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MicroRNA-323-3p inhibits cell invasion and metastasis in pancreatic ductal adenocarcinoma via direct suppression of SMAD2 and SMAD3.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC), which accounts for 96% of all pancreatic cancer cases, is characterized by rapid progression, invasion and metastasis. Transforming growth factor-beta (TGF-?) signaling is an essential pathway in metastatic progression and microRNAs (miRNA) play central roles in the regulation of various biological and pathologic processes including cancer metastasis. However, the molecular mechanisms involved in regulation of miRNAs and activation of TGF-? signaling in PDAC remain to be established. The results of this study suggested that miR-323-3p expression in PDAC tissues and cell lines was significantly decreased compared to levels in normal pancreatic tissues and primary cultured pancreatic duct epithelial cells. Further investigation revealed that miR-323-3p directly targeted and suppressed SMAD2 and SMAD3, both key components in TGF-? signaling. Lower levels of miR-323-3p predicted poorer prognosis in patients with PDAC. Ectopic overexpression of miR-323-3p significantly inhibited, while silencing of miR-323-3p increased the migration and invasion abilities of PDAC cells in vitro. Moreover, using an in vivo mouse model, we demonstrated that overexpressing of miR-323-3p significantly reduced, while knockdown of miR-323-3p enhanced lung metastatic colonization of PANC-1 cells. Furthermore, miR-323-3p-induced TGF-b signaling inhibition and cell motility suppression were partially rescued by overexpressing of Smad2 and Smad3 in PDAC cells. Our findings suggest that re-expression of miR-323-3p might offer a novel therapeutic target against metastasis in patients with PDAC.

SUBMITTER: Wang C

PROVIDER: S-EPMC4924761 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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MicroRNA-323-3p inhibits cell invasion and metastasis in pancreatic ductal adenocarcinoma via direct suppression of SMAD2 and SMAD3.

Wang Chunyou C Liu Pian P Wu Heshui H Cui Pengfei P Li Yongfeng Y Liu Yao Y Liu Zhiqiang Z Gou Shanmiao S

Oncotarget 20160301 12

Pancreatic ductal adenocarcinoma (PDAC), which accounts for 96% of all pancreatic cancer cases, is characterized by rapid progression, invasion and metastasis. Transforming growth factor-beta (TGF-β) signaling is an essential pathway in metastatic progression and microRNAs (miRNA) play central roles in the regulation of various biological and pathologic processes including cancer metastasis. However, the molecular mechanisms involved in regulation of miRNAs and activation of TGF-β signaling in P ...[more]

PMID: 26908446

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Project description:IntroductionPancreatic ductal adenocarcinoma (PDAC) is projected to rise to the second leading cause of U.S. cancer-related deaths by 2020. Novel therapeutic targets are desperately needed. MicroRNAs (miRs) are small noncoding RNAs that function by suppressing gene expression and are dysregulated in cancer. miR-21 is overexpressed in PDAC tumor cells (TC) and is associated with decreased survival, chemoresistance and invasion. Dysregulation of miR regulatory networks in PDAC tumor-associated fibroblasts (TAFs) have not been previously described. In this study, we show that miR-21 expression in TAFs promotes TC invasion.MethodsIn-situ hybridization for miR-21 was performed on the 153 PDAC patient UCLA tissue microarray and 23 patient-matched lymph node metastases. Stromal and TC histoscores were correlated with clinicopathologic parameters by univariate and multivariate Cox regression. miR-21 positive cells were further characterized by immunofluorescence for mesenchymal/epithelial markers. For in vitro studies, TAFs were isolated from freshly resected human PDAC tumors by the outgrowth method. miR-21 was overexpressed/inhibited in fibroblasts and then co-cultured with GFP-MiaPaCa TCs to assess TC invasion in modified Boyden chambers.ResultsmiR-21 was upregulated in TAFs of 78% of tumors, and high miR-21 significantly correlated with decreased overall survival (P = 0.04). Stromal miR-21 expression was also significantly associated with lymph node invasion (P = 0.004), suggesting that it is driving TC spread. Co-immunofluorescence revealed that miR-21 colocalized with peritumoral fibroblasts expressing ?-smooth muscle actin. Moreover, expression of miR-21 in primary TAFs correlated with miR-21 in TAFs from patient-matched LN metastases; evidence that PDAC tumor cells induce TAFs to express miR-21. miR-21 expression in TAFs and TCs promotes invasion of TCs and is inhibited with anti-miR-21.ConclusionsmiR-21 expression in PDAC TAFs is associated with decreased overall survival and promotes TC invasion. Anti-miR-21 may represent a novel therapeutic strategy for dual targeting of both tumor and stroma in PDAC.

Project description:BackgroundMicroRNAs (miRNAs) are short non-coding RNAs that regulate gene expression, influence cellular processes, and promote disease development. Variations in miRNA expression have been observed in many diseases, including hepatitis, cardiovascular disease, and cancer. The aim of this study is to investigate the effect of miR-144-3p on the invasion and metastasis of lung adenocarcinoma by targeting recombinant insulin receptor substrate 1 (IRS1).MethodsThe expression of miR-144-3p in patients with lung adenocarcinoma was queried through bioinformatics database. MirTarPathway was used to analyze the KEGG enrichment pathway of miRNA. The expression and plasmid transfection efficiency of miR-144-3p in lung adenocarcinoma cell lines were detected by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Transwell assay was used to detect the changes of cell invasion and migration ability in different groups. Bioinformatics determined the key genes (Hub genes) of miR-144-3p; Double luciferase target assay was used to detect the mutual binding of miR-144 and IRS1. Western blot assay was used to detect the expression of IRS1 in different cell lines and the expression of after overexpression of miR-144.ResultsThe expression of miR-144-3p in lung adenocarcinoma tissues was decreased, qRT-PCR results indicated that the expression of miR-144-3p in lung adenocarcinoma cell A549 was significantly decreased (P<0.05), and the overexpressed plasmid was successfully transfected (P<0.05). Overexpression of miR-144 decreased the ability of cell migration and invasion (P<0.05). The expression of IRS1 was up-regulated in lung adenocarcinoma tissues. Survival analysis showed that patients with lung adenocarcinoma with high IRS1 expression had a poor prognosis (P<0.05). Double luciferase assay results showed that miR-144 could specifically identify 3'-UTR of IRS1 and inhibit reporter enzyme expression (P<0.05). Western blot indicated that the expression of IRS1 was increased in A549 cells (P<0.05). After overexpression of miR-144, the expression level of IRS1 protein was decreased (P<0.05). Transwell experiment proved that miR-144-3p could inhibit invasion and metastasis of lung adenocarcinoma cells by targeting IRS1 (P<0.05).ConclusionsMiR-144-3p inhibits the invasion and migration of A549 cells through targeted regulation of IRS1, thus playing an anticancer role in tumors.

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MicroRNA-323-3p inhibits cell invasion and metastasis in pancreatic ductal adenocarcinoma via direct suppression of SMAD2 and SMAD3.

Publications

MicroRNA-323-3p inhibits cell invasion and metastasis in pancreatic ductal adenocarcinoma via direct suppression of SMAD2 and SMAD3.

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