LncRNA HOTAIR Gene And Its Genetic Variation And Gastric Cancer Susceptibility And Prognosis

LncRNA HOTAIR genetic variation involved in gastric cancer susceptibilityLong noncoding RNA(lncRNA)refers to RNA that is greater than 200 nucleotides in length and generally does not encode proteins.As an important part of epigenetics,lncRNA can participate in many physiological processes such as cell growth and differentiation,which makes it become a research hotspot in the field of tumor research.This part of the study focuses on the association between the SNP of tumor susceptibility gene lncRNA HOTAIR and gastric cancer susceptibility,and uncovers the underlying mechanisms of lncRNA HOTAIR and its genetic variation in the development and progression of gastric cancer.We used the Hap Map database to screen the representative tag SNPs of the lncRNA HOTAIR.A two-stage case control study was conducted to analyze the relationship between the selected SNPs and the risk of gastric cancer in the four genetic effect models(additive,dominant,recessive,and co-dominant models).This study found that lncRNA HOTAIR has a significant SNP locus rs4759314 associated with the onset of gastric cancer,and in the dominant and co-dominant models,carriers of the AG genotype had a significantly increased risk of gastric cancer.To reveal the underlying mechanism of rs4759314 affecting gastric cancer susceptibility,we detected the expression levels of the host genes of rs4759314,HOTAIR and HOXC11,in gastric cancer patients and found that the expression levels of HOTAIR and HOXC11 genes were significantly decreased in patients with AA genotype.We obtained a same result in the TCGA database(The Cancer Genome Atlas).We further constructed cell models to examine the effect of different alleles of rs4759314 on luciferase activity in gastric cancer cells.It was found that luciferase activity was significantly higher in gastric cancer cells carrying the G allele than in the A genotype,suggested that some allele-specific transcription factors may exist in the region of rs4759314 and participated in gastric cancer susceptibility.These studies preliminarily demonstrated that rs4759314 on lncRNA HOTAIR is involved in gastric cancer susceptibility and its possible mechanism.The study of expression of lncRNA HOTAIR involved in the prognosis of gastric cancerAs one of the most common malignant tumor in the world,gastric cancer has a poor prognosis and a low 5-year survival rate.At the current level of diagnosis and treatment,even if patients with gastric cancer receive the same treatment,only a few have achieved better therapeutic effects.Therefore,it is necessary to find a positive marker to predict the prognosis of patients with gastric cancer.Although a number of studies have evaluated the prognostic value of HOTAIR in patients with gastric cancer,the results are not completely consistent.Therefore,we performed a meta-analysis to assess the relationship between HOTAIR gene expression and the prognosis of gastric cancer and conducted an independent cohort to validate it with gastric cancer tissue samples.At the same time,the relationship between HOTAIR gene expression and the prognosis of digestive system tumors was discussed.The Pub Med database was searched to identify the eligible studies about the relationship between the HOTAIR and the prognosis of gastric cancer and digestive system tumors.In addition,the total RNA was extracted from 71 gastric tissue samples with survival information,and the expression of HOTAIR gene in gastric cancer tissues was detected by RT-PCR.Finally,the Kaplan-Meier method was used to calculate the overall survival curve and a log-rank test was applied for comparison.Through the search,a total of 6 studies on the relationship between the expression level of HOTAIR gene and the prognosis of gastric cancer patients were included in the meta-analysis.The analysis showed that high HOTAIR levels was associated with poor prognosis of gastric cancer(HR: 1.63,95% CI: 1.30-2.04).Subgroup analysis identified that the results were consistent with the overall analysis when stratified by HR resource and number of patients.The heterogeneity of this meta-analysis was low(I2 = 0.0%,P = 0.474).No obvious publication bias was found by the Egger test(P = 0.909)and Begg test(P = 0.881).Further validation in gastric cancer tissue found that 18 gastric cancer patients had an elevated HOTAIR expression and 53 had a low HOTAIR expression,and there were no statistically significant differences in age,gender,clinical pathology and adjuvant chemotherapy between the two groups(P > 0.05).Patients with high HOTAIR expression had a worse prognosis(HR: 2.10;95% CI: 1.10-4.03;log-rank P = 0.022),which was consistent with the meta-analysis.Finally,a total of 15 studies including 1,563 patients was enrolled in the meta-analysis of the relationship between HOTAIR gene expression levels and prognosis of patients with digestive system tumors.It was found that the HOTAIR high expression group had a poorer prognosis(HR: 2.07;95% CI: 1.76-2.45)and it was consistent with the results of the gastric cancer,stratified analysis showed that high expression of HOTAIR was also significantly associated with the prognosis of esophageal cancer(HR: 2.19;95% CI: 1.62-2.94)and colorectal cancer(HR: 5.10;95% CI: 2.64-9.84).Our study found that high expression of HOTAIR gene in gastric cancer tissues indicates poor prognosis of gastric cancer patients,suggesting that HOTAIR gene may serve as a potential biomarker to predict the prognosis of patients with gastric cancer.