Retraction Notice to: YTHDF1 Facilitates the Progression of Hepatocellular Carcinoma by Promoting FZD5 mRNA Translation in an m6A-Dependent Manner.

[This retracts the article DOI: 10.1016/j.omtn.2020.09.036.].

Long intergenic non-coding RNA LINC00485 exerts tumor-suppressive activity by regulating miR-581/EDEM1 axis in colorectal cancer.

Long non-coding RNAs (lncRNA) play a vital role in colorectal cancer (CRC) progression. To investigate the role of long intergenic non-coding RNA LINC00485 in CRC, we performed in vitro functional experiments. LoVo tumor-bearing and liver metastasis mice were used as in vivo models. We found that LINC00485 expression was significantly lower in CRC tissues and cancer cells than in paired normal samples and human normal colonic epithelial cells. Lower expression of LINC00485 predicted poor prognosis in CRC patients. LINC00485 knockdown promoted the proliferation, migration, and invasion of FHC cells, while LINC00485 overexpression weakened these abilities of LoVo cells. MicroRNA miR-581 was the downstream target of LINC00485, which was downregulated in CRC samples and cancer cells compared to normal tissues and normal colonic epithelial cells. MiR-581 overexpression induced proliferation, migration, and invasion of FHC cells, while miR-581 antagomir treatment produced opposite results. MiR-581 directly targeted the 3'UTR of EDEM1 and inhibited its expression and induction of epithelial-mesenchymal transition of CRC. In mouse models, LINC00485 knockdown or down-regulation of miR-581 significantly repressed CRC cell growth and prevented CRC liver metastasis. Overall, LINC00485 suppressed CRC tumorigenesis and progression by targeting the miR-581/EDEM1 axis. LINC00485 may be a potential therapeutic target for CRC.

Analysis of METTL3 and METTL14 in hepatocellular carcinoma.

N6-methyladenosine (m6A) RNA methylation is the most prevalent modification of messenger RNAs (mRNAs) and catalyzed by a multicomponent methyltransferase complex (MTC), among which methyltransferase-like 3 (METTL3) and METTL14 are two core molecules. However, METTL3 and METTL14 play opposite regulatory roles in hepatocellular carcinoma (HCC). Based on The Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) database, we conducted a multi-omics analysis of METTL3 and METTL14 in HCC, including RNA-sequencing, m6ARIP-sequencing, and ribosome-sequencing profiles. We found that the expression and prognostic value of METTL3 and METTL14 are opposite in HCC. Besides, after METTL3 and METTL14 knockdown, most of the dysregulated mRNAs, signaling pathways and biological processes are distinct in HCC, which partly explains the contrary regulatory role of METTL3 and METTL14. Intriguingly, these mRNAs whose stability or translation efficiency are influenced by METTL3 or METTL14 in an m6A dependent manner, jointly regulate multiple signaling pathways and biological processes, which supports the cooperative role of METTL3 and METTL14 in catalyzing m6A modification. In conclusion, our study further clarified the contradictory role of METTL3 and METTL14 in HCC.

YTHDF1 Facilitates the Progression of Hepatocellular Carcinoma by Promoting FZD5 mRNA Translation in an m6A-Dependent Manner.

Hepatocellular carcinoma (HCC), one of the most aggressive malignancies, ranks as the fourth leading cause of cancer-related deaths worldwide. Emerging evidence indicates that RNA N6-methyladenosine (m6A) plays a critical role in tumor progression. However, the biological function of YTHDF1 in HCC remains unclear. Here, we found that YTHDF1 expression was strikingly elevated in HCC tissues and cell lines and significantly associated with prognosis of HCC patients. Moreover, YTHDF1 expression was transcriptionally regulated by USF1 and c-MYC in HCC. Functional studies showed that YTHDF1 can promote HCC cell proliferation and metastasis both in vitro and in vivo. Multi-omics analysis revealed that YTHDF1 can accelerate the translational output of FZD5 mRNA in an m6A-dependent manner and function as an oncogene through the WNT/ß-catenin pathway. Taken together, our study revealed an essential role of YTHDF1 in the progression of HCC cells, which indicated that targeting YTHDF1 may be a potential therapeutic strategy in HCC.

