title: Downregulation of miR-199b is associated with distant metastasis in colorectal cancer via activation of SIRT1 and inhibition of CREB/KISS1 signaling.
abstract: The progression of distant metastasis cascade is a multistep and complicated process, frequently leading to a poor prognosis in cancer patients. Recently, growing evidence has indicated that deregulation of microRNAs (miRNAs) contributes to tumorigenesis and tumor progression in colorectal cancer (CRC). In the present study, by comparing the miRNA expression profiles of CRC tissues and corresponding hepatic metastasis tissues, we established the downregulation of miR-199b in CRC metastasis tissues. The decrease in miR-199b expression was significantly correlated to late TNM stage and distant metastasis. Moreover, Kaplan-Meier curves showed that CRC patients with high expression level of miR-199b had a longer median survival. Functional assays results indicated that the restoration of miR-199b considerably reduced cell invasion and migration in vitro and in vivo, and increased the sensitivity to 5-FU and oxaliplatin. Further dual-luciferase reporter gene assays revealed that SIRT1 was the direct target of miR-199b in CRC. The expression of miR-199b was inversely correlated with SIRT1 in CRC specimens. SIRT1 knockdown produced effects on biological behavior that were similar to those of miR-199b overexpression. Furthermore, through Human Tumor Metastasis PCR Array we discovered KISS1 was one of the downstream targets of SIRT1. Silencing of SIRT1 upregulated KISS1 expression by enhancing the acetylation of the transcription factor CREB. The latter was further activated via binding to the promoter of KISS1 to induce transcription. Thus, we concluded that miR-199b regulates SIRT1/CREB/KISS1 signaling pathway and might serve as a prognosis marker or a novel therapeutic target for patients with CRC.
authors.affiliation: Department of Gastroenterological Surgery, Peking University People's Hospital, Beijing, 100044, PR China.|Laboratory of Surgical Oncology, Peking University People's Hospital, Beijing, 100044, PR China.
authors.forename: Zhan-Long
authors.initials: ZL
authors.lastname: Shen
authors.affiliation: Department of Gastroenterological Surgery, Peking University People's Hospital, Beijing, 100044, PR China.|Laboratory of Surgical Oncology, Peking University People's Hospital, Beijing, 100044, PR China.
authors.forename: Bo
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Gastroenterological Surgery, Peking University People's Hospital, Beijing, 100044, PR China.|Laboratory of Surgical Oncology, Peking University People's Hospital, Beijing, 100044, PR China.
authors.forename: Ke-Wei
authors.initials: KW
authors.lastname: Jiang
authors.affiliation: Department of Gastroenterological Surgery, Peking University People's Hospital, Beijing, 100044, PR China.|Laboratory of Surgical Oncology, Peking University People's Hospital, Beijing, 100044, PR China.
authors.forename: Chun-Xiang
authors.initials: CX
authors.lastname: Ye
authors.affiliation: Department of General Surgery, Tangshan Gongren Hospital, Hebei Medical University, Tangshan, Hebei, 063000, PR China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Cheng
authors.affiliation: Department of Gastroenterological Surgery, Peking University People's Hospital, Beijing, 100044, PR China.|Laboratory of Surgical Oncology, Peking University People's Hospital, Beijing, 100044, PR China.
authors.forename: Yi-Chao
authors.initials: YC
authors.lastname: Yan
authors.affiliation: Department of Gastroenterological Surgery, Peking University People's Hospital, Beijing, 100044, PR China.|Laboratory of Surgical Oncology, Peking University People's Hospital, Beijing, 100044, PR China.
authors.forename: Ji-Zhun
authors.initials: JZ
authors.lastname: Zhang
authors.affiliation: Department of Gastroenterological Surgery, Peking University People's Hospital, Beijing, 100044, PR China.|Laboratory of Surgical Oncology, Peking University People's Hospital, Beijing, 100044, PR China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Gastroenterological Surgery, Peking University People's Hospital, Beijing, 100044, PR China.|Laboratory of Surgical Oncology, Peking University People's Hospital, Beijing, 100044, PR China.
authors.forename: Zhi-Dong
authors.initials: ZD
authors.lastname: Gao
authors.affiliation: Department of Gastroenterological Surgery, Peking University People's Hospital, Beijing, 100044, PR China.|Laboratory of Surgical Oncology, Peking University People's Hospital, Beijing, 100044, PR China.
authors.forename: Ying-Jiang
authors.initials: YJ
authors.lastname: Ye
authors.affiliation: Department of Gastroenterological Surgery, Peking University People's Hospital, Beijing, 100044, PR China.|Laboratory of Surgical Oncology, Peking University People's Hospital, Beijing, 100044, PR China.
authors.forename: Shan
authors.initials: S
authors.lastname: Wang
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D064593:Heterografts; D006801:Humans; D053208:Kaplan-Meier Estimate; D059648:Kisspeptins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000235:genetics* / Q000473:pathology; D011379:Prognosis; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; C106628:KISS1 protein, human; D059648:Kisspeptins; D035683:MicroRNAs; C531408:mirn199 microRNA, human; C447939:SIRT1 protein, human; D056564:Sirtuin 1
keywords: KISS1; SIRT1; colorectal cancer; metastasis; miR-199b