Department of Human Oncology, Wisconsin Institute of Medical Research, Paul Carbone Comprehensive Cancer Center, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin 53792, USA.
Cancer Res. 2011 Mar 15;71(6):2318-27. doi: 10.1158/0008-5472.CAN-10-4170.
Protein kinase C epsilon (PKCε), a novel PKC isoform, is overexpressed in prostate cancer (PCa) and correlates with disease aggressiveness. However, the functional contribution of PKCε to development or progression of PCa remained to be determined. Here we present the first in vivo genetic evidence that PKCε is essential for both the development and metastasis of PCa in the transgenic mouse model of prostate adenocarcinoma (TRAMP). Heterozygous or homozygous genetic deletions of PKCε in FVB/N TRAMP inhibited PCa development and metastasis as analyzed by positron emission tomography/computed tomography, tumor weight determinations, and histopathology. We also examined biomarkers associated with tumor progression in this model, including markers of survival, proliferation, angiogenesis, inflammation, and metastatic progression. To find clues about the genes regulated by PKCε and linked to the Stat3 signaling pathway, we carried out focused PCR arrays of JAK/STAT signaling in excised PCa tissues from PKCε wild-type and nullizygous TRAMP mice. Notably, PKCε loss was associated with significant downregulation of proliferative and metastatic genes C/EBPβ (CCAAT/enhancer binding protein β), CRP (C-reactive protein), CMK, EGFR (epidermal growth factor receptor), CD64, Jun B, and gp130. Taken together, our findings offer the first genetic evidence of the role of PKCε in PCa development and metastasis. PKCε may be potential target for prevention and/or treatment of PCa.
蛋白激酶 C ɛ（PKCε）是一种新型的 PKC 同工型，在前列腺癌（PCa）中过度表达，并且与疾病的侵袭性相关。然而，PKCε 对 PCa 的发展或进展的功能贡献仍有待确定。在这里，我们首次提供了体内遗传证据，表明 PKCε 对于前列腺腺癌（TRAMP）转基因小鼠模型中 PCa 的发展和转移都是必需的。PKCε 的杂合或纯合基因缺失抑制了 FVB/N TRAMP 中的 PCa 发展和转移，这通过正电子发射断层扫描/计算机断层扫描、肿瘤重量测定和组织病理学进行了分析。我们还在该模型中检查了与肿瘤进展相关的生物标志物，包括与生存、增殖、血管生成、炎症和转移进展相关的标志物。为了寻找与 Stat3 信号通路相关的受 PKCε 调节的基因的线索，我们对来自 PKCε 野生型和纯合缺失型 TRAMP 小鼠的切除 PCa 组织中的 JAK/STAT 信号进行了聚焦 PCR 阵列分析。值得注意的是，PKCε 的缺失与增殖和转移基因 C/EBPβ（CCAAT/增强子结合蛋白β）、CRP（C 反应蛋白）、CMK、EGFR（表皮生长因子受体）、CD64、Jun B 和 gp130 的显著下调有关。总之，我们的研究结果为 PKCε 在 PCa 发展和转移中的作用提供了首个遗传证据。PKCε 可能是预防和/或治疗 PCa 的潜在靶点。
