Identification of tumor antigens and immune subtypes of hepatocellular carcinoma for mRNA vaccine development.

BACKGROUND: mRNA vaccines have been investigated in multiple tumors, but limited studies have been conducted on their use for hepatocellular carcinoma (HCC). AIM: To identify candidate mRNA vaccine antigens for HCC and suitable subpopulations for mRNA vaccination. METHODS: Gene expression profiles and clinical information of HCC datasets were obtained from International Cancer Genome Consortium and The Cancer Genome Atlas. Genes with somatic mutations and copy number variations were identified by cBioPortal analysis. The differentially expressed genes with significant prognostic value were identified by Gene Expression Profiling Interactive Analysis 2 website analysis. The Tumor Immune Estimation Resource database was used to assess the correlation between candidate antigens and the abundance of antigen-presenting cells (APCs). Tumor-associated antigens were overexpressed in tumors and associated with prognosis, genomic alterations, and APC infiltration. A consensus cluster analysis was performed with the Consensus Cluster Plus package to identify the immune subtypes. The weighted gene coexpression network analysis (WGCNA) was used to determine the candidate biomarker molecules for appropriate populations for mRNA vaccines. RESULTS: AURKA, CCNB1, CDC25C, CDK1, TRIP13, PES1, MCM3, PPM1G, NEK2, KIF2C, PTTG1, KPNA2, and PRC1 were identified as candidate HCC antigens for mRNA vaccine development. Four immune subtypes (IS1-IS4) and five immune gene modules of HCC were identified that were consistent in both patient cohorts. The immune subtypes showed distinct cellular and clinical characteristics. The IS1 and IS3 immune subtypes were immunologically "cold". The IS2 and IS4 immune subtypes were immunologically "hot", and the immune checkpoint genes and immunogenic cell death genes were upregulated in these subtypes. IS1-related modules were identified with the WGCNA algorithm. Ultimately, five hub genes (RBP4, KNG1, METTL7A, F12, and ABAT) were identified, and they might be potential biomarkers for mRNA vaccines. CONCLUSION: AURKA, CCNB1, CDC25C, CDK1, TRIP13, PES1, MCM3, PPM1G, NEK2, KIF2C, PTTG1, KPNA2, and PRC1 have been identified as candidate HCC antigens for mRNA vaccine development. The IS1 and IS3 immune subtypes are suitable populations for mRNA vaccination. RBP4, KNG1, METTL7A, F12, and ABAT are potential biomarkers for mRNA vaccines.

Efficacy and Safety of Radical Resection of Rectal Cancer Combined with Selective Lateral Lymph Node Dissection in the Treatment of Low Rectal Cancer under Meta-analysis.

Rectal cancer mostly occurs in the middle and low position in China, and many anatomical evidence has confirmed that Lateral Lymph Node Metastasis (LLNM) exists in middle and low rectal cancer. Laparoscopic surgery can penetrate into the pelvic cavity and magnify and narrow the visual field, which is helpful for lymph node dissection and vascular nerve protection, while it has minimally invasive characteristics and is considered to be more suitable for LLND. Relevant articles published from January 2000 to May 2022 are searched using "Rectal cancer, Lateral lymph node dissection, Radical resection of rectal cancer, Low rectal cancer, Laparoscopic therapy, Treatment of rectal cancer" as test terms, analyzed and assessed using Rev Man 5.3 software and Stata software to assess the risk bias of included references, and heterogeneity among each study is evaluated using Q test and heterogeneity (I2). The experimental results show that there is no heterogeneity among the studies (I2 = 8.46%). The heterogeneity of lymphatic metastasis in the included literature is evaluated, and the results show that there is heterogeneity between the studies (I2 = 52.06%).

Over-expression of NFYB affects stromal cells reprogramming and predicts worse survival in gastric cancer patients.

