LncRNA CamK-A Regulates Ca2+-Signaling-Mediated Tumor Microenvironment Remodeling
LncRNA CamK-A Regulates Ca2+-Signaling-Mediated Tumor Microenvironment Remodeling
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LncRNA CamK-A 调节 Ca2 信号介导的肿瘤微环境重塑
DOI：
10.1016/j.molcel.2018.08.014
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发表时间：
2018-10-04
期刊：
影响因子：
16
通讯作者：
Lin, Aifu
中科院分区：
文献类型：
--
作者：
Sang, Ling-jie;Ju, Huai-qiang;Lin, Aifu
癌细胞需要代谢适应和微环境重塑才能生存和发展。钙(Ca~(2+))通量和Ca~(2+)依赖的信号转导在这一过程中都起着至关重要的作用，但其机制尚不清楚。通过RNA筛选，我们发现了一个与肿瘤发生有关的非编码长链RNA(LncRNA)，命名为CaMK-A(钙依赖激酶激活的LncRNA)。CaMK-A在多种人类肿瘤中高表达，并通过激活钙离子触发的信号通路参与肿瘤微环境的重塑。在机制上，CaMK-A激活钙/钙调蛋白依赖的蛋白激酶PNCK，进而磷酸化I kappaBα，触发钙依赖的核因子Kb(NF-kappa B)的激活。这种调节导致肿瘤微环境重建，包括巨噬细胞募集、血管生成和肿瘤进展。值得注意的是，我们的人-患者来源的异种移植(PDX)模型研究表明，靶向CaMK-A强烈地损害了癌症的发展。在临床上，CaMK-A的表达与CaMK-NF-kappa B轴的激活相协调，其高表达提示患者的生存率较低，提示其作为潜在的生物标志物和治疗靶点。
Cancer cells entail metabolic adaptation and microenvironmental remodeling to survive and progress. Both calcium (Ca2+) flux and Ca2+-dependent signaling play a crucial role in this process, although the underlying mechanism has yet to be elucidated. Through RNA screening, we identified one long noncoding RNA (lncRNA) named CamK-A (lncRNA for calcium-dependent kinase activation) in tumorigenesis. CamK-A is highly expressed in multiple human cancers and involved in cancer microenvironment remodeling via activation of Ca2+-triggered signaling. Mechanistically, CamK-A activates Ca2+/calmodulin-dependent kinase PNCK, which in turn phosphorylates I kappa B alpha and triggers calcium-dependent nuclear factor KB (NF-kappa B) activation. This regulation results in the tumor microenvironment remodeling, including macrophage recruitment, angiogenesis, and tumor progression. Notably, our human-patient-derived xenograft (PDX) model studies demonstrate that targeting CamK-A robustly impaired cancer development. Clinically, CamK-A expression coordinates with the activation of CaMK-NF-kappa B axis, and its high expression indicates poor patient survival rate, suggesting its role as a potential biomarker and therapeutic target.