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.

Long-term survival of patients with hepatocellular carcinoma with hepatic, pulmonary, peritoneal and rare colon metastasis: A case report.

BACKGROUND: Hepatocellular carcinoma (HCC) is a highly malignant cancer that often metastasizes and has a poor prognosis. Gastrointestinal tract metastases are rare, and colon metastases are even rarer. The long-term survival of patients with multiple intrahepatic and extrahepatic metastases, especially to the colon, has not been previously reported. CASE SUMMARY: We present an atypical clinical case of a patient with liver, right lung, peritoneal, and colon metastases diagnosed successively following hepatic resection for primary HCC. Comprehensive treatment, including partial liver, lung and colon resection, palliative management such as systemic chemotherapy, trans-arterial chemoembolization, targeted therapy with sorafenib, and cryotherapy were attempted. Despite his early metastases, the patient remained relatively healthy for 8 years after diagnosis. CONCLUSION: This case indicates that comprehensive treatment is beneficial for certain patients with metastatic HCC. Clinicians should be alert as to the possibility of rare site metastatic tumors that may be easily misdiagnosed as primary tumors.

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.

Novel Insights into the Roles and Mechanisms of GLP-1 Receptor Agonists against Aging-Related Diseases.

Aging and aging-related diseases have emerged as increasingly severe health and social problems. Therefore, it is imperative to discover novel and effective therapeutics to delay the aging process and to manage aging-related diseases. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), one of the classes of antihyperglycemic drugs, have been recommended to manage type 2 diabetes mellitus (T2DM). Moreover, GLP-1 RAs have been shown to protect against oxidative stress, cellular senescence and chronic inflammation, which are widely accepted as the major risk factors of aging. However, their significance in aging or aging-related diseases has not been elucidated. Herein, we explain the underlying mechanisms and protective roles of GLP-1 RAs in aging from a molecular, cellular and phenotypic perspective. We provide novel insights into the broad prospect of GLP-1 RAs in preventing and treating aging-related diseases. Additionally, we highlight the gaps for further studies in clinical applications of GLP-1 RAs in aging-related diseases. This review forms a basis for further studies on the relationship between aging-related diseases and GLP-1 RAs.

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.

Low expression of miR-199 in hepatocellular carcinoma contributes to tumor cell hyper-proliferation by negatively suppressing XBP1.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality worldwide, and microRNAs (miRs) are considered to serve important functions in the pathogenesis of HCC by regulating the expression of specific target genes. The present study was conducted to investigate the role of miR-199 and its putative target X-box binding protein 1 (XBP1) in HCC, as well as of the downstream gene cyclin D. The expression levels of miR-199, XBP1 and cyclin D were detected in clinical HCC specimens. The effect of miR-199 on the regulation of HCC cell proliferation and its underlying mechanism were examined in Hep3B2.1-7 cells, through expression assays and measurement of cell proliferation (via Cell Counting Kit-8, and 5-ethynyl-2'-deoxyuridine and DAPI double-staining assays) coupled with gain- and lose- of function experiments. The expression of XBP1 and cyclin D was significantly increased in HCC tissues when compared with adjacent non-HCC tissues, while the expression of miR-199 was decreased. Exogenous miR-199 significantly suppressed the expression of XBP1 and cyclin D in Hep3B2.1-7 cells. However, the expression of XBP1 and cyclin D significantly increased on treatment with miR-199 inhibitor. Consistently, Hep3B2.1-7 cells co-transfected with a wild type reporter plasmid [XBP1-3'untranslated region (UTR)-WT] and exogenous miR-199 exhibited lower relative luciferase enzyme activity than cells co-transfected with negative control miRNA and XBP1-3'UTR-WT, while cells co-transfected with mutated plasmid (XBP1-3'UTR-MU) and miR-199 exhibited no change. It was further observed that knockdown of XBP1 by small interfering RNA significantly decreased the expression of cyclin D in Hep3B2.1-7 cells. Additionally, exogenous miR-199 decreased the proliferation of Hep3B2.1-7 cells, which was contrary to the effect of miR-199 inhibitor. In conclusion, it was demonstrated that miR-199 negatively regulated the expression of XBP1 by directly binding to its 3'UTR and that XBP1 impacted cyclin D expression, which was associated with the cell cycle regulation in Hep3B2.1-7 cells. These findings suggested that a miR-199/XBP1/cyclin D axis may serve an important role in the pathogenesis of HCC.