METTL14-mediated N6-methyladenosine modification of SOX4 mRNA inhibits tumor metastasis in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is one of the leading causes of tumor-related death worldwide, and its main cause of death is distant metastasis. Methyltransferase-like 14(METTL14), a major RNA N6-adenosine methyltransferase, is involved in tumor progression via regulating RNA function. The goal of the study is to uncover the biological function and molecular mechanism of METTL14 in CRC. METHODS: Quantitative real-time PCR (qRT-PCR), western blot and immunohistochemical (IHC) assays were employed to detect METTL14 and SOX4 in CRC cell lines and tissues. The biological functions of METTL14 were demonstrated using in vitro and in vivo experiments. Chromatin immunoprecipitation (ChIP), Transcrptomic RNA sequencing (RNA-Seq), m6A-RNA immunoprecipitation sequencing (MeRIP-Seq), RNA immunoprecipitation and luciferase reporter assays were used to explore the mechanism of METTL14 action. RESULTS: METTL14 expression was significantly downregulated in CRC and decreased METTL14 was associated with poor overall survival (OS). Both the univariate and multivariate Cox regression analysis indicated that METTL14 was an independent prognostic factor in CRC. Moreover, lysine-specific histone demethylase 5C(KDM5C)-mediated demethylation of histone H3 lysine 4 tri-methylation(H3K4me3) in the promoter of METTL14 inhibited METTL14 transcription. Functionally, we verified that METTL14 inhibited CRC cells migration, invasion and metastasis through in vitro and in vivo assays, respectively. Furthermore, we identified SRY-related high-mobility-group box 4(SOX4) as a target of METTL14-mediated m6A modification. Knockdown of METTL14 markedly abolished SOX4 mRNA m6A modification and elevated SOX4 mRNA expression. We also revealed that METTL14-mediated SOX4 mRNA degradation relied on the YTHDF2-dependent pathway. Lastly, we demonstrated that METTL14 might inhibit CRC malignant process partly through SOX4-mediated EMT process and PI3K/Akt signals. CONCLUSIONS: Decreased METTL14 facilitates tumor metastasis in CRC, suggesting that METTL14 might be a potential prognostic biomarker and effective therapeutic target for CRC.

LRIG3 represses cell motility by inhibiting slug via inactivating ERK signaling in human colorectal cancer.

Metastasis is responsible for 90% of colorectal cancer (CRC)-related deaths. In the present study, we identified a novel key regulator of CRC metastasis, leucine-rich repeats and immunoglobulin-like domains protein 3 (LRIG3), which was significantly decreased in CRC tissues and cell lines. Downregulation of LRIG3 was attributed to copy number loss and promoter hypermethylation. Low LRIG3 expression was positively correlated with metastatic clinical features and shorter survival time. Functional experiments showed that knockout of LRIG3 markedly enhanced CRC cell migration and invasion ability, whereas reintroduction of LRIG3 exerted the opposite effects. Regarding the mechanism, LRIG3 could facilitate the binding of DUSP6 to ERK1/2, resulting in the dephosphorylation of ERK1/2 and subsequently downregulation of slug, an epithelial-to-mesenchymal transition trigger, thereby constraining CRC cell motility. Importantly, LRIG3 expression was strongly negatively correlated with slug or p-ERK1/2 expression in CRC tissues. Collectively, our data suggest that LRIG3 is a novel suppressor of CRC metastasis, reactivation of LRIG3 may be a promising therapeutic approach for metastatic CRC patients.

Serum exosomal miR-122 as a potential diagnostic and prognostic biomarker of colorectal cancer with liver metastasis.

