CAMK2γ in intestinal epithelial cells modulates colitis-associated colorectal carcinogenesis via enhancing STAT3 activation.
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.
Molecular and Cellular Biology of Cancer Program, Department of Diabetes Complications and Metabolism, Diabetes and Metabolism Research Institute, City of Hope National Medical Center, Duarte, CA, USA.|Irell and Manella Graduate School of Biological Sciences, City of Hope National Medical Center, Duarte, CA, USA.
X
X
Ma
Molecular and Cellular Biology of Cancer Program, Department of Diabetes Complications and Metabolism, Diabetes and Metabolism Research Institute, City of Hope National Medical Center, Duarte, CA, USA.
Z
Z
Meng
Molecular and Cellular Biology of Cancer Program, Department of Diabetes Complications and Metabolism, Diabetes and Metabolism Research Institute, City of Hope National Medical Center, Duarte, CA, USA.|State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Innovation Center for Cell Signaling Network, Xiamen University, Xiamen, Fujian, China.
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L
Jin
Molecular and Cellular Biology of Cancer Program, Department of Diabetes Complications and Metabolism, Diabetes and Metabolism Research Institute, City of Hope National Medical Center, Duarte, CA, USA.|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
Z
Xiao
Molecular and Cellular Biology of Cancer Program, Department of Diabetes Complications and Metabolism, Diabetes and Metabolism Research Institute, City of Hope National Medical Center, Duarte, CA, USA.|Robert J Tomsich Institute of Pathology and Laboratory Medicine, Cleveland Clinic, Cleveland, OH, USA.
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X
Wang
Transgenic Mouse Core, City of Hope National Medical Center, Duarte, CA, USA.
W M
WM
Tsark
Molecular and Cellular Biology of Cancer Program, Department of Diabetes Complications and Metabolism, Diabetes and Metabolism Research Institute, City of Hope National Medical Center, Duarte, CA, USA.
L
L
Ding
Molecular and Cellular Biology of Cancer Program, Department of Diabetes Complications and Metabolism, Diabetes and Metabolism Research Institute, City of Hope National Medical Center, Duarte, CA, USA.
Y
Y
Gu
Molecular and Cellular Biology of Cancer Program, Department of Diabetes Complications and Metabolism, Diabetes and Metabolism Research Institute, City of Hope National Medical Center, Duarte, CA, USA.|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
J
Zhang
Molecular and Cellular Biology of Cancer Program, Department of Diabetes Complications and Metabolism, Diabetes and Metabolism Research Institute, City of Hope National Medical Center, Duarte, CA, USA.|Irell and Manella Graduate School of Biological Sciences, City of Hope National Medical Center, Duarte, CA, USA.
B
B
Kim
School of Public Health, Guangxi Medical University, Nanning, Guangxi, China.
M
M
He
Molecular and Cellular Biology of Cancer Program, Department of Diabetes Complications and Metabolism, Diabetes and Metabolism Research Institute, City of Hope National Medical Center, Duarte, CA, USA.
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X
Gan
Departments of Immunology, City of Hope National Medical Center, Duarte, CA, USA.
J E
JE
Shively
Department of Cancer Immunotherapeutics and Tumor Immunology Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA.
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H
Yu
Molecular and Cellular Biology of Cancer Program, Department of Diabetes Complications and Metabolism, Diabetes and Metabolism Research Institute, City of Hope National Medical Center, Duarte, CA, USA.|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.
R
R
Xu
Molecular and Cellular Biology of Cancer Program, Department of Diabetes Complications and Metabolism, Diabetes and Metabolism Research Institute, City of Hope National Medical Center, Duarte, CA, USA.|Irell and Manella Graduate School of Biological Sciences, City of Hope National Medical Center, Duarte, CA, USA.
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Huang
D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000502:physiology*; D063646:Carcinogenesis / Q000235:genetics*; D049109:Cell Proliferation / Q000235:genetics; D003092:Colitis / Q000150:complications* / Q000235:genetics / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050796:STAT3 Transcription Factor / Q000378:metabolism*
D050796:STAT3 Transcription Factor; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; C517674:Camk2g protein, mouse