Downregulation of miR-199b is associated with distant metastasis in colorectal cancer via activation of SIRT1 and inhibition of CREB/KISS1 signaling
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Zhan-long Shen1,2,*, Bo Wang1,2,*, Ke-wei Jiang1,2, Chun-xiang Ye1,2, Cheng Cheng3, Yi-chao Yan1,2, Ji-zhun Zhang1,2, Yang Yang1,2, Zhi-dong Gao1,2, Ying-jiang Ye1,2, Shan Wang1,2
1Department of Gastroenterological Surgery, Peking University People’s Hospital, Beijing, 100044, PR China
2Laboratory of Surgical Oncology, Peking University People’s Hospital, Beijing, 100044, PR China
3Department of General Surgery, Tangshan Gongren Hospital, Hebei Medical University, Tangshan, Hebei, 063000, PR China
*These authors have contributed equally to this work
Shan Wang, e-mail: [email protected]
Ying-jiang Ye, e-mail: [email protected]
Zhan-long Shen, e-mail: [email protected]
Keywords: miR-199b, SIRT1, KISS1, colorectal cancer, metastasis
Received: September 05, 2015 Accepted: April 11, 2016 Published: April 27, 2016
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.
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