Overexpression of LncRNA GHET1 predicts an unfavourable survival and clinical parameters of patients in various cancers

Abstract Recently, increasing studies have reported that long non‐coding RNA (lncRNA) gastric carcinoma highly expressed transcript 1 (GHET1) is highly expressed in variety of cancers and relevant to poor prognosis of cancer patients. Nevertheless, the results were inconsistent and the systematic analysis of lncRNA GHET1 in cancers has not been inspected. Thus, we aim to evaluate the relationship between lncRNA GHET1 expression and clinical outcomes in human cancers. We searched keywords in PubMed, Web of Science, Embase, Cochrane Library and ClinicalTrial.gov. Stata SE12.0 software was used in the quantitative meta‐analysis. Pooled hazard ratio (HR) and odds ratio with 95% confidence interval (95% Cl) were calculated to evaluate the clinical significance of lncRNA GHET1. Twelve studies totalling 761 patients with cancers were included for analysis. The pooled results of this study indicated that high lncRNA GHET1 expression level was significantly associated with poor overall survival (OS, HR = 2.30, 95% CI: 1.75‐3.02) in human cancers. The statistical significance was also detected in subgroup analysis stratified by analysis method, cancer type, sample size and follow‐up time respectively. In addition, the elevated lncRNA GHET1 expression was also significantly related to more advanced clinical stage, earlier lymph node metastasis, earlier distant metastasis and bigger tumour size. LncRNA GHET1 may serve as a promising biomarker for prognosis in Asians with cancers.

there were more and more lncRNAs found every year. Although some lncRNAs functioned as protective genes, such as ANRIL, GAS5, MEG3, [9][10][11] most act as oncogenes, such as HOTAIR, RMRP, CCAT2 and TUG1. [12][13][14][15] Therefore, although IncRNAs were known as the noise of transcriptions initially, increasing attentions were attached to them because of their important roles in development of diseases and diverse biological processes, and they may serve as promising biomarkers in predicting prognosis of cancer. [14][15][16] Gastric carcinoma highly expressed transcript 1 (GHET1), has been identified as an lncRNA recently. It has been confirmed to be an oncogene in a variety of cancers, including the hepatocellular carcinoma, gastric cancer and colorectal cancer. LncRNA GHET1 activated by H3K27 acetylation promotes cell tumorigenesis through regulating ATF1 in the hepatocellular carcinoma. 17 Knockdown of lncRNA GHET1 inhibits cell-cycle progression and invasion. 18 Knockdown of lncRNA GHET1 inhibits cell proliferation and invasion of the colorectal cancer. 19 Overexpression of lncRNA GHET1 promotes the development of multidrug resistance in the gastric cancer cells. 20 Despite some studies that reported the association between ln-cRNA GHET1 and cancers, there has been still no consistent conclusion on the prognostic value of lncRNA GHET1 in cancer patients because of different outcomes and limited sample size in each individual study. [17][18][19][20][21][22] Therefore, we conducted this meta-analysis to identify the relationship between the expressions of lncRNA GHET1 in a variety of human cancers and the patients' overall survival (OS) as well as other clinical parameters, identifying the prognostic value of lncRNA GHET1 as a novel biomarker for human cancers.

| MATERIAL S AND ME THODS
Our systematic review and meta-analysis was reported according to the recommendations of the PRISMA statement. 23

| Literature retrieval strategy
In order to collect all articles eligible for this study, we retrieved key- Other additional studies were obtained by screening the reference list.
The articles only written in English were included in this meta-analysis.

| Inclusion and exclusion criteria
Eligible articles enrolled in this meta-analysis meet the following criteria:  or (c) letters, reviews, case reports and expert opinions.

| Data extraction and quality assessment
Two authors extracted the information and data from included studies independently, and any disagreement was resolved by consulting with the third author. The information and data were as following: To evaluate the quality of included studies, the Newcastle-Ottawa Scale (NOS) was applied, whose score is ranging from 0 to 9 points. 24,25 Studies' NOS score, 7-9, has been regarded as high quality. also did a sensitivity analysis to check the stability of results for OS.

| Statistical methods
Moreover, subgroup analyses of OS were performed.

| Main information of included studies
In these studies, the sample size ranged from 42 to 105, among a total of 761 participants. The main characteristics of included studies were presented in

| Association between lncRNA GHET1 expression and OS
Seven articles investigated the association between lncRNA GHET1 expression and OS with a total of 553 cancer patients. 21,22,30,32,[34][35][36]38 We used fix-effect model to analysis the HR of OS because of no

| Association between lncRNA GHET1 expression and clinical parameters
According to meta-analysis results of  Figure 5).

| Publication bias
No obvious bias was detected by the funnel plot ( Figure 6) and Begg's test in HRs for OS (P = 1.000). We did not proceed Begg's test for other clinical parameters, because of no enough studies included (n < 10).

| Sensitivity analysis
Sensitivity analysis was performed by removing one study every time from the pooled analysis to check the stability of results for OS of each study (Figure 7).

| D ISCUSS I ON
As lncRNAs play important roles in the process of genes' transcription and translation, their dysregulation has been increasingly identified as a hallmark feature in the progression of cancer. GHET1, a novel identified lncRNA, was significantly over-expressed in the gastric cancer. 36 It has been confirmed to be an oncogene through some biological process in a variety of cancers although the role of GHET1 in cancers remains unclear yet. 17,21,31,35 In addition, the prognosis value of GHET1 expression in cancer and association between high expression of GHET1 and tumour stage, differentiation, has also been widely reported. 21,22,30 In our meta-analysis, we found that lncRNA GHET1 might be an unfavourable prognosis factor for cancer patients. However, all of them can reflect the tendency of GHET1 expression and no statistical heterogeneity was found among them, including publication bias analysis and sensitivity analysis. Fourth, the HRs