Search

Background Previous study has shown that chemokine-like factor (CKLF)-like MARVEL transmembrane domain-containing family member 4 (CMTM4) can bind and maintain programmed cell death ligand 1 (PD-L1) expression to promote tumor progression by alleviating the suppression of tumor-specific T cell activity, suggesting its potential role in tumor immunotherapy. However, the role of CMTM4 in tumor immunity has not been well clarified, especially in hepatocellular carcinoma (HCC). Methods The protein expression of CMTM4/PD-L1/CD4/CD8 was detected by immunohistochemistry (IHC) detection in 90 cases of HCC tissues. The mRNA expression profiles and related prognosis data were obtained from The Cancer Genome Atlas-Liver Hepatocellular Carcinoma (TCGA-LIHC). Two immune therapy cohorts were from Imvigor210 and GSE176307. Results Though the single protein expression of CMTM4, PD-L1, CD4 or CD8 in HCC tissues by IHC detection didn’t show a significant relationship with the prognosis of HCC patients, we found that high co-expression of CMTM4/PD-L1/CD4 showed a good prognosis of HCC patients. Further Timer 2.0 analysis identified that HCC patients with high expression of CMTM4/PD-L1 and high infiltration of CD4+ T cells had a better overall survival than those with low infiltration of CD4+ T cells. Moreover, a series of bioinformatics analyses revealed that CMTM4-related genes posed important effects on prognosis and immunity in HCC patients, and CMTM4 had a positive correlation with infiltration of CD4+ and CD8+ T cells in HCC. At last, we used two immunotherapy cohorts to verify that the combination of CMTM4 with PD-L1 could improve the prognosis of tumor patients underwent immunotherapy. Conclusions CMTM4 and PD-L1 co-expression with T cell infiltration shows prognostic significance in HCC, suggesting combined effect from multiple proteins should be considered in HCC treatment.

Aims: The aim of this study was to examine the RNA and protein expression levels and clinical significance of the pore membrane protein 121 kDa (POM121) in lung cancer. Materials and Methods: Paire...

We aim to investigate the expression and clinical significance of the tubulin gamma complex-associated protein 4 (TUBGCP4) in hepatocellular carcinoma (HCC). The mRNA expression of TUBGCP4 in HCC tissues was analyzed using The Cancer Genome Atlas (TCGA) database. Paired HCC and adjacent nontumor tissues were obtained from HCC patients to measure the protein expression of TUBGCP4 by immunohistochemistry (IHC) and to analyze the relationship between TUBGCP4 protein expression and the clinicopathological characteristics and the prognosis of HCC patients. We found that TUBGCP4 mRNA expression was upregulated in HCC tissues from TCGA database. IHC analysis showed that TUBGCP4 was positively expressed in 61.25% (49/80) of HCC tissues and 77.5% (62/80) of adjacent nontumor tissues. The Chi-square analysis indicated that the positive rate of TUBGCP4 expression between HCC tissues and the adjacent nontumor tissues was statistically different ( P < 0.05 ). Furthermore, we found that TUBGCP4 protein expression was correlated with carbohydrate antigen (CA-199) levels of HCC patients ( P < 0.05 ). Further, survival analysis showed that the overall survival time and tumor-free survival time in the TUBGCP4 positive group were significantly higher than those of the negative group ( P < 0.05 ), indicating that the positive expression of TUBGCP4 was related to a better prognosis of HCC patients. COX model showed that TUBGCP4 was an independent prognostic factor for HCC patients. Our study indicates that TUBGCP4 protein expression is downregulated in HCC tissues and has a relationship with the prognosis of HCC patients.

