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Functional polymorphisms in LncRNA HOTAIR contribute to susceptibility of pancreatic cancer.

ABSTRACT: Background:Pancreatic cancer (PC) remains one of the most aggressive cancers worldwide. However, genetic factors underlying PC susceptibility remain largely unclear. Long noncoding RNA (lncRNA) HOX transcript antisense RNA (HOTAIR) acts as an oncogene and its genetic variation has been linked to many cancers. However, the associations between genetic variants in HOTAIR gene and PC risk has not yet been reported. Methods:A two-stage, case-control study was conducted to investigate the associations between HOTAIR SNPs and the PC risk. Dual luciferase reporter assay and real-time -PCR (RT-PCR) was conducted to evaluate the potential regulatory function of HOTAIR rs4759314 and rs200349340. Results:We found the minor alleles of rs4759314 (OR?=?1.76; 95 CI 1.37-2.25; P?=?0.001) and rs200349340 (OR?=?1.32; 95 CI 1.12-1.56; P?=?0.001) were significantly associated with PC susceptibility. In functional experiments, we found subjects carrying the minor alleles of rs4759314 and rs200349340 had significantly higher HOTAIR RNA levels (mean?±?SD) than those carrying the major alleles in PC tissues. For rs4759314, cells transfected with rs4759314 -G allele construct showed higher relative luciferase activity; while for rs200349340, cells transfected with rs200349340 -G allele construct showed more sensitive change of the relative luciferase activity. Conclusion:Our studies revealed that functional SNP rs4759314 and rs200349340 of HOTAIR had strong associations with PC susceptibility. These findings elucidate that functional genetic variants influencing lncRNA expression may explain a portion of PC genetic basis.

SUBMITTER: Jiang D

PROVIDER: S-EPMC6396528 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Functional polymorphisms in LncRNA HOTAIR contribute to susceptibility of pancreatic cancer.

Jiang Dawei D Xu Liu L Ni Jianqi J Zhang Jie J Cai Min M Shen Lan L

Cancer cell international 20190228

<h4>Background</h4>Pancreatic cancer (PC) remains one of the most aggressive cancers worldwide. However, genetic factors underlying PC susceptibility remain largely unclear. Long noncoding RNA (lncRNA) HOX transcript antisense RNA (HOTAIR) acts as an oncogene and its genetic variation has been linked to many cancers. However, the associations between genetic variants in HOTAIR gene and PC risk has not yet been reported.<h4>Methods</h4>A two-stage, case-control study was conducted to investigate ...[more]

PMID: 30867650

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Project description:Background:The long non-coding RNA H19 plays critical roles in cancer occurrence, development, and progression. The present study is for the first time to evaluate the association of genetic variations in the H19 promoter region with advanced colorectal cancer (CRC) susceptibility, environmental factors, and clinical outcomes. Methods:16 single-nucleotide polymorphisms (SNPs) were identified in the H19 gene promoter by DNA sequencing, and 3 SNPs among which including rs4930101, rs11042170, and rs2735970 further expanded samples with 572 advanced CRC patients and 555 healthy controls. Results:We found that harboring SNP [rs4930101 (P?=?0.009), rs2735970 (P?=?0.003), and rs11042170 (P?=?0.003)] or carrying more than one combined risk genotypes significantly increased the risk for CRC [P?<?0.0001, adjusted OR (95% CI) 6.48 (2.97-14.15)]. In the correlation analysis with environmental factors, rs2735970 and gender, combined risk genotypes (>?1 vs.???1) and family history of cancer demonstrated significant interactions. Furthermore, a remarkably worse clinical outcome was found in combined risk genotypes (>?1 vs.???1), especially in CRC patients with body weight???61 kg, smoking, and first-degree family history of cancer (Log-rank test: P?=?0.006, P?=?0.018, and P?=?0.013, respectively). More importantly, the multivariate Cox regression analyses further verified that combined risk genotypes?>?1 showed a prognostic risk factor for CRC patients with body weight???61 kg (P?=?0.002), smoking (P?=?0.008), and family history of cancer (P?=?0.006). In addition, MDR analysis consistently revealed that the combination of selected SNPs and nine known risk factors showed a better prediction prognosis and represented the best model to predict advanced CRC prognosis. Conclusion:3 SNPs of rs4930101, rs11042170, and rs27359703 among 16 identified SNPs of H19 gene remarkably increased CRC risk. Furthermore, the combined risk genotypes had a significant impact on environmental factors and clinical outcomes in the advanced CRC patients with body weight???61 kg, ever-smoking, and first-degree family history of cancer. These data suggest that H19 promoter SNPs, especially these combined SNPs might be more potentially functional biomarkers in the prediction of advanced CRC risk and prognosis.

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Functional polymorphisms in LncRNA HOTAIR contribute to susceptibility of pancreatic cancer.

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Functional polymorphisms in LncRNA HOTAIR contribute to susceptibility of pancreatic cancer.

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