Identification of molecular heterogeneity of hepatocellular carcinoma based on immune gene expression signatures.

Although various molecular subtypes of hepatocellular carcinoma (HCC) have been investigated, most of these studies identify HCC subtype based on genomic profiling. Few studies have investigated the classification based on immune signatures, and none have classified HCC based on Immune activation and immunosuppressive. We performed immune gene expression of tumor tissue in 374 HCC patients from The Cancer Genome Atlas (TCGA) database and used unsupervised consensus clustering to stratify tumors. We then used HCC patients from the International Cancer Genome Consortium (ICGC) and Gene Expression Omnibus (GEO) as replication datasets. Based on the expression of 782 immune-related genes, HCC was stratified into four distinct immune subtypes. Tumors in one cluster (high immune activation; high-IA) indicate a higher level of Immune activation, which was characterized by higher anti-tumor immunity, higher pro-tumor immune-suppressive cell types, higher fractions of CD8+ T cells and M0 Macrophages compared with other subtypes. The high-IA also presents higher cancer-related hallmark signatures, such as epithelial-mesenchymal transition (EMT), angiogenesis, and apoptosis. We also found subpopulations of regulatory and exhaustion T lymphocyte were characterized by an opposite trend in high-IA, though samples in high-IA response to immunotherapy with better survival. The comparison of the immune profile in tumor and normal tissue indicates the activation of immune responses which only occurred in high-IA patients, while we conducted comparison of cirrhosis and non-cirrhosis tumor immune signatures, immune response activation was almost occurred in high-IA, but some of immune responses occurred in low-IA (low immune activation).

Emerging role of RNA modification N6-methyladenosine in immune evasion.

The innate and adaptive immune cells have complex signaling pathways for sensing and initiating immune responses against disease. These pathways are interrupted at different levels to occur immune evasion, including by N6-methyladenosine (m6A) modification. In this review, we discuss studies revealing the immune evasion mechanism by m6A modification, which underlies the retouching of these signaling networks and the rapid tolerance of innate and adaptive immune molecules during disease. We also focus on the functions of m6A in main chemokines regulation, and their roles in promotive and suppressive immune cell recruitment. We then discuss some of the current challenges in the field and describe future directions for the immunological mechanisms of m6A modification.

Comparable prevalence of distant metastasis and survival of different primary site for LN + pancreatic tumor.

BACKGROUND: Few studies have delved into the prevalence of distant metastasis (DM +) and survival for patients with lymph node metastases (LN +) by primary site. We aimed to detect differences in distant metastasis and prognosis between pancreatic head and bodytail tumors for LN + patients. METHODS: Patients with chemotherapy, histologically diagnosed, primary site between 2004 and 2016 were included from the SEER (Surveillance, Epidemiology, and End Results) database. Pancreatic head tumors were compared with pancreatic bodytail tumors using the odds ratio (OR) for rates of distant metastasis, hazard ratios (HR) for overall survival (OS) and cancer-specific survival (CSS). The competing risk model and propensity score matching (PSM) were performed to further explore. RESULTS: Of 5726 LN + patients identified from the SEER database, pancreatic head tumors account for 85.2% (4877 of 5726) and 14.8% (849 of 5726) were pancreatic bodytail tumors. The incidence of DM was lower in pancreatic head than in pancreatic bodytail tumors (OR, 0.29; 95% CI 0.23-0.37; P < 0.001). The multivariate Cox regression show pancreatic head tumors have a significantly shorter survival rate relative to pancreatic bodytail (HR, 1.12; 95% CI 1.03-1.22; P = 0.008), but the primary site was not a significant independent risk factor for prognosis by log-rank test (P = 0.39) and multivariate competing risk model [subdistribution HR (SHR), 1.08; 95% CI 0.98-1.19; P = 0.087].We then examined our conclusion by 1:1 propensity score matching, and the result reflected pancreatic head tumors have a lower risk of DM compared with pancreatic bodytail tumors (OR, 0.22; 95% CI 0.15-0.34; P < 0.001), but the primary site of pancreatic tumors was not associated with LN + patient survival based on univariate Cox regression (HR, 1.04; 95% CI 0.93-1.17; P = 0.435) and competing risk analysis (SHR, 1.01; 95% CI 0.89-1.12; P = 0.947). CONCLUSIONS: LN + pancreatic head tumors were significantly lower risk of DM relative to pancreatic bodytail tumors. Survival outcome in LN + pancreatic tumors didn't exist significant differences split by primary site, which indicates that the prognosis of LN + patients with chemotherapy isn't associated with the primary site of metastasis, but with the occurrence of metastasis.

Comprehensive analysis of five long noncoding RNAs expression as competing endogenous RNAs in regulating hepatoma carcinoma.

Liver cancer is the most common cancer and is the epitome of a recalcitrant cancer. Increasing evidence shown that long noncoding RNAs (lncRNA) were associated with cancer-related death and could function as a competing endogenous RNA (ceRNA). To explore regulatory roles and potential prognostic biomarkers of lncRNA for liver cancer, RNA-sequencing expression data were downloaded from the TCGA database and GEO database. A total of 357 patients were randomly divided into a discovery group and a validation group, of which 313 patients can obtain clinical data. In discovery phrase, 58 lncRNAs, 16 miRNAs, and 34 mRNAs were screened to construct the ceRNA network based on 252 patients employed from discovery group. Univariate and multivariate Cox hazard regression analysis model revealed that five lncRNAs (AATK-AS1, C10orf91, LINC00162, LINC00200, and LINC00501) from 58 lncRNAs were formulated to predict the overall survival (OS). We used the value of gene expression and regression coefficients to construct a risk score based on the five lncRNAs. Next, we validated our model in the GSE116174 dataset (n = 64) and the validation group (n = 94) from TCGA database. Subgroup analysis suggest that the five lncRNAs played critical parts in early stage in cancer from both discovery and validation groups. The five lncRNAs were also found to be associated with immune cells infiltration including CD4+ memory activated, NK cells activated and mast cells activated, then the results were also validated according to the validation group. Furthermore, KEGG pathway enrichment analysis showed that these nine coexpressed modules using the method of WGCNA, and many of these pathways are associated with the development and progression of disease. At last, the transcription factor binding sites (TFBS) of the five lncRNAs were predicted, which help us to understand the potential mechanism that the TFBS adjusted the ceRNA network. In summary, the ceRNA regulatory network may contribute to a better understanding of liver cancer mechanism and provide potential prognostic biomarkers and therapeutic targets.