Background Human chemokine-like factor (CKLF)-like MARVEL transmembrane domain-containing family (CMTM) is implicated in the pathogenesis of immune, reproductive systems and various cancers. However, the expression and clinical significance of CMTM4 in lung cancer have not been identified. Methods We performed immunohistochemistry to detect the expression of CMTM4 in 75 paired lung adenocarcinoma and non-tumor lung tissues. The correlation between CMTM4 expression and clinical significance of lung cancer patients was analyzed by Chi-square test. Kaplan-Meier method and Log-Rank test were used to calculate the survival time of lung cancer patients. Results We found that CMTM4 was positively expressed in 34/75 (45.3%) cases of lung adenocarcinoma tissues, while positively expressed in 59/75 (78.6%) cases of non-tumor lung tissues, suggesting a lower expression of CMTM4 in lung adenocarcinoma tissues than non-tumor lung tissues (P

As a specific inhibitor of serine/threonine protein phosphatases, okadaic acid (OA) has been found to be a tumor promoter. However, whether OA plays a role in metastasis of hepatocellular carcinoma (HCC) has not been well elucidated. In this study, Hep3B and HepG2 cells were treated with different doses of OA and the cell viability was determined by CCK8 test. As a result, Hep3B and HepG2 cells showed no obvious cytotoxicity after OA treatment below 20 or 25 nM for 12 or 24 hours. However, wound healing, invasion, and migration abilities of HCC cells were significantly enhanced in the OA-treated groups than those of the control group (P < .05), measured by cell scratching and BD transwell assays. Moreover, we found that the expression of epithelial-mesenchymal transition (EMT)-related key factors was changed upon OA treatment in a dose-dependent manner. In addition, the activity of protein phosphatase 2A (PP2A) in OA-treated cells was also decreased significantly compared with the control cells (P < .05). Interfering of PP2A subunit A or C caused a similar expression change of EMT-related key factors as the OA treatment in HCC cells. Our results suggest that OA promotes the EMT process of HCC cells by inhibiting the activity of PP2A.

Background Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, especially in China, with high metastasis and poor prognosis. Recently, as the core component of the polycomb repressive complexes 1 (PRC1), chromobox protein homolog 8 (CBX8) is considered as an oncogene and prognostic marker in HCC. Methods A tissue microarray of 166 paired HCC and adjacent non-tumor samples were collected to identify the relationship between CBX8 and epithelial mesenchymal transition (EMT) associated proteins by Spearman correlation analysis. Knock-down of CBX8 in HCC cells was conducted to detect the biologic functions of CBX8 in HCC metastasis. Results We found out that CBX8 was over-expressed in HCC and its expression was closely related to the metastasis of HCC patients. In addition, knock-down of CBX8 was found to inhibit the invasion and migration ability of HCC cells. Moreover, there was a significant relationship between expression of CBX8 and EMT associated proteins both in HCC cells and tumor tissues. Conclusions Our results indicate that CBX8 promotes metastasis of HCC by inducing EMT process.

Background. The chromobox (CBX) proteins CBX2, CBX4, CBX6, CBX7, and CBX8, also known as Polycomb (Pc) proteins, are canonical components of the Polycomb repressive complex 1 (PRC1). Abundant evidence indicates that abnormal expression of Pc proteins is associated with a variety of tumors, but their role in the pathogenesis of hepatocellular carcinoma (HCC) has not been fully elucidated. In the present study, we performed a case-control study to investigate the relationship between single nucleotide polymorphisms (SNPs) ofCBXgenes and HCC.Methods. Nine SNPs onCBXgenes (rs7217395, rs2036316 ofCBX2; rs3764374, rs1285251, rs2289728 ofCBX4; rs7292074 ofCBX6; and rs710190, rs139394, rs5750753 ofCBX7) were screened and genotyped using MassARRAY technology in 334 HCC cases and 321 controls. The association between SNPs and their corresponding gene expressions was analyzed through bioinformatics methods using the Ensembl database and Blood eQTL browser online tools.Results. The results indicated that rs2289728 (G>A) ofCBX4(P= 0.03, OR = 0.56, 95% CI: 0.33-0.94) and rs139394 (C>A) ofCBX7(P= 0.02, OR = 0.55, 95% CI: 0.33-0.90) decreased the risk of HCC. Interaction between rs2036316 and HBsAg increased the risk of HCC (P= 0.02, OR = 6.88, 95% CI: 5.20-9.11), whereas SNP-SNP interaction between rs710190 and rs139394 reduced the risk of HCC (P= 0.03, OR = 0.33, 95% CI: 0.12-0.91). Gene expression analyses showed that the rs2289728 A allele and the rs139394 A allele significantly reducedCBX4andCBX7expression, respectively.Conclusion. Our findings suggest thatCBX4rs2289728 andCBX7rs139394 are protective SNPs against HCC. The two SNPs may reduce the risk of HCC while suppressing the expression ofCBX4andCBX7.

