title: Jak-STAT3 pathway triggers DICER1 for proteasomal degradation by ubiquitin ligase complex of CUL4A(DCAF1) to promote colon cancer development.
abstract: Chronic intestinal inflammation is closely associated with colon cancer development and STAT3 seems to take center stage in bridging chronic inflammation to colon cancer progress. Here, we discovered that DICER1 was significantly downregulated in response to IL-6 or LPS stimulation and identified a novel mechanism for DICER1 downregulation via proteasomal degradation by ubiquitin ligase complex of CUL4A(DCAF1) in colon cancer cells. Meanwhile, PI3K-AKT signaling pathway phosphorylated DICER1 and contributed to its proteasomal degradation. The regulation of DICER1 by CUL4A(DCAF1) affected cell growth and apoptosis which is controlled by IL-6 activated Jak-STAT3 pathway. Intervention of CUL4A(DCAF1) ubiquitin ligase complex led to fluctuation in expression levels of DICER1 and microRNAs, and thus affected tumor growth in a mouse xenograft model. A panel of microRNAs that were downregulated by IL-6 stimulation was rescued by siRNA-CUL4A, and their predicated functions are involved in regulation of cell proliferation, apoptosis and motility. Furthermore, clinical specimen analysis revealed that decreased DICER1 expression was negatively correlated with STAT3 activation and cancer progression in human colon cancers. DICER1 and p-STAT3 expression levels correlated with 5-year overall survival of colon cancer patients. Consequently, this study proposes that inflammation-induced Jak-STAT3 signaling leads to colon cancer development through proteasomal degradation of DICER1 by ubiquitin ligase complex of CUL4A(DCAF1), which suggests a novel therapeutic opportunity for colon cancer.
authors.affiliation: Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, Hunan, China; Cancer Research Institute, Central South University, Key Laboratory of Carcinogenesis, Ministry of Health, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Changsha, Hunan, China.
authors.forename: Weiguo
authors.initials: W
authors.lastname: Ren
authors.affiliation: Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, Hunan, China.
authors.forename: Shourong
authors.initials: S
authors.lastname: Shen
authors.affiliation: Cancer Research Institute, Central South University, Key Laboratory of Carcinogenesis, Ministry of Health, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Changsha, Hunan, China.
authors.forename: Zhenqiang
authors.initials: Z
authors.lastname: Sun
authors.affiliation: Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Shu
authors.affiliation: Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Shen
authors.affiliation: Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China.
authors.forename: Chibin
authors.initials: C
authors.lastname: Bu
authors.affiliation: Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, Hunan, China.
authors.forename: Feiyan
authors.initials: F
authors.lastname: Ai
authors.affiliation: Cancer Research Institute, Central South University, Key Laboratory of Carcinogenesis, Ministry of Health, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Changsha, Hunan, China.
authors.forename: Xuemei
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, Hunan, China.
authors.forename: Anliu
authors.initials: A
authors.lastname: Tang
authors.affiliation: Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, Hunan, China.
authors.forename: Li
authors.initials: L
authors.lastname: Tian
authors.affiliation: Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, Hunan, China; Cancer Research Institute, Central South University, Key Laboratory of Carcinogenesis, Ministry of Health, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Changsha, Hunan, China.
authors.forename: Guiyuan
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, Hunan, China. Electronic address: lixiayu@163.com.
authors.forename: Xiayu
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, Hunan, China; Cancer Research Institute, Central South University, Key Laboratory of Carcinogenesis, Ministry of Health, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Changsha, Hunan, China. Electronic address: majian@csu.edu.cn.
authors.forename: Jian
authors.initials: J
authors.lastname: Ma
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D063646:Carcinogenesis / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology; D044842:Cullin Proteins / Q000096:biosynthesis / Q000235:genetics*; D053487:DEAD-box RNA Helicases / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015850:Interleukin-6 / Q000008:administration & dosage / Q000235:genetics; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000096:biosynthesis; D008875:Middle Aged; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D043244:Ribonuclease III / Q000096:biosynthesis* / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction; D016019:Survival Analysis; D054875:Ubiquitination / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: C114234:CUL4A protein, human; D044842:Cullin Proteins; C508600:IL6 protein, human; D015850:Interleukin-6; D035683:MicroRNAs; D050796:STAT3 Transcription Factor; D019869:Phosphatidylinositol 3-Kinases; C408087:DICER1 protein, human; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases
keywords: CUL4A(DCAF1) ligase complex; Colon cancer; DICER1; IL-6; Jak-STAT3; Ubiquitination