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.

Upregulated miR‐132 in Lgr5+ gastric cancer stem cell‐like cells contributes to cisplatin‐resistance via SIRT1/CREB/ABCG2 signaling pathway

“…In our present study, we demonstrate that SIRT1 protein directly interactes with CREB protein and deacetylates CREB at the post‐translational level in Lgr5 + GCSCs. CREB deacetylation status led to suppression of the forskolin‐induced CREB phosphorylation, which was in accordance with the conclusions outlined above which also helps to suggest the down‐expression of SIRT1 in Lgr5 + GCSCs.…”

MiR‐199b‐5p inhibits osteogenic differentiation in ligamentum flavum cells by targeting JAG1 and modulating the Notch signalling pathway

“…MiR‐199b, which is located on chromosome 9q34.11, has been widely researched in recent years and implicated in tumour progression in tumours such as myeloid leukaemia , lymphoid leukaemia , medulloblastoma , choriocarcinoma , endometrioid endometrial carcinoma , ovarian cancer , breast cancer , prostate cancer , hepatocellular carcinoma , colorectal cancer , Kaposi's sarcoma , osteosarcoma and Ewing's sarcoma . Additionally, miR‐199b has also been implicated in other pathologies such as heart failure , idiopathic pulmonary arterial hypertension and intractable epilepsy .…”

MicroRNAs as potential therapeutic targets to predict responses to oxaliplatin in colorectal cancer: From basic evidence to therapeutic implication

“…Sirtuin 1 (SIRT1) is another protein, which regulates the expression of MMPs and E‐cadherin. Several studies indicated that Sirtuin1 overexpression leads to an upregulation of MMPs and downregulation of E‐cadherin in various cancers, and therefore stimulates cells invasion, metastasis, and EMT …”

“…In addition, transfection with miR‐199b lentivirus inhibits lung and liver metastasis in CRC nude mice model. The downregulation of miR‐199b predicts a poor prognosis in patients of CRC . These items were presented in Figure .…”