The purpose of this study was to investigate the expression and clinical significance of N6-methyladenosine demethylase FTO in thyroid cancer. Bioinformatic analysis showed that FTO expression was downregulated in thyroid cancer tissues and correlated with lymph node metastasis in thyroid cancer patients. We conducted experimental verification by collecting Asian samples. The results of quantitative reverse transcription-PCR showed that the mRNA expression of FTO in the blood of 30 thyroid cancer patients was lower than that of the control population. At the same time, we found that FTO expression was negative in tissues of 16/56 (28.57%) thyroid cancer cases and 4/40 (10.00%) nontumor thyroid cases through the immunohistochemical method, indicating a lower FTO expression in thyroid cancer tissues than nontumor thyroid tissues (

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, especially in China, with high metastasis and poor prognosis. Recently, as the core component of the polycomb repressive complexes 1 (PRC1), chromobox protein homolog 8 (CBX8) is considered as an oncogene and prognostic marker in HCC. A tissue microarray of 166 paired HCC and adjacent non-tumor samples were collected to identify the relationship between CBX8 and epithelial mesenchymal transition (EMT) associated proteins by Spearman correlation analysis. Knock-down of CBX8 in HCC cells was conducted to detect the biologic functions of CBX8 in HCC metastasis. We found out that CBX8 was over-expressed in HCC and its expression was closely related to the metastasis of HCC patients. In addition, knock-down of CBX8 was found to inhibit the invasion and migration ability of HCC cells. Moreover, there was a significant relationship between expression of CBX8 and EMT associated proteins both in HCC cells and tumor tissues. Our results indicate that CBX8 promotes metastasis of HCC by inducing EMT process.

Background Human chemokine-like factor (CKLF)-like MARVEL transmembrane domain-containing family (CMTM) members are found deregulated in various cancers and play a role in cancer development. Recent studies showed that CMTM7 was down-regulated in liver cancer and functioned as a tumor suppressor. Methods The expression of CMTM7 in hepatocellular carcinoma (HCC) tissues was measured by bioinformatics analysis, Western blot, and quantitative reverse-transcription polymerase chain reaction (qRT-PCR). CCK8 and cell colony formation assays were conducted to detect the cell proliferation. Cell invasion and migration ability was assessed by wound healing and Transwell assays. Results We identified a decreased expression of CMTM7 in HCC tissues was closely related to the metastasis and prognosis of HCC patients. To explore the effect of CMTM7 on the biological function of HCC cells, we over-expressed CMTM7 in two HCC cell lines, SK-Hep-1 and Bel-7402 cells. Cell proliferation was reduced significantly after exogenous expression of CMTM7, detected by both CCK8 and colony formation assay. Moreover, the invasion and migration ability of HCC cells were also inhibited by exogenous expression of CMTM7 in wound healing and Transwell assay. Furthermore, there was a significantly positive correlation between CMTM7 and CMTM3 both in HCC cells and tumor tissues. Conclusions Our results suggest that down-regulated CMTM7 promotes metastasis of HCC through inducing the expression of its family member CMTM3.