Gastric cancer (GC) is the fifth most common cancer worldwide and the third most fatal. Cancer-associated fibroblasts (CAFs) play an essential role in promoting the occurrence and development of gastric cancer in all stages. NFYB is highly expressed in multiple tumors and promotes tumor invasion, metastasis, and drug resistance, but its role in the occurrence and development of gastric cancer remains unclear. Hence, we used TCGA, TIMER, Kaplan-Meier Plot, and UALCAN databases to analyze the expression of NFYB in pan-cancers and assess its clinical prognostic value. We found that high expression of NFYB may be a promising prognostic biomarker in patients with gastric cancer. High expression of NFYB was associated with high T stage, high histological grade, diffuse gastric cancer, and early-onset GC. Moreover, High expression of NFYB was associated with CAFs infiltration in the GC microenvironment. The prognosis of GC patients with high expression of NFYB and high infiltration of CAFs was worse. Therefore, NFYB may serve as a potential prognostic biomarker in patients with GC.

Antisense long non-coding RNAs in gastric cancer.

Gastric cancer is a global health problem with high mortality. The incidence of gastric cancer has significant regional differences. Helicobacter pylori (H. pylori) infection and its interaction with epigenetics are closely related to the occurrence of gastric cancer. It is of great significance to explore the early diagnosis and effective therapeutic targets of gastric cancer. Emerging evidence indicates that antisense long non-coding RNAs (lncRNAs) are closely associated with various biological and functional aspects of gastric cancer. However, diverse antisense lncRNAs in gastric cancer have not been compiled and discussed. In this review, we summarize the predisposing factors and compile the interaction between H. pylori and epigenetics in gastric cancer. Moreover, we focus on the underlying molecular mechanism and regulatory role of each antisense lncRNA in gastric cancer. In addition, we provide a new insight into the potential diagnosis and treatment of antisense lncRNAs in gastric cancer.

The interaction between long non-coding RNA LINC01564 and POU2F1 promotes the proliferation and metastasis of gastric cancer.

BACKGROUND: An increasing number of studies have demonstrated that long non-coding RNAs (lncRNAs) serve as key regulators in tumor development and progression. However, only a few lncRNAs have been functionally characterized in gastric cancer (GC). METHODS: Bioinformatics analysis was conducted to find lncRNAs that are associated with GC metastasis. RNA FISH, RIP, and RNA pull down assays were used to study the complementary binding of LINC01564 complementary to the 3'UTR of transcription factor POU2F1. The transcription activation of LINC01564 by POU2F1 as a transcription factor was examined by ChIP assay. In vitro assays such as MTT, cell invasion assay, and clonogenic assay were conducted to examined the impacts of LINC01564 and POU2F1 on GC cell proliferation and invasion. Experiments in vivo were performed to access the impacts of LINC01564 and POU2F1 on GC metastasis. RESULTS: The results showed that LINC01564 complementary bound to the 3'UTR of POU2F1 to form an RNA duplex, whereby stabilizing POU2F1 mRNA and increasing the enrichment in cells. The level of LINC01564 was also increased by POU2F1 through transcription activation. In vitro assays showed that LINC01564 promoted the proliferation, invasion and migration of GC cells through increasing POU2F1. In vivo experiments indicate the promotion of GC proliferation and metastasis by the interaction between LINC01564 and POU2F1. CONCLUSION: Taken together, our results indicate that the interaction between LINC01564 and POU2F1 promotes the proliferation, migration and invasion of GC cells.

The mechanisms and roles of melatonin in gastrointestinal cancer.

Gastrointestinal (GI) cancer is a global health problem with wide lesions and numerous cases. The increased morbidity and mortality of GI cancer is a socio-economic challenge for decades to come. Melatonin, a nature indolamine, exerts a crucial role in molecular interactions involved in multiple functional and physiological processes. Increasing evidence indicates that melatonin can modulate GI tract, decrease the occurrence of GI cancer, and enhance the sensitivity to chemoradiotherapy. However, little is known about the exact role of melatonin in anti-carcinogenesis. In this review, we discuss the action of the beneficial effects of melatonin in GI carcinogenesis. Furthermore, we compile the understanding of the role of melatonin in GI cancer, including esophageal cancer (EC), gastric cancer (GC), hepatocellular carcinoma (HCC), colorectal cancer (CRC), and pancreatic cancer (PC). In addition, the potential therapeutic application and clinical evaluation of melatonin in GI cancer are also discussed.