Background: Liver is the most common site for metastatic spread of CRC at the time of diagnosis which leads to high mortality. This study aimed to identify novel circulating exosomal miRNAs as biomarkers of colorectal cancer (CRC) with liver metastasis (LM). Materials and methods: Candidate miRNAs were selected through integrated analysis of Gene Expression Omnibus (GEO) database as well as clinical samples. Exosomes isolated from serum and cultured media were identified by using transmission electron microscopy (TEM) and western blot. The expression levels and diagnostic value of candidate miRNAs were further tested and validated through qRT-PCR and receiver operating characteristic curve (ROC) analysis. The association of candidate miRNA expressions with patients' prognosis was analyzed with logistic regression and Cox proportional hazards regression models. Results: After integrated analysis of three GEO datasets and clinical samples, miR-122 was discovered to be remarkably overexpressed in tissues of CRC patients. Then we revealed that elevated serum miR-122 was tumor-derived by being packaged into exosomes. The expressions of serum exosomal miR-122 were significantly upregulated in CRC patients, especially in those with LM. Serum exosomal miR-122 expressions could differentiate CRC patients with LM from healthy controls and patients without LM with area under the ROC curve (AUC) of 0.89 and 0.81. Uni- and multivariate logistic regression showed that serum exosomal miR-122 was an independent prognostic indicator of CRC patients. Conclusions: Serum exosomal miR-122 was a novel potential diagnostic and prognostic biomarker in CRC patients with LM.

MiR-142-3p functions as a tumor suppressor by targeting RAC1/PAK1 pathway in breast cancer.

MicroRNA-142-3p (miR-142-3p) was previously investigated in various cancers, whereas, it's role in breast cancer (BC) remains far from understood. In this study, we found that miR-142-3p was markedly decreased both in cell lines and BC tumor tissues. Elevated miR-142-3p expression suppressed growth and metastasis of BC cell lines via gain-of-function assay in vitro and in vivo. Mechanistically, miR-142-3p could regulate the ras-related C3 botulinum toxin substrate 1 (RAC1) expression in protein level, which simultaneously suppressed the epithelial-to-mesenchymal transition related protein levels and the activity of PAK1 phosphorylation, respectively. In addition, rescue experiments revealed RAC1 overexpression could reverse tumor-suppressive role of miR-142-3p. Our results showed miR-142-3p could function as a tumor suppressor via targeting RAC1/PAK1 pathway in BC, suggesting a potent therapeutic target for BC treatment.

Identification of Serum Exosomal hsa-circ-0004771 as a Novel Diagnostic Biomarker of Colorectal Cancer.

Background: Exosomal circular RNAs (circRNAs) in peripheral blood are considered as emerging diagnostic biomarkers of cancers. Owing to the lack of sensitive and specific biomarkers, a large number of colorectal cancer (CRC) patients were diagnosed in advanced stages leading to high mortality. This study aimed to identify circulating exosomal circRNAs as novel diagnostic biomarkers of CRC. Materials and Methods: Candidate circRNA was selected by integrating analysis of Gene Expression Omnibus (GEO) database with online program GEO2R. A total of 170 patients and 45 healthy controls were enrolled to assess the diagnostic value of circRNAs for CRC. Exosomes isolated from the serum of participants and cell cultured media were confirmed by transmission electron microscope (TEM), Nanoparticle Tracking Analysis and western blot. The expression and the diagnostic utility of circRNA were tested by qRT-PCR and receiver operating characteristic (ROC) analysis, respectively. Results: The circulating exosomal hsa-circ-0004771 with most abundant among the top ten differentially expressed circRNAs (fold change ≥1.5) was selected for further study based on the results of GEO dataset analysis. The up-regulated exosomal hsa-circ-0004771 was verified in serum of CRC patients compared to healthy controls (HCs) and patients with benign intestinal diseases (BIDs) by qRT-PCR. The area under the ROC curves (AUCs) of circulating exosomal hsa-circ-0004771 were 0.59 (95%CI, 0.457-0.725), 0.86 (95%CI, 0.785-0.933) and 0.88 (95%CI, 0.815-0.940) to differentiate BIDs, stage I/II CRC patients and CRC patients from HCs, respectively. The AUC was 0.816 (95%CI, 0.728-0.9) to differentiate stage I/II CRC patients from patients with BIDs. In addition, the elevated expression of exosomal hsa-circ-0004771 in the serum of CRC patients was tumor-derived. It was found that the expression of exosomal hsa-circ-0004771 was down-regulated expression of in the serum of postoperative CRC patients as well as cultured media of CRC cells treated with GW4869. Conclusions: Circulating exosomal hsa-circ-0004771 was significantly up-regulated in CRC patients and served as a novel potential diagnostic biomarker of CRC.