This study aimed to investigate the expression and clinical significance of chemokine-like factor-like MARVEL transmembrane domain-containing family member 2 (CMTM2) in hepatocellular carcinoma (HCC) tissues. Bioinformatics analysis showed that CMTM2 was downregulated in HCC tissues and correlated with vascular invasion of HCC patients. The immunohistochemistry (IHC) method found that CMTM2 expression was negative in 29/75 (38.67%) cases of HCC tissues and 13/75 (17.33%) cases of paracancerous tissues, also showed a significantly lower expression of CMTM2 in HCC tissues than the paired paracancerous tissues (

The defects of DNA repair genes may lead to genomic instability and cancer. As an important DNA mismatch repair gene that maintains genomic stability from DNA replication errors, genetic variants of mutS homolog 2 (MSH2) are associated with some cancers. In this study, 1021 hepatocellular carcinoma (HCC) cases and 1021 non-HCC controls from Guangxi were included to explore the association between MSH2 single-nucleotide polymorphisms (SNPs) and HCC. Among the eight MSH2 SNPs, only genotype distribution of rs2303428 was significantly different from HCC and non-HCC patients (p 0.05). Moreover, CT, TT, and CT/TT genotype of rs2303428 could increase HCC risk [OR (95% CI) = 1.758 (1.195-2.657), 1.846 (1.213-2.896), and 1.823 (1.219-2.763), respectively] and decrease the survival time of HCC patients [codominant, HR (95% CI) = 1.267 (1.046-1.535); dominant, HR (95% CI) = 1.675 (1.162-2.414)]. In addition, rs2303428 was found to interact with HBV infection and family history to increase HCC risk by gene-environment analysis (p 0.05). Finally, multivariate COX regression analysis showed that rs2303428, tumor number, tumor staging, and metastasis had a significant influence on HCC prognosis. Our results provide MSH2 SNP, rs2303428, as a new prognostic biomarker for HCC patients.

Hepatocellular carcinoma (HCC) is a malignant cancer causing deleterious health effect worldwide, especially in China. So far clinical cure rate and long-term survival rate of HCC remains low. Most HCC patients after cancer resection have recurrence or metastasis within 5 years. This study aims to explore the genetic association of mutL homolog 1 (MLH1) polymorphisms with HCC risk and prognosis. Four candidate MLH1 polymorphisms, rs1800734, rs10849, rs3774343 and rs1540354 were studied from a hospital-based case-control study including 1,036 cases (HCC patients) and 1,036 controls (non-HCC patients) in Guangxi, China. All these SNPs interacted with environmental risk factors, such as HBV infection, alcohol intake and smoking in the pathogenesis of HCC. However, only rs1800734 had significant difference between cases and controls. Compared to the AA genotype, patients with AG, GG and AG/GG genotype of rs1800734 had an increased risk of HCC [ORs (95% CI) = 1.217 (1.074∼1.536), 1.745 (1.301∼2.591) and 1.291 (1.126∼1.687)] and a decreased survival time [co-dominant, HR (95% CI) = 1.553 (1.257∼1.920); dominant, HR (95% CI) = 2.207 (1.572∼3.100)]. Furthermore, we found that tumor number, tumor staging, metastasis and rs1800734 were associated with the overall survival of HCC patients by multivariate COX regression analysis. No significant difference was found between the other three MLH1 polymorphisms with HCC risk and prognosis. Our study suggests MLH1 SNP, rs1800734 as a new predictor for poor prognosis of HCC patients.