POU2F1 Promotes Cell Viability and Tumor Growth in Gastric Cancer through Transcriptional Activation of lncRNA TTC3-AS1.

POU domain, class 2, transcription factor 1 (POU2F1) is involved in the development of gastric cancer (GC). However, the molecular mechanism has not been fully elucidated. Here, we identified a novel lncRNA named TTC3-AS1 that was potentially regulated by POU2F1 and investigated their roles in GC progression. Bioinformatics analysis suggested that high expression of POU2F1 predicted poor prognosis in patients with GC. We further screened out an lncRNA TTC3-AS1 that may be transcriptionally activated by POU2F1 according to the JASPAR database, and POU2F1 and TTC3-AS1 were highly expressed in GC cells and tissues compared with normal controls (NCs). Function analysis revealed that both POU2F1 and TTC3-AS1 played oncogenic roles by promoting cell viability, migration, and invasion in GC. qRT-PCR analysis showed that POU2F1 improved the expression of TTC3-AS1 in GC cells, while TTC3-AS1 knockdown or overexpression had no effect on POU2F1 expression. The results of chromatin immunoprecipitation and DNA-affinity precipitation assays indicated that POU2F1 directly bound to the promoter region of TTC3-AS1 and activated its transcription. TTC3-AS1 knockdown neutralized the protumor effects of POU2F1 overexpression in GC cell lines as well as mouse models of GC, which suggested that TTC3-AS1 mediates the oncogenic function of POU2F1. In summary, POU2F1 promoted GC progression by transcriptionally activating TTC3-AS1; thus, this study provided a new perspective for the mechanism of GC progression.

CXCR4/TGF-ß1 mediated hepatic stellate cells differentiation into carcinoma-associated fibroblasts and promoted liver metastasis of colon cancer.

Background: Liver metastasis of colon cancer is strongly affected by the tumor microenvironment (TME), with interactions between tumor cells and cancer-associated fibroblasts (CAFs) in particular. TGF-ß is well known for its ability to mediate the CAF phenotype, and CXCR4 expression is closely correlated to poor prognosis in CRC. The relationship between these two signaling pathways remains to be delineated in liver metastasis of colon cancer.Methods: Immunohistochemistry was employed to investigate CXCR4 expression in 45 human specimens of primary colorectal cancer (CRC) and liver metastasis. The functions of SDF-1 released by hepatic stellate cells (HSCs) on CXCR4 and TGF-ß1 in CRC cells were investigated in vitro. The effects of CRC on HSCs differentiation into CAFs were confirmed using co-culture technology and expression analysis of CAFs markers by qPCR, western blot and immunofluorescence. The involvement of CXCR4 and TGF-ß1 was verified with addition of CXCR4 inhibitor AMD3100 and TGF-ß1 inhibitor cyclophosphamide (Cy) both in vitro and in vivo.Results: There were more CXCR4-positive cells at the liver metastatic tissues compared to the primary sites. CRC cells activated and transformed HSCs to CAFs after co-cultivating with HSCs. Activated HSCs stimulated TGF-ß1 secretion from CRC cells after co-culture with CRC cells in vitro. Moreover, the expression of CAFs markers was increasing in the activated HSCs. In a mouse hepatic metastasis model, treated with AMD3100 or Cy blocked the metastatic potential of HCT116 cells and the hepatic CAFs differentiation.Conclusions: These results indicated that CXCR4/TGF-ß1 axis plays an important role in CRC liver metastasis through mediating HSCs differentiation into CAFs, providing preclinical evidences that blockade of the axis might be beneficial for anti-metastasis therapy in CRC.

Overexpression of G6PD is associated with poor clinical outcome in gastric cancer.