miR-375-3p suppresses tumorigenesis and partially reverses chemoresistance by targeting YAP1 and SP1 in colorectal cancer cells.

Clinically, one of the principal factors in the failure of advanced colorectal cancer (CRC) treatment is chemoresistance to 5-fluorouracil (5FU)-based chemotherapy. Although microRNA-375-3p (miR-375) is considered a tumor suppressor in multiple cancers, the mechanism of miR-375 in the regulation of drug resistance in CRC remains unclear. In this study, we investigated the chemosensitivity of miR-375 to 5FU in CRC from biological and clinical aspects. We found that miR-375 was significantly downregulated in CRC tissues and cell lines, and low miR-375 expression was strongly correlated with poor overall survival in CRC patients. Overexpression of miR-375 sensitized CRC cells to a broad spectrum of chemotherapeutic drugs in vitro and in vivo. Further mechanistic analysis demonstrated that miR-375 enhanced CRC cell sensitivity to 5FU by directly targeting YAP1 and SP1. MiR-375 downregulated YAP1, resulting in reduced expression of the Hippo-YAP1 pathway downstream genes CTGF, cyclin D1 and BIRC5 (also known as survivin). Overall, miR-375 was confirmed as a prospective molecular biomarker in the chemoresistance and prognosis of CRC patients, and the synergy between miR-375 and chemotherapeutic drugs could be a promising therapeutic strategy for CRC patients, especially with chemoresistance.

LncRNA SATB2-AS1 inhibits tumor metastasis and affects the tumor immune cell microenvironment in colorectal cancer by regulating SATB2.

BACKGROUND: Emerging studies suggest that long non-coding RNAs (lncRNAs) play crucial roles in colorectal cancer (CRC). Here, we report a lncRNA, SATB2-AS1, which is specifically expressed in colorectal tissue and is significantly reduced in CRC. We systematically elucidated its functions and possible molecular mechanisms in CRC. METHODS: LncRNA expression in CRC was analyzed by RNA-sequencing and RNA microarrays. The expression level of SATB2-AS1 in tissues was determined by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and in situ hybridization (ISH). The functional role of SATB2-AS1 in CRC was investigated by a series of in vivo and in vitro assays. RNA pull-down, RNA immunoprecipitation (RIP), chromatin immunoprecipitation (ChIP), chromatin isolation by RNA purification (ChIRP), Bisulfite Sequencing PCR (BSP) and bioinformatics analysis were utilized to explore the potential mechanisms of SATB2-AS1. RESULTS: SATB2-AS1 is specifically expressed in colorectal tissues and downregulated in CRC. Survival analysis indicates that decreased SATB2-AS1 expression is associated with poor survival. Functional experiments and bioinformatics analysis revealed that SATB2-AS1 inhibits CRC cell metastasis and regulates TH1-type chemokines expression and immune cell density in CRC. Mechanistically, SATB2-AS1 directly binds to WDR5 and GADD45A, cis-activating SATB2 (Special AT-rich binding protein 2) transcription via mediating histone H3 lysine 4 tri-methylation (H3K4me3) deposition and DNA demethylation of the promoter region of SATB2. CONCLUSIONS: This study reveals the functions of SATB2-AS1 in CRC tumorigenesis and progression, suggesting new biomarkers and therapeutic targets in CRC.