Xiaonian Zhu,1,* Wei Luo,2,* Wenjin Liang,2 Fen Tang,3 Chunhua Bei,1 Yuan Ren,1 Linyuan Qin,1 Chao Tan,1 Ying Zhang,1 Shengkui Tan1 1School of Public Health, Guilin Medical University, Guilin, People’s Republic of China; 2Department of Hepatobiliary Surgery, The Affiliated Hospital of Guilin Medical University, Guilin, People’s Republic of China; 3Department of Hepatology, Nanxishan Hospital of Guangxi Zhuang Autonomous Region, Guilin, People’s Republic of China *These authors contributed equally to this work Abstract: This study aimed to investigate the expression and clinical significance of MYC-associated zinc finger protein (MAZ) in pancreatic carcinoma (PC), and the biological functions of MAZ in PC cells. MAZ expression was detected in 57 PC tissues and 41 paired adjacent nontumor tissues by immunohistochemistry. Compared to the expression in adjacent nontumor tissues, MAZ was significantly higher expressed in PC tissues (P

Background: As an essential member of the Polycomb group (PcG) proteins, chromobox homolog 7 (CBX7) is found deregulated in some human cancers, and is thought to be a contributing factor in carcinogenesis. However, the expression and role of CBX7 in hepatocellular carcinoma (HCC) is still not well characterized. Materials and Methods: The levels of the CBX7 protein were quantified in 75 paired HCC and adjacent nontumor tissues by immunohistochemistry; comparisons were made using McNemar's chi-square test. The Kaplan-Meier estimate was used for survival analysis. Results: We found that the expression of CBX7 in HCC tissues was significantly lower than that of adjacent nontumor tissues. In addition, decreased CBX7 expression levels were correlated with liver cirrhosis in HCC patients. Furthermore, the survival times of HCC patients who were CBX7-expression-negative were shorter than HCC patients who were CBX7-expression-positive. Conclusion: Our results show that downregulation of CBX7 is related to HCC progression and a poor prognosis in HCC patients.

This study aimed to examine the expression level and clinical significance of chemokine-like factor-like MARVEL transmembrane domain-containing family member 6 (CMTM6) in paired hepatocellular carcinoma (HCC) and adjacent nontumor tissues. The expression of CMTM6 was detected in 75 paired HCC and adjacent nontumor tissues by immunohistochemistry. Chi-square test was used to compare the difference of CMTM6 expression between HCC tissues and adjacent nontumor tissues. The clinic-pathological features and prognosis of HCC patients were collected to analyze the relationship with CMTM6 expression. The positive expression of CMTM6 in HCC tissues was significantly lower than that of adjacent nontumor tissues. The difference of CMTM6 expression between HCC tissues and paired adjacent nontumor tissues was statistically significant (p 0.05). Furthermore, CMTM6 expression was correlated with HCC metastasis and alpha-fetoprotein (AFP) (p 0.05). Multivariate logistic regression analysis showed tumor staging, metastasis, and AFP had a significant relationship with CMTM6 expression. In addition, the survival time of HCC patients was different between CMTM6 positive group and CMTM6 negative group by Kaplan-Meier survival analysis (p 0.05). Downregulation of CMTM6 is related to HCC metastasis and the prognosis of HCC patients.

// Wei Luo 1, * , Xiaonian Zhu 1, * , Wei Liu 1 , Yuan Ren 1 , Chunhua Bei 1 , Linyuan Qin 1 , Xueyan Miao 1 , Fen Tang 2 , Guifang Tang 2 , Shengkui Tan 1 1 School of Public Health, Guilin Medical University, Guilin 541004, Guangxi, People’s Republic of China 2 Department of Hepatology, The Affiliated Nanxishan Hospital of Guilin Medical University, Guilin 541004, Guangxi, People’s Republic of China * These authors contributed equally to this work Correspondence to: Shengkui Tan, email: sktan2008@sina.cn Keywords: MYC associated zinc finger protein (MAZ), hepatocellular carcinoma (HCC), zinc finger E-box binding homeobox 1 (ZEB1), zinc finger E-box binding homeobox 2 (ZEB2), epithelial-mesenchymal transition (EMT) Received: July 11, 2016 Accepted: November 09, 2016 Published: November 16, 2016 ABSTRACT MYC associated zinc finger protein (MAZ) plays a key role in regulation of gene expression and tumor development. Studies have shown that deregulated expression of MAZ is closely related to the progression of tumors such as glioblastoma, breast cancer, prostate cancer and liposarcoma. However, the role of MAZ in hepatocellular carcinoma (HCC) has not been fully elucidated. Here, we found that expression of MAZ was increased in HCC and correlated to the distant metastasis of HCC. Moreover, we found that MAZ had a relationship with zinc finger E-box binding homeobox 1 and 2 (ZEB1 and ZEB2), two important mesenchymal markers in epithelial-mesenchymal transition (EMT) that were over-expressed in HCC. After knocking-down MAZ expression in HCC cell lines using RNA interruption, HCC cell proliferation, tumorigenesis, invasion and migration were significantly inhibited. In addition, we found that expression of other EMT markers was also changed besides ZEB1 and ZEB2 by decreasing MAZ expression, both detected in vivo and in vitro assays. Therefore, we conclude that MAZ can promote the invasion and metastasis of HCC by inducing EMT.

