title: Interleukin-22 promotes epithelial cell transformation and breast tumorigenesis via MAP3K8 activation.
abstract: Interleukin-22 (IL-22), one of the cytokines secreted by T-helper 17 (Th17) cells, binds to a class II cytokine receptor containing an IL-22 receptor 1 (IL-22R1) and IL-10R2 and influences a variety of immune reactions. IL-22 has also been shown to modulate cell cycle and proliferation mediators such as extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK), but little is known about the underlying molecular mechanisms of IL-22 in tumorigenesis. In this paper, we propose that IL-22 has a crucial role to play in controlling epithelial cell proliferation and tumorigenesis in the breast. IL-22 increased MAP3K8 phosphorylation through IL-22R1, followed by the induction of MEK-ERK, JNK-c-Jun, and STAT3 signaling pathways. Furthermore, IL-22-IL-22R1 signaling pathway activated activator protein-1 and HER2 promoter activity. In addition, Pin1 was identified as a key positive regulator for the phosphorylation-dependent MEK, c-Jun and STAT3 activity induced by IL-22. Pin1(-/-) mouse embryonic fibroblasts (MEF) exhibited significantly a decrease in IL-22-induced MEK1/2, c-Jun, and STAT3 phosphorylation compared with Pin1(+/+) MEF. In addition, a knockdown of Pin1 prevented phosphorylation induced by IL-22. The in vivo chorioallantoic membrane assay also showed that IL-22 increased tumor formation of JB6 Cl41 cells. Moreover, the knockdown of MAP3K8 and Pin1 attenuated tumorigenicity of MCF7 cells. Consistent with these observations, IL-22 levels positively correlate with MAP3K8 and Pin1 expression in human breast cancer. Overall, our findings point to a critical role for the IL-22-induced MAP3K8 signaling pathway in promoting cancer-associated inflammation in the tumor microenvironment.
authors: College of Pharmacy, Chosun University and Department of Pathology, School of Medicine, Chosun University, Gwangju 501-759, South Korea.
authors: Karam
authors: K
authors: Kim
authors: College of Pharmacy, Chosun University and Department of Pathology, School of Medicine, Chosun University, Gwangju 501-759, South Korea.
authors: Garam
authors: G
authors: Kim
authors: College of Pharmacy, Chosun University and Department of Pathology, School of Medicine, Chosun University, Gwangju 501-759, South Korea.
authors: Jin-Young
authors: JY
authors: Kim
authors: College of Pharmacy, Chosun University and Department of Pathology, School of Medicine, Chosun University, Gwangju 501-759, South Korea.
authors: Hyo Jeong
authors: HJ
authors: Yun
authors: Department of Pathology, School of Medicine, Chosun University, Gwangju 501-759, South Korea.
authors: Sung-Chul
authors: SC
authors: Lim
authors: College of Pharmacy, Chosun University and Department of Pathology, School of Medicine, Chosun University, Gwangju 501-759, South Korea chs@chosun.ac.kr.
authors: Hong Seok
authors: HS
authors: Choi
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D064593:Heterografts; D006801:Humans; D007378:Interleukins / Q000378:metabolism* / Q000494:pharmacology; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019696:Peptidylprolyl Isomerase / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D000097043:Interleukin-22
chemical_list: D007378:Interleukins; D020930:MAP Kinase Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019696:Peptidylprolyl Isomerase; D011518:Proto-Oncogene Proteins; D016755:Proto-Oncogene Proteins c-jun; D050796:STAT3 Transcription Factor; D018808:Transcription Factor AP-1; D000097043:Interleukin-22; C069937:MAP3K8 protein, human; C000606846:PIN1 protein, human; C000606850:Pin1 protein, mouse