IL-4/IL-4R and IL-6/IL-6R genetic variations and gastric cancer risk in the Chinese population.

OBJECTIVE: The IL-4/IL-4R and IL-6/IL-6R signaling pathways are involved in immune response and play roles in gastric carcinogenesis. To investigate the association between IL-4/IL-4R and IL-6/IL-6R genetic variations and gastric cancer risk, and their prognostic values, we performed a case-control study. The genotypes of the genetic variations were detected using a Mass-array platform. The Helicobacter pylori infection status was determined using a commercial H. pylori immunogold testing kit. We found that the IL-6 rs1800796 G allele was associated with an increased risk of gastric cancer (GG vs. CC: ORadjusted = 2.20, 95% CI = 1.33-3.63; GG/CG vs. CC: ORadjusted = 1.41, 95% CI = 1.09-1.82). The stratified analysis showed that rs1800796 G allele carriers (GG/CG) were associated with an increased risk of gastric cancer in the following subgroups: age >64 years old (ORadjusted = 1.67, 95% CI = 1.17-2.39), female (ORadjusted = 1.82, 95% CI = 1.09-3.05), positive for H. pylori infection (ORadjusted = 1.54, 95% CI = 1.07-2.22), non-cardiac gastric cancer (ORadjusted = 1.53, 95% CI = 1.15-2.04), stage T3-T4 tumor (ORadjusted = 1.41, 95% CI = 1.06-1.88), and gastric cancer with median to high differentiation (ORadjusted = 1.45, 95% CI = 1.08-1.96). None of the genetic variations were associated with overall survival. In short, we concluded that the IL-6 rs1800796 GG genotype is a risk factor for gastric cancer and that rs1800796 G allele carriers have an increased risk of gastric cancer; this association was stronger in individuals that were >64 years old, female, or positive for H. pylori infection. None of the genetic variations were associated with gastric cancer prognosis.

MicroRNA-371-3 cluster as biomarkers for the diagnosis and prognosis of cancers.

Purpose: To date, increasing evidences have demonstrated that the aberrant expression of miR-371-3 cluster has been verified in various cancers and could be potentially used as a biomarker for tumor diagnosis and prognosis. To explore the role of miR-371-3 cluster in tumor diagnosis and prognosis, we conducted this study based on the published data. Methods: We searched electronic databases (PubMed, EMBASE and Web of Science databases) (Jan 1, 2007 to Jun 1, 2018). The pooled sensitivity, specificity and area under the curve (AUC) of summary receiver operator characteristic (SROC) curve were used for diagnostic values, meanwhile the pooled hazard ration (HR) and 95% CI were used to explore the prognosis capacity of miR-372 and miR-373. In addition, the publication bias of the enrolled studies was tested and a sensitivity analysis of each study was performed to evaluate the stability of the pooled result. Results: A total of eleven eligible studies containing six eligible studies containing 870 participants for diagnosis and 1218 cancer cases for prognosis were selected for this study. For diagnosis, the pooled results revealed that the miR-371 (sensitivity: 0.85, specificity: 0.92, AUC: 0.92) and miR-373 (sensitivity: 0.81, specificity: 0.93, AUC: 0.93) could be used as diagnostic biomarkers. For prognosis, we observed that elevated miR-372 indicated poor prognosis (HR=2.31, 95% CI: 1.04-5.14), especially in the cutoff value subgroup of median (HR=2.62, 95% CI: 1.54-4.46). In addition, pooled results showed that expression of miR-373 was not related to prognosis because of the significant heterogeneity, and the high miR-373 expression presented favorable prognosis in Asians (HR=0.34, 95% CI: 0.23-0.50) after omitting the study of heterogeneity origin. Conclusion: The current studies demonstrated that miR-371 and miR-373 could be predictive tumor diagnostic biomarkers and the expression of miR-372 and miR-373 may indicate prognosis of cancer patients.