Ring1 and YY1 binding protein (RYBP), a member of the polycomb group proteins, has been implicated in transcription repression and tumor cell-specific apoptosis. Previously, RYBP has been reported as a putative tumor suppressor in cancer tissues by regulating mouse double minute 2 homolog-p53 signaling. However, the exact role and underlying mechanisms of RYBP in cancer remain to be fully elucidated. The present study investigated the expression profile of RYBP in hepatocellular carcinoma (HCC) and examined the association between the expression of RYBP and metastasis of HCC. It was found that RYBP was downregulated in HCC tissues, compared with matched adjacent non-tumor tissues, as detected by reverse transcription-quantitative polymerase chain reaction and immunohistochemistry. In addition, Kaplan-Meier survival analysis showed that the negative expression of RYBP was associated with decreased overall survival rates in patients with HCC. It was also found that RYBP was associated with zinc finger E-box binding homeobox 1 and zinc finger E-box binding homeobox 2, which were overexpressed in HCC and correlated with epithelial-mesenchymal transition. The results of the present study suggested the importance of RYBP in HCC and its possible mechanism in the metastasis of HCC.

Chunhua Bei,1,* Ying Zhang,1,* Riming Wei,1 Xiaonian Zhu,1 Zhigang Wang,1 Wen Zeng,2 Qiuyue Chen,3 Shengkui Tan1 1Department of Epidemiology and Statistics, School of Public Health, Guilin Medical University, 2Department of Hepatobiliary Surgery, The Affiliated Hospital of Guilin Medical University, 3Department of Pathology,181st Hospital of Chinese People’s Liberation Army, Guilin, People’s Republic of China *These authors contributed equally tothis work Abstract: CMTM4 is the most conserved member of chemokine-like factor (CKLF)-like MARVEL transmembrane domain-containing (CMTM) family on chromosome 16q22.1, a locus that harbors a number of tumor-suppressor genes. In previous studies, CMTM4 was reported to be downregulated and exhibited tumor-suppressor activities by regulating cell growth and cell cycle in clear cell renal cell carcinoma. However, its roles in tumorigenesis of hepatocellular carcinoma (HCC) remain poorly studied. This study first investigated the expression of CMTM4 in HCC, and then examined the association between the expression of CMTM4 with the clinicopathological features and prognosis of HCC patients. It was found that CMTM4 was downregulated in HCC tissues, compared with matched adjacent nontumor tissues, as detected by immunohistochemistry. In addition, Kaplan–Meier survival analysis showed that the negative expression of CMTM4 was associated with decreased overall survival rates in patients with HCC. The results of this study suggest CMTM4 plays a role as a tumor suppressor in HCC and CMTM4 negative expression is a risk factor for poor prognosis of HCC. Keywords: chemokine-like factor-like MARVEL transmembrane domain-containing 4, hepatocellular carcinoma, immunohistochemistry, prognosis

