LncRNA CamK-A Regulates Ca2+-Signaling-Mediated Tumor Microenvironment Remodeling.
LncRNA CamK-A Regulates Ca2+-Signaling-Mediated Tumor Microenvironment Remodeling.
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DOI：
10.1016/j.molcel.2018.10.024
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发表时间：
2018-11
期刊：
影响因子：
16
通讯作者：
L. Sang;Huai-qiang Ju;Guang-ping Liu;Tian Tian-Tian;G. Ma;Yun-xin Lu;Ze-xian Liu;Ruo-lang Pan;
中科院分区：
文献类型：
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作者：
L. Sang;Huai-qiang Ju;Guang-ping Liu;Tian Tian-Tian;G. Ma;Yun-xin Lu;Ze-xian Liu;Ruo-lang Pan;
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+）流和Ca 2+依赖性信号在这一过程中起着至关重要的作用，但其潜在的机制尚未阐明。通过RNA筛选，我们发现了一种与肿瘤发生有关的长链非编码RNA（lncRNA）CamK-A（lncRNA for calcium-dependent kinase activation），CamK-A在多种人类肿瘤中高表达，并通过激活Ca ~（2+）信号参与肿瘤微环境的重塑。从机制上讲，CamK-A激活Ca 2 +/钙调蛋白依赖性激酶PNCK，进而磷酸化IκBα并触发钙依赖性核因子κB（NF-κB）激活。这种调节导致肿瘤微环境重塑，包括巨噬细胞募集、血管生成和肿瘤进展。值得注意的是，我们的人类患者来源的异种移植物（PDX）模型研究表明，靶向CamK-A强烈削弱了癌症的发展。在临床上，CamK-A的表达与CaMK-NF-κB轴的激活相协调，其高表达提示患者生存率低，提示其作为潜在的生物标志物和治疗靶点的作用。
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) namedCamK-A(lncRNA for calcium-dependent kinase activation) in tumorigenesis.CamK-Ais highly expressed in multiple human cancers and involved in cancer microenvironment remodeling via activation of Ca2+-triggered signaling. Mechanistically,CamK-Aactivates Ca2+/calmodulin-dependent kinase PNCK, which in turn phosphorylates IκBα and triggers calcium-dependent nuclear factor κB (NF-κB) 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 targetingCamK-Arobustly impaired cancer development. Clinically,CamK-Aexpression coordinates with the activation of CaMK-NF-κB axis, and its high expression indicates poor patient survival rate, suggesting its role as a potential biomarker and therapeutic target.