Li Peng, Liu Guangshi, Zhang Wenbin, Li Tao, Yang Xinhui
Gastrointestinal Surgery department, People's Hospital of Xinjiang Uygur Autonomous Region, Xinjiang, Urumqi 830000, China.
Department of Gastrointestinal Surgery, Xinjiang Medical University Affiliated Cancer Hospital, Gastrointestinal Surgery department, Xinjiang, Urumqi 830000, China.
Neoplasia. 2025 Oct;68:101219. doi: 10.1016/j.neo.2025.101219. Epub 2025 Aug 20.
Tumor angiogenesis is essential for colorectal cancer (CRC) progression, providing oxygen and nutrients to sustain tumor growth and metastasis. Protein kinase C iota (Prkci) is an atypical protein kinase known for its oncogenic roles in various cancers; however, its function in CRC angiogenesis remains largely unexplored. This study investigates the role of Prkci in regulating tumor angiogenesis through the Jak2/Stat3 signaling pathway.
Prkci expression levels in CRC tissues and their correlation with micro-vessel density and patient prognosis were analyzed. Functional experiments, including endothelial cell proliferation, migration, and tube formation assays, were performed in vitro to assess the angiogenic effects of Prkci. In vivo, a CRC xenograft mouse model with Prkci knockout was used to evaluate tumor growth and angiogenesis. Mechanistic studies explored how Prkci activates Jak2 by phosphorylating it at the S633 site, leading to downstream Stat3 activation and Vegfa expression.
Prkci was upregulated in CRC tissues and correlated with increased micro-vessel density and poor patient prognosis. In vitro, Prkci overexpression enhanced endothelial cell proliferation, migration, and tube formation, while Prkci knockout inhibited these processes. Mechanistically, Prkci phosphorylated Jak2 at S633, leading to enhanced Stat3 activation and increased Vegfa expression, which promoted angiogenesis. In vivo, Prkci knockout in CRC cells significantly reduced tumor growth, angiogenesis, and prolonged survival in a mouse model.
These findings identify Prkci as a key regulator of angiogenesis in CRC through Jak2/Stat3 signaling activation. Targeting Prkci could provide a novel therapeutic approach to inhibit tumor angiogenesis and limit CRC progression.
肿瘤血管生成对于结直肠癌（CRC）的进展至关重要，它为肿瘤生长和转移提供氧气和营养物质。蛋白激酶C ι（Prkci）是一种非典型蛋白激酶，因其在多种癌症中的致癌作用而闻名；然而，其在CRC血管生成中的功能在很大程度上仍未被探索。本研究调查了Prkci通过Jak2/Stat3信号通路在调节肿瘤血管生成中的作用。
分析CRC组织中Prkci的表达水平及其与微血管密度和患者预后的相关性。进行了功能实验，包括体外内皮细胞增殖、迁移和管腔形成试验，以评估Prkci的血管生成作用。在体内，使用具有Prkci基因敲除的CRC异种移植小鼠模型来评估肿瘤生长和血管生成。机制研究探讨了Prkci如何通过在S633位点磷酸化Jak2来激活它，从而导致下游Stat3激活和Vegfa表达。
Prkci在CRC组织中上调，与微血管密度增加和患者预后不良相关。在体外，Prkci过表达增强了内皮细胞增殖、迁移和管腔形成，而Prkci基因敲除则抑制了这些过程。机制上，Prkci在S633位点磷酸化Jak2，导致Stat3激活增强和Vegfa表达增加，从而促进血管生成。在体内，CRC细胞中的Prkci基因敲除显著降低了小鼠模型中的肿瘤生长、血管生成，并延长了生存期。
这些发现确定Prkci是通过Jak2/Stat3信号激活在CRC血管生成中的关键调节因子。靶向Prkci可能提供一种新的治疗方法来抑制肿瘤血管生成并限制CRC进展。
