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CAMK2γ in intestinal epithelial cells modulates colitis-associated colorectal carcinogenesis via enhancing STAT3 activation

Oncogene volume 36, pages 4060–4071 (2017)Cite this article

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Abstract

Inflammation is one of the major risk factors for cancer. Here, we show that calcium/calmodulin-dependent protein kinase II gamma (CAMK2γ) in intestinal epithelial cells (IECs) modulates inflammatory signals and promotes colitis-associated cancer (CAC) in mice. We have identified CAMK2γ as a downstream target of colitis-induced WNT5A signaling. Furthermore, we have shown that CAMK2γ protects against intestine tissue injury by increasing IEC survival and proliferation. Calcium/calmodulin-dependent protein kinase II gamma knockout mice displayed reduced CAC. Furthermore, we used bone marrow transplantation to reveal that CAMK2γ in IECs, but not immune cells, was crucial for its effect on CAC. Consistently, transgenic over-expression of CAMK2γ in IECs accelerated CAC development. Mechanistically, CAMK2γ in IECs enhanced epithelial signal transducer and activator of transcription 3 (STAT3) activation to promote survival and proliferation of colonic epithelial cells during CAC development. These results thus identify a new molecular mechanism mediated by CAMK2γ in IECs during CAC development, thereby providing a potential new therapeutic target for CAC.

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Acknowledgements

We thank Dr Johannes Backs for providing the Camk2γ KO mice. We thank Dr Richard Ermel and the Animal Resource Center for the technical resources. We thank the pathologists from the City of Hope Pathology Core Lab for sample processing and analysis. We thank Dr Fong-Fong Chu and Dr Mei Kong at City of Hope for discussion. We also thank Dr Nancy Linford for providing editing assistance. This work is supported in part by 2NCI R01-CA139158, the National Natural Science Foundation of China (81270601 and 81328016) and the Open Research Fund of State Key Laboratory of Cellular Stress Biology, Xiamen University (SKLCSB2016KF002). Research reported in this publication was also supported by the National Cancer Institute of the National Institutes of Health under award number P30CA33572.

Author contributions

WH and RX supervised the project, designed the experiments and revised the manuscript. XM and ZM designed the experiments, performed most of the experiments and wrote the manuscript. XW, ZX, YG, JZ, LD, BK, MH, and XG performed the experiments. WMT assisted with the transgenic mouse line generation. LJ, JES, HY discussed the project, provided suggestions and revised the manuscript.

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  1. X Ma and Z Meng: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Diabetes Complications and Metabolism, Molecular and Cellular Biology of Cancer Program, Diabetes and Metabolism Research Institute, City of Hope National Medical Center, Duarte, CA, USA

    X Ma, Z Meng, L Jin, Z Xiao, X Wang, L Ding, Y Gu, J Zhang, B Kim, X Gan, R Xu & W Huang

  2. Irell and Manella Graduate School of Biological Sciences, City of Hope National Medical Center, Duarte, CA, USA

    X Ma, B Kim & W Huang

  3. State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Innovation Center for Cell Signaling Network, Xiamen University, Xiamen, Fujian, China

    L Jin

  4. Department of Clinical Laboratory, Fujian Provincial Key Laboratory of Tumor Biotherapy, Fujian Provincial Cancer Hospital, Teaching Hospital of Fujian Medical University, Fuzhou, Fujian, China

    Z Xiao

  5. Robert J Tomsich Institute of Pathology and Laboratory Medicine, Cleveland Clinic, Cleveland, OH, USA

    X Wang

  6. Transgenic Mouse Core, City of Hope National Medical Center, Duarte, CA, USA

    W M Tsark

  7. Department of Hematology (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China

    J Zhang & R Xu

  8. School of Public Health, Guangxi Medical University, Nanning, Guangxi, China

    M He

  9. Departments of Immunology, City of Hope National Medical Center, Duarte, CA, USA

    J E Shively

  10. Department of Cancer Immunotherapeutics and Tumor Immunology Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA

    H Yu

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Ma, X., Meng, Z., Jin, L. et al. CAMK2γ in intestinal epithelial cells modulates colitis-associated colorectal carcinogenesis via enhancing STAT3 activation. Oncogene 36, 4060–4071 (2017). https://doi.org/10.1038/onc.2017.16

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