular bioscienceSwedish Research CouncilSwedish Cancer Society, CAN 2017/544Swedish Cancer Society, 2016/387Knut and Alice Wallenberg Foundation, 2012.0090Available from: 2019-06-17 Created: 2019-06-17 Last updated: 2019-06-17Bibliographically approved

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Zang, GuangxiangMu, YabingBergh, AndersLandström, Maréne

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