Th22 cells control colon tumorigenesis through STAT3 and Polycomb Repression complex 2 signaling.
Th22 cells traffic to and retain in the colon cancer microenvironment, and target core stem cell genes and promote colon cancer stemness via STAT3 and H3K79me2 signaling pathway and contribute to colon carcinogenesis. However, whether Th22 cells affect colon cancer cell proliferation and apoptosis remains unknown. We studied the interaction between Th22 cells and colon cancer cells in the colon cancer microenvironment. Colon cancer proliferation was examined by flow cytometry analysis and H(3) thymidine incorporation. Cell cycle related genes were quantified by real-time PCR and Western blotting. We transfected colon cancer cells with lentiviral vector encoding specific gene shRNAs and used chromatin immunoprecipitation (ChIP) assay to determine the genetic signaling involved in interleukin (IL)-22-mediated colon cancer cell proliferation. We showed that Th22 cells released IL-22 and stimulated colon cancer proliferation. Mechanistically, IL-22 activated STAT3, and subsequently STAT3 bound to the promoter areas of the Polycomb Repression complex 2 (PRC2) components SUZ12 and EED, and stimulated the expression of PRC2. Consequently, the activated PRC2 catalyzed the promoters of the cell cycle check-point genes p16 and p21, and inhibited their expression through H3K27me3-mediated histone methylation, and ultimately caused colon cancer cell proliferation. Bioinformatics analysis revealed that the levels of IL-22 expression positively correlated with the levels of genes controlling cancer proliferation and cell cycling in colon cancer. In addition to controlling colon cancer stemness, Th22 cells support colon carcinogenesis via affecting colon cancer cell proliferation through a distinct histone modification.
Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA; State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology & Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, Shanghai, China.
Danfeng
D
Sun
Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA; State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology & Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, Shanghai, China.
Yanwei
Y
Lin
State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology & Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease , Shanghai, China.
Jie
J
Hong
State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology & Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease , Shanghai, China.
Haoyan
H
Chen
Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA; Graduate Programs in Immunology, University of Michigan School of Medicine, Ann Arbor, MI, USA.
Nisha
N
Nagarsheth
Department of Surgery, University of Michigan School of Medicine , Ann Arbor, MI, USA.
Dongjun
D
Peng
Department of Surgery, University of Michigan School of Medicine , Ann Arbor, MI, USA.
Shuang
S
Wei
Department of Colorectal Surgery, Cleveland Clinic, Western Reserve University , Cleveland, OH, USA.
Emina
E
Huang
State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology & Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease , Shanghai, China.
Jingyuan
J
Fang
Department of Surgery, University of Michigan School of Medicine , Ann Arbor, MI, USA.
Ilona
I
Kryczek
Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA; Graduate Programs in Immunology, University of Michigan School of Medicine, Ann Arbor, MI, USA; Tumor Biology, University of Michigan School of Medicine, Ann Arbor, MI, USA; The University of Michigan Comprehensive Cancer Center, University of Michigan School of Medicine, Ann Arbor, MI, USA.
Weiping
W
Zou
Colon cancer; IL-22; PRC2; STAT3; Th22