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Mol Cell. 2018 Oct 4;72(1):71-83.e7. doi: 10.1016/j.molcel.2018.08.014. Epub 2018 Sep 13.

LncRNA CamK-A Regulates Ca2+-Signaling-Mediated Tumor Microenvironment Remodeling.

Author information

1
College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China.
2
Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong 510060, China.
3
College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China; College of Life Sciences, Yan'an University, Yan'an, Shaanxi 716000, China.
4
Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, TX 77030, USA.
5
CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, Liaoning 116023, China.
6
Department of Surgery, Division of Surgical Science, School of Medicine, Duke University, Durham, NC 27710, USA.
7
Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA 92697, USA.
8
Department of Cell Biology and Program in Molecular Cell Biology, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China.
9
College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China; Key Laboratory for Cell and Gene Engineering of Zhejiang Province, Hangzhou, Zhejiang 310058, China; The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China. Electronic address: linaifu@zju.edu.cn.

Abstract

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 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 targeting CamK-A robustly impaired cancer development. Clinically, CamK-A expression 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.

KEYWORDS:

Ca(2+); LncRNA; NF-κB; PDX; cancer; glycolysis; metabolism; signal transduction; tumor microenvironment

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