Polymorphisms of IL-23R predict survival of gastric cancer patients in a Chinese population.

IL-17/IL-23 pathway has been hypothesized to play a role in occurrence and progression of gastric cancer. To investigate the susceptibility and prognostic value of polymorphisms in genes in the IL-17/IL-23 pathway to gastric cancer, we performed a case-control study combined a retrospective study in a Chinese population. The Sequenom's MassARRAY® genotyping platform was used to genotype the polymorphisms, and infection of Helicobacter pylori (H. pylori) was determined by using a commercial H. pylori immunogold testing kit. The results showed that IL-17A rs3748067 T allele carriers have a higher gastric cancer risk than non-carriers in the subgroup of individuals with age >64 years old (CT/TT vs. CC: adjusted OR = 1.55, 95% CI = 1.04-2.29). The result of prognosis shown that IL-23R rs1884444 GG and rs6682925 CC genotype were associated with unfavorable survival (rs1884444 GG vs. GT/TT: adjusted HR = 1.40, 95%CI:1.02-1.93; rs6682925 CC vs. CT/TT: HR = 1.43, 95%CI:1.06-1.92), respectively. The stratified analysis revealed that the significant association of rs1884444 was maintained in the subgroup of older than 64 years old, and that rs6682925 was associated with unfavorable survival in the subgroup of female and patients received chemotherapy. In short, we concluded two polymorphisms (rs1884444 and rs6682925) in IL-23R were associated with prognosis of gastric cancer patients.

lncRNA SNHG6 regulates EZH2 expression by sponging miR-26a/b and miR-214 in colorectal cancer.

BACKGROUND: Abnormal expression of long non-coding RNAs (lncRNAs) has been found in almost all human tumors, providing numerous potential diagnostic biomarkers, prognostic biomarkers, and therapeutic targets. METHODS: We analyzed RNA sequencing data to explore abnormally expressed lncRNAs in colorectal cancer (CRC). The functions of small nucleolar RNA host gene 6 (SNHG6) were investigated through in vitro and in vivo assays (CCK-8 assay, colony formation assay, flow cytometry assay, EdU assay, wound healing assay, transwell assay, and xenograft model). The mechanism of action of SNHG6 was explored through bioinformatics, RNA fluorescence in situ hybridization, luciferase reporter assay, RNA pull-down assay, chromatin immunoprecipitation assay, and RNA immunoprecipitation assay. RESULTS: We identified aberrantly expressed lncRNAs in CRC. We found that elevated SNHG6 expression was associated with poor prognosis and CRC progression. We also demonstrated that the high SNHG6 expression was partly due to DNA copy number gains and SP1 induction. Functional studies showed that SNHG6 promoted CRC cell growth, migration, and invasion both in vitro and in vivo. Mechanistically, we found that SNHG6 expressed predominantly in the cytoplasm. SNHG6 could interact with miR-26a, miR-26b, and miR-214 and regulate their common target EZH2. CONCLUSIONS: Our study elucidated that SNHG6 acted as an oncogene in CRC, which might serve as a novel target for CRC diagnosis and therapy.

Circulating miR-1290 and miR-320d as Novel Diagnostic Biomarkers of Human Colorectal Cancer.

