前列腺癌
癌症研究
生物
转移
小发夹RNA
癌症
基因敲除
淋巴系统
前列腺
蛋白激酶B
淋巴管新生
医学
内科学
信号转导
免疫学
细胞培养
细胞生物学
遗传学
作者
Guangxiang Zang,Yabing Mu,Linlin Gao,Anders Bergh,Maréne Landström
出处
期刊:Oncogene
[Springer Nature]
日期:2019-01-31
卷期号:38 (22): 4215-4231
被引量:13
标识
DOI:10.1038/s41388-019-0722-9
摘要
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.
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