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Pre-miR-149 rs71428439 polymorphism is associated with increased cancer risk and AKT1/cyclinD1 signaling in hepatocellular carcinoma.

ABSTRACT: Hepatocellular carcinoma (HCC) is one of the most common lethal malignancies in the world, and the current knowledge on the molecular and genetic basis of HCC is still limited. Previous study has shown miR-149 plays a tumor suppressive role in HCC, here we aimed to investigate the association between rs71428439 polymorphism, which located in the pre-miR-149, and the risk of HCC in a Chinese Han population. A total of 177 HCC patients and 103 healthy controls were genotyped, by a multivariate logistic regression, we found that individuals with GG genotype have significantly higher risk of HCC (adjusted OR=3.397, 95% CI=1.565-7.375, P=0.002) compared with those with AA genotype, similar results were also observed in recessive model (adjusted OR=2.563, 95% CI=1.300-5.054, P=0.007) and dominant model (adjusted OR=2.074, 95% CI=1.147-3.752, P=0.016). We further observed that tumor tissues in patients with GG genotype expressed lower level of miR-149 compared with those with AA or AG genotype, and consequently, AKT1, a pre-validated miR-149 target in vitro, was found to have higher expression level in tumors with GG genotype. In summary, our data indicated that rs71428439 may be a genetic risk factor of HCC in the Chinese Han population, and its mechanism possibly involves downregulated miR-149 expression and upregulated AKT1 expression.

SUBMITTER: Wu J

PROVIDER: S-EPMC4612990 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Pre-miR-149 rs71428439 polymorphism is associated with increased cancer risk and AKT1/cyclinD1 signaling in hepatocellular carcinoma.

Wu Jiantao J Lv Shemin S An Jianbo J Lu Chunhui C

International journal of clinical and experimental medicine 20150815 8

Hepatocellular carcinoma (HCC) is one of the most common lethal malignancies in the world, and the current knowledge on the molecular and genetic basis of HCC is still limited. Previous study has shown miR-149 plays a tumor suppressive role in HCC, here we aimed to investigate the association between rs71428439 polymorphism, which located in the pre-miR-149, and the risk of HCC in a Chinese Han population. A total of 177 HCC patients and 103 healthy controls were genotyped, by a multivariate log ...[more]

PMID: 26550305

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Project description:CircRNA/miRNA/mRNA axis has been reported to play crucial regulatory roles in multiple cancers, including hepatocellular carcinoma (HCC). In addition, recent investigations revealed that aloin exerted anti-tumor functions in HCC. However, the underlying mechanism of aloin on anti-tumor functions in HCC remained elusive. Therefore, this study aimed to investigate whether circRNA/miRNA/mRNA axis medicated the anti-tumor effect of aloin in HCC. Cell viability, invasion, apoptosis and autophagy were accessed by cell counting kit-8 (CCK-8), transwell invasion assay, flow cytometry, Western blot and immunofluorescence analysis, respectively. Expression levels of circ_0011385, miR-149-5p and WT1 mRNA were determined using qRT-PCR assay. Binding sites between miR-149-5p and circ_0011385 or WT1 were predicted in starBase database. The binding relationship among circ_0011385, miR-149-5p and WT1 were verified by dual-luciferase reporter assay and RNA immunoprecipitation. Besides, the rescue experiments were performed by co-transfection with cric_0011385 overexpression plasmid, si-cric_0011385, miR-149-5p mimic and inhibitor, WT1 pDNA and si-WT1 in HCC cells. Furthermore, tumor growth was also investigated in the xenograft mouse model. Aloin inhibited HCC proliferation and invasion as well as promoted apoptosis and autophagy both in vitro and in vivo. Besides, aloin suppressed circ_0011385 expression. Overexpressed circ_0011385 partially reversed the anti-tumor effect of aloin on HCC. In addition, it was revealed that the circ_0011385, miR-149-5p and WT1 genes were abnormally expressed in HCC. Furthermore, the binding interactions between circ_0011385, miR-149-5p and WT1 were predicted and confirmed. Moreover, the effect of circ_0011385 on the anti-tumor role of aloin in HCC was rescued by miR-149-5p mimics. MiR-149-5p regulated HCC progression via modulating WT1. Aloin suppressed cell proliferation, invasion and tumor growth and promoted apoptosis and autophagy in HCC through regulating circ_0011385/miR-149-5p/WT1 axis. Aloin may be a potential candidate drug for HCC treatment.Abbrevations: HCC: Hepatocellular carcinoma; ceRNA: competing endogenous RNA; miRNA: microRNA; MREs: miRNA response elements; WT1: Wilms' tumor 1; MMP-2: Matrix metalloproteinase; EMT: epithelial-mesenchymal transition; GADPH: glyceraldehyde 3-phosphate dehydrogenase; WT: wild type; MUT: mutant type; DMEM: dulbecco's modified eagle medium.

Project description:Polymorphisms in pre-miRNAs may affect its expression, then having effect on its target mRNAs and be associated with cancer susceptibility. In the current study, we evaluated the association of a 3-base pair (3-bp) indel polymorphism (rs57408770) in pre-miR-3131 with hepatocellular carcinoma (HCC) susceptibility in a Chinese population. Logistic regression analysis showed that the insertion allele of rs57408770 was significantly associated with an increased risk for HCC occurrence in both case-control studies. To further investigated the molecular mechanism underlying the correlation between rs57408770 and the risk of HCC, overexpression of pre-miR-3131 in HCC cell line was performed. Human HCC cell lines Sk-Hep-1 was obtained from Shanghai Cell Bank of Chinese Academy of Sciences on 9 December 2013.The fragment of 366bp including the insert allele of rs57408770 in pre-miR-3131 was directly synthesized and cloned into BamHI and EcoRI sites of pEGFP-N1 yielding the wild-type vector (pEGFP-N1-miR3131-WT). The mutant-type vector (pEGFP-N1-miR3131-MT) including the delete allele of rs57408770 was generated using QuikChange Lightening Site-Directed Mutagenesis Kit. The resulting constructs were verified by direct sequencing. For overexpression experiments, cells were cultured in 6-well plates at a density of 200 000 cells per well the day before transfection. 2.5Î¼g plasmids of empty vector pEGFP-N1, pEGFP-N1-miR3131-WT or pEGFP-N1-miR3131-MT were transfected into the growing cells (about 80%-90% confluent) using Lipofectamine2000. After 24 hours of the transfection, the cells were collected for subsequent experiments.And human genome-wide gene expression profile assay was used to screen the targets of miR-3131. For overexpression experiments, cells were cultured in 6-well plates at a density of 200 000 cells per well the day before transfection. 2.5Î¼g plasmids of empty vector pEGFP-N1, pEGFP-N1-miR3131-WT or pEGFP-N1-miR3131-MT were transfected into the growing cells (about 80%-90% confluent) using Lipofectamine2000 (Invitrogen). After 24 hours of the transfection, the cells were collected for subsequent experiments. There are 3 samples in this experiment.

Dataset Information

Pre-miR-149 rs71428439 polymorphism is associated with increased cancer risk and AKT1/cyclinD1 signaling in hepatocellular carcinoma.

Publications

Pre-miR-149 rs71428439 polymorphism is associated with increased cancer risk and AKT1/cyclinD1 signaling in hepatocellular carcinoma.

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