Background: The lack of screening methods with high diagnostic utility leads to colorectal cancer (CRC) patients usually diagnosed in advanced stages which results in high mortality. This study aimed to identify novel circulating miRNAs as biomarkers for the early detection of CRC. Materials and Methods: Total 205 participants were enrolled in this study. First, two dysregulated candidate miRNAs were selected after integrated analysis of four GEO datasets. Then, the expression of these two miRNAs in plasma samples were tested through qRT-PCR. Training phase and validation phase were designed to verify the diagnostic value of these two miRNAs using receiver operating characteristic curve (ROC) analysis. Results: After integrated analysis of GEO datasets, we discovered miR-1290 and miR-320d were dysregulated in colorectal adenoma and adenocarcinoma tissues, and circulating miR-1290 and miR-320d in CRC patients were tumor-derived. Thereafter, circulating miR-1290 and miR-320d were selected to further investigate their potential for early diagnosis of CRC. Plasma miR-1290 expression could differentiate adenoma and CRC patients from healthy controls with area under the curve (AUC) of 0.78 and 0.88. Similarly, plasma miR-320d expression could discriminate adenoma and CRC patients from healthy controls with AUC of 0.74 and 0.81. Conclusions: Circulating miR-1290 and miR-320d are novel promising biomarkers for early diagnosis of CRC.

miR-150-5p suppresses tumor progression by targeting VEGFA in colorectal cancer.

MicroRNA-150-5p (miR-150-5p) has been implicated in tumor initiation and progression in a variety of cancers. However, its roles in colorectal cancer (CRC) remain largely unknown. In our study, a decreased miR-150-5p expression in CRC tissues was found to be associated with poor overall survival. Moreover, miR-150-5p inhibited CRC cell proliferation, migration, invasion and angiogenesis in vitro and in vivo, and its inhibitory effect could be reversed by transfection of vascular epithelial growth factor A (VEGFA) expression plasmid. Lastly, we demonstrated that miR-150-5p inactivated VEGFA/VEGFR2 and the downstream Akt/mTOR signaling pathway in CRC. Based on these results, we conclude that miR-150-5p may function as a tumor suppressor in CRC, and miR-150-5p/VEGFA axis may be a potential therapeutic target candidate in CRC treatment.

Polymorphisms of TGFBR1, TLR4 are associated with prognosis of gastric cancer in a Chinese population.

BACKGROUND: Helicobacter pylori (H. pylori)-induced gastric cancer is an intricate progression of immune response against H. pylori infection. IL-16, TGF-ß1 and TLR4 pathways were the mediators involved in the immune response. We hypothesized that genetic variations in genes of these pathways have potential susceptibility to gastric cancer risk, and predict clinical outcomes of patients. METHODS: To investigate the susceptibility and prognostic value of genetic variations of IL-16, TGFBR1 and TLR4 pathways to gastric cancer, we performed a case-control study combined a retrospective study in a Chinese population. Genotyping for all polymorphisms was based on the Sequenom's MassARRAY platform, and H. pylori infection was determined by using an immunogold testing kit. RESULTS: We found rs10512263 CC genotype was found to be a decreased risk of gastric cancer (CC vs. TT: adjusted OR = 0.54, 95% CI 0.31-0.97); however, rs334348 GG genotype was associated with increased risk of gastric cancer (GG vs. AA: adjusted OR = 1.51, 95% CI 1.05-2.18). We found that carriers harboring rs1927911 A allele (GA/AA) or rs10512263 C allele (CT/CC) have unfavorable survival time than none carriers (rs1927911: GA/AA vs. GG: adjusted HR = 1.27, 95% CI 1.00-1.63; rs10512263: CT/CC vs. TT: adjusted HR = 1.29, 95% CI 1.02-1.63) and that individuals harboring both two minor alleles (rs1927911 GA/AA and rs10512263 CT/CC) suffered a significant unfavorable survival (adjusted HR = 1.64, 95% CI 1.17-2.31). CONCLUSION: In short, we concluded that two polymorphisms (rs334348, rs10512263) in TGFBR1 were associated with risk of gastric cancer, and that TLR4 rs1927911 and TGFBR1 rs10512263 were associated with clinical outcomes of gastric cancer patients.