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.

中文翻译：

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PKCζ在小鼠异种移植模型中促进前列腺癌细胞的淋巴转移转移。

前列腺癌主要扩散到邻近的淋巴结，这与不良的预后有关。非典型蛋白激酶Cζ（PKCζ）在侵略性前列腺癌中高表达，并与格里森评分，临床分期和不良预后相关。在这里，我们报告前列腺癌进展过程中淋巴转移的PKCζ的分子机制。使用锌指核酸酶技术或PKCζshRNA慢病毒颗粒和原位小鼠异种移植物，我们显示PKCζ基因敲除或从侵袭性前列腺癌（PC3和PC3U）细胞中剔除，可降低体内肿瘤的生长和淋巴转移。有趣的是，PKCζ基因敲除或敲低会损害前列腺癌细胞中AKT，ERK和NF-κB信号的激活，从而损害淋巴管生成因子的表达和巨噬细胞募集，导致异常的淋巴管生成。此外，PKCζ调节了透明质酸合酶的表达，这对透明质酸介导的淋巴引流和肿瘤的传播很重要。因此，PKCζ在前列腺癌的淋巴转移中起着至关重要的致癌作用，并被认为是前列腺癌的新型治疗靶标。