Down-regulated RINGl and YYl binding protein (RYBP) is reported to be an independent predictor of a poor prognosis in patients with hepatocellular carcinoma (HCC). However, the genetic association of RYBP polymorphisms with HCC risk and prognosis has not been investigated now. In this study, five RYBP SNPs, rs12956, rs2118593, rs17009699, rs4676875 and rs4532099, were studied from a hospital-based case-control study including 1100 cases (HCC patients) and 1100 controls (non-HCC patients) in Guangxi, China. All these SNPs interacted with environmental risk factors, such as HBV infection, alcohol intake and smoking in the pathogenesis of HCC. Compared to the CC genotype, patients with TT genotype of rs12956 had a decreased risk of HCC (OR = 0.587, 95% CI = 0.403~0.923) and an increased survival time (Co-dominant, HR = 0.745, 95% CI = 0.594~0.934), while those with TT genotype of rs2118593 had an increased risk of HCC (OR = 1.538, 95% CI = 1.093~2.735) and a decreased survival time (Co-dominant, HR = 1.447, 95% CI = 1.174~1.782). No significant difference was found between the other three RYBP polymorphisms with HCC risk and prognosis. Furthermore, we found that tumor number, tumor staging, metastasis and rs2118593 were associated with the overall survival of HCC patients by multivariate COX regression analysis. Our study suggests RYBP SNP, rs2118593 as a new predictor for poor prognosis of HCC patients.

Cytokine gene single nucleotide polymorphisms (SNPs) are involved in the genesis and progression of hepatocellular carcinoma (HCC). We hypothesized that combined effects of cytokine gene SNPs and SNP-SNP interactions are associated with HCC risk. Six SNPs in cytokine genes (IL-2, IFN-γ, IL-1β, IL-6, and IL-10) were genotyped in a study of 720 Chinese HCC cases and 784 cancer-free controls. Although none of these SNPs individually had a significant effect on the risk of HCC, we found that the combined effects of these six SNPs may contribute to HCC risk (OR=1.821, 95% CI=1.078-3.075). This risk was pronounced among smokers, drinkers, and hepatitis B virus carriers. A SNP-SNP interaction between IL-2-330 and IFN-γ-1615 was associated with an increased HCC risk (OR=1.078, 95% CI=1.022-1.136). In conclusion, combined effects of SNPs and SNP-SNP interactions in cytokine genes may contribute to HCC risk.

The forkhead box O (FOXO) transcription factors play important roles in various cancer development including Hepatocellular Carcinoma (HCC). In this study we conducted a hospital-based case control study including 1049 cases (HCC patients) and 1052 controls (non-tumor patients) to examine whether single nucleotide polymorphisms (SNPs) within microRNA (miRNA) target sites of FOXO genes confer HCC susceptibility. A total of three miRNA target site SNPs in the 3’ untranslated regions (UTR) of FOXO1 (rs17592236), FOXO3 (rs4946936) and FOXO4 (rs4503258) were analyzed. No statistically significant differences were found in genotype distribution for rs17592236, rs4946936, and rs4503258 between the HCC patient group and the tumor-free control group using single factor chi-square analysis (P>0.05). However, multivariate logistic regression analysis showed that the CT/TT genotype in rs17592236 was significantly associated with decreased risk of HCC development (P = 0.010, OR = 0.699, 95% CI: 0.526–0.927) as compared to the CC genotype in rs17592236. Additionally, a genetic interaction was found between rs17592236 and rs4503258 (P = 0.003, OR = 0.755, 95% CI: 0.628–0.908). Functional dual luciferase reporter assays verified that the rs17592236 SNP was a target site of human miRNA miR-137. Together, these results indicate that the rs17592236 polymorphism is associated with decreasing of HCC hereditary susceptibility likely through modulating the binding affinity of miR-137 to the 3’UTR in FOXO1 messenger RNA (mRNA). Further knowledge obtained from this study may provide important evidence for the prevention and targeted therapy of HCC.