This study aims to investigate the expression and significance of glucose-6-phosphate dehydrogenase (G6PD) in human gastric cancer progression and prognosis. Using immunohistochemistry and real-time RT-PCR assay, we identified abnormally elevated expression of G6PD in gastric cancer tissues compared to paired normal stomach mucosa tissues in 24 patients (p < 0.05). In order to investigate the correlations between G6PD and the clinicopathological features of gastric cancer, the expression of G6PD in 167 patients with gastric cancer were detected by immunohistochemistry, and the results showed that overexpression of G6PD was associated with the size of tumor (p = 0.039), depth of invasion (p = 0.039), lymph node metastasis (p = 0.044), distant metastasis (p = 0.003), TNM stage (p = 0.030), and survival rate (p = 0.010). Further, Cox multivariates analysis indicated that G6PD expression level was an independent prognostic factor for patients after radical resection (p = 0.013). In conclusion, overexpression of G6PD is closely related to progression of gastric cancer, and might be regarded as an independent predictor of poor prognosis for gastric cancer.

Overexpression of EphA2 correlates with epithelial-mesenchymal transition-related proteins in gastric cancer and their prognostic importance for postoperative patients.

The expression of EphA2 and three epithelial-mesenchymal transition-related proteins (E-cadherin, ß-catenin and vimentin) was detected by immunohistochemistry in human gastric cancer and normal gastric mucosa. The expression of EphA2 and vimentin was significantly higher in gastric cancer tissues than in normal gastric mucosa tissues, and similar results were found for negative E-cadherin expression and ectopic ß-catenin expression. Further analysis showed that the expression of EphA2 was closely correlated with the depth of tumor invasion, tumor-node-metastasis (TNM) stages and lymph node metastasis. Down-regulated expression of the epithelial protein E-cadherin, overexpression of the mesenchymal protein vimentin and ectopic expression of ß-catenin were associated with the depth of tumor invasion, tumor differentiation, TNM stages and lymph node metastasis. The Spearman rank test indicated that the positive expression of EphA2 was negatively associated with E-cadherin expression and was positively correlated with ß-catenin ectopic expression and vimentin expression. In addition, the Kaplan-Meier survival analysis showed that the overexpression of EphA2 and vimentin, ectopic expression of ß-catenin and down-regulation of E-cadherin indicate a poor outcome. Moreover, multivariate Cox analysis showed that TNM stages, lymph node metastasis, EphA2 expression, E-cadherin expression and ß-catenin ectopic expression were independent prognostic factors for postoperative gastric cancer. These findings indicate that the overexpression of EphA2 correlates with the loss of epithelial proteins and the appearance of mesenchymal proteins. Therefore, EphA2 may play a role in epithelial-mesenchymal transition in gastric cancer.

Haplotype analysis of CTLA4 gene and risk of esophageal squamous cell carcinoma in Anyang area of China.

BACKGROUND/AIMS: To study the effect of cytotoxic T-lymphocyte antigen 4 gene haplotypes to susceptibility of esophageal squamous cell carcinoma. METHODOLOGY: A gender- and age-matched case-control design was used in this study. PCR-RFLP method was used to detect the genotype of CTLA4 in 205 patients and 205 control individuals in the Anyang area. Furthermore, haplotypes were calculated by PHASE2.1 software. Finally, the conditional logistic regression analysis was carried out to analyze the relevance between the risk of ESCC and the genotypes or haplotypes of CTLA4 gene. RESULTS: The CTLA4 rs231775 and rs4553808 genotypes in patients with ESCC were significantly different from controls (p=0.004, p=0.023, respectively). The AG and AA genotypes of rs231775 were highly correlated with the risk of ESCC (Adjusted OR=2.280, 95%CI=1.433-3.629, p=0.001; Adjusted OR=2.192, 95%CI=1.229-3.911, p=0.008, respectively), and AG genotype of rs4553808 also increased the susceptibility of ESCC (Adjusted OR=1.848, 95%CI=1.220-2.800, p=0.004). Further study suggested that AAG haplotype may enhance the risk of ESCC (Adjusted OR=5.035, 95%CI=1.599-15.860, p=0.005), but GAA haplotype played a protective role (Adjusted OR=0.413, 95%CI=0.251-0.680, p=0.001). CONCLUSIONS: Our research confirmed that CTLA4 genetic variation was related to ESCC in the Anyang area and GAA haplotype was the protective factor of ESCC.