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MicroRNA-301a-3p promotes pancreatic cancer progression via negative regulation of SMAD4.

ABSTRACT: Aim to determine the clinicopathological and prognostic role of miR-301a-3p in pancreatic ductal adenocarcinoma(PDAC), to investigate the biological mechanism of miR-301a-3p in vitro and in vivo.By tissue microarray analysis, we studied miR-301a-3p expression in PDAC patients and its clinicopathological correlations as well as prognostic significance. qRT-PCR was used to test miR-301a-3p expression in PDAC tissues and cell lines. Functional experiments including in vitro and in vivo were performed.Significantly higher expression of miR-301a-3p were found in PDAC patients with lymph node metastasis and advanced pathological stages and identified as an independent prognostic factor for worse survival. In PDAC samples and cell lines, miR-301a-3p was significantly up-regulated compared with matched non-tumor tissues and normal pancreatic ductal cells, respectively. Overexpression of miR-301a-3p enhanced PDAC cells colony, invasion and migration abilities in vitro as well as tumorigenicity in vivo. Furthermore, SMAD4 was identified as a target gene of miR-301a-3p by cell as well as mice xenograft experiments. In PDAC tissue microarray, a significantly inverse correlation between miR-301a-3p ISH scores and SMAD4 IHC scores were observed in both tumor and corresponding non-tumor tissues.MiR-301a-3p functions as a novel oncogene in PDAC and the oncogenic activity may involve its inhibition of the target gene SMAD4.

SUBMITTER: Xia X

PROVIDER: S-EPMC4673249 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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MicroRNA-301a-3p promotes pancreatic cancer progression via negative regulation of SMAD4.

Xia Xiang X Zhang Kundong K Cen Gang G Jiang Tao T Cao Jun J Huang Kejian K Huang Chen C Zhao Qian Q Qiu Zhengjun Z

Oncotarget 20150801 25

<h4>Background</h4>Aim to determine the clinicopathological and prognostic role of miR-301a-3p in pancreatic ductal adenocarcinoma(PDAC), to investigate the biological mechanism of miR-301a-3p in vitro and in vivo.<h4>Methods</h4>By tissue microarray analysis, we studied miR-301a-3p expression in PDAC patients and its clinicopathological correlations as well as prognostic significance. qRT-PCR was used to test miR-301a-3p expression in PDAC tissues and cell lines. Functional experiments includin ...[more]

PMID: 26019136

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Project description:MicroRNA?301a (miRNA/miR?301a) and nuclear factor (NF)??B signaling play important roles in tumor invasion, migration and progression. However, the role of miRNA?301a?3p in human gastric cancer (GC), and specifically in the activation of NF??B signaling, remains unclear. The aim of the present study was to investigate miRNA?301a?3p expression in GC progression and the molecular mechanisms as regards the regulation of NF??B signaling. Reverse transcription?quantitative polymerase chain reaction (RT?qPCR) was used to detect miRNA?301a?3p expression in GC and paired normal tissues. The association between the expression of miRNA?301a?3p and patient pathological parameters and the prognosis of GC was statistically analyzed using an in situ hybridization (ISH) assay. An MTS assay and a Transwell assay were performed to evaluate the effects of miRNA?301a?3p on the proliferation, invasion and migration of GC cells. RT?qPCR and western blot analysis were used to analyze the association between miRNA?301a?3p and nuclear factor??B repressing factor (NKRF) expression and the corresponding downstream NF??B signaling molecules. A luciferase assay was used to verify the target effect of miRNA?301a?3p and NKRF. It was found that miRNA?301a?3p expression was significantly higher in 30 cases of primary GC compared with matched normal tissues. Additionally, the ISH assay indicated that the high expression of miRNA?301a?3p in GC was associated with tumor invasion depth, lymph node metastasis, lymph node invasion and tumor metastasis stage. Patients whose tumors had a higher miRNA?301a?3p expression level exhibited a poorer prognosis. The in vitro assay indicated that miRNA?301a?3p affected the proliferative and invasive ability of GC cells by targeting the expression of NKRF, which then affected NF??B signaling. Therefore, it was hypothesize that miRNA?301a?3p promotes GC progression and affects the prognosis of patients with GC by targeting NKRF, which in turn, directly influences NF??B activation.

Project description:Purpose:STARD13 is regulated by various miRNAs. However, there are relatively few reports describing the relationship between miRNAs and STARD13 in pancreatic cancer. Therefore, the aim of this study was to explore the relationship between miRNA and STARD13 in pancreatic cancer. Patients and Methods:By analyzing the data from Gene Expression Omnibus (GEO) database, the relationship between STARD13 expression and pancreatic cancer was explored. Then, through sequence alignment, the sequence complementary to miR-887-3p in the 3'UTR of STARD13 mRNA was found, mutated and cloned. Dual-luciferase reporter assay was used to test the relationship between STARD13 and miR-887-3p. Pancreatic cancer tumor tissue and its adjacent tissues collected, and the expression of STARD13 and miR-887-3p in pancreatic cancer tissues was analyzed by RT-qPCR. After, miR-887-3p and its inhibitor were transfected into PANC-1 cells to further confirm the regulatory relationship between miR-887-3 and STARD13 by RT-qPCR, and CCK-8, colony formation assays, cell cycle analysis, apoptosis detection and transwell analysis were used to detect changes of proliferation, apoptosis, migration and invasion in PANC-1 cells. Finally, through in vivo experiments, the effect of miR-887-3p on tumor growth was researched. Results:We found that STARD13 expression is lower in pancreatic cancer tissues, with the level of miR-887-3p being higher in these tissues. Pancreatic cancer patients with particularly low levels of STARD13 presented with a poor prognosis. MiR-887-3p negatively regulates the expression of STARD13. Increasing levels of miR-887-3p decreased the expression of STARD13, which promoted the proliferation, cell cycle process, cell migration and invasion, and inhibited the apoptosis of pancreatic cancer cells. Inhibition of miR-887-3p in SCID mice could inhibit tumor growth and promote tumor cell apoptosis. Conclusion:In conclusion, STARD13 is negatively regulated by miR-887-3p in pancreatic cancer. MiR-877-3p may act to promote cancer progression, and as such, it is a viable target for intervention and diagnostic development.

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MicroRNA-301a-3p promotes pancreatic cancer progression via negative regulation of SMAD4.

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MicroRNA-301a-3p promotes pancreatic cancer progression via negative regulation of SMAD4.

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