Ubiquitin signalling is a fundamental eukaryotic regulatory system, controlling diverse cellular functions. A cascade of E1, E2, and E3 enzymes is required for assembly of distinct signals, whereas an array of deubiquitinases and ubiquitin-binding modules edit, remove, and translate the signals. In the centre of this cascade sits the E2-conjugating enzyme, relaying activated ubiquitin from the E1 activating enzyme to the substrate, usually via an E3 ubiquitin ligase. Many disease states are associated with dysfunction of ubiquitin signalling, with the E3s being a particular focus. However, recent evidence demonstrates that mutations or impairment of the E2s can lead to severe disease states, including chromosome instability syndromes, cancer predisposition, and immunological disorders. Given their relevance to diseases, E2s may represent an important class of therapeutic targets. In the present study, we review the current understanding of the mechanism of this important family of enzymes, and the role of selected E2s in disease.

/pdf/mechanism-and-disease-association-of-e2-conjugating-enzymes-38q5ctme5s.pdf

Mechanism and disease association of E2-conjugating enzymes: lessons from UBE2T and UBE2L3

Identification of an immune-related gene-based signature to predict prognosis of patients with gastric cancer

Identification of an immune-related gene-based signature to predict prognosis of patients with gastric cancer.

Helicobacter pylori is closely associated with gastric cancer. During persistent infection, Helicobacter pylori can form a microenvironment in gastric mucosa which facilitates the survival and colony formation of Helicobacter pylori. Tumor stromal cells are involved in this process, including tumor-associated macrophages, mesenchymal stem cells, cancer-associated fibroblasts, and myeloid-derived suppressor cells, and so on. The immune checkpoints are also regulated by Helicobacter pylori infection. Helicobacter pylori virulence factors can also act as immunogens or adjuvants to elicit or enhance immune responses, indicating their potential applications in vaccine development and tumor immunotherapy. This review highlights the effects of Helicobacter pylori on the immune microenvironment and its potential roles in tumor immunotherapy responses.

/pdf/effects-of-helicobacter-pylori-on-tumor-microenvironment-and-13lcf4jg.pdf

Effects of helicobacter pylori on tumor microenvironment and immunotherapy responses

Objective To investigate miR-524-5p expression in gastric cancer (GC) tissues and the regulatory mechanism of miR-524-5p on biological behaviors of GC cell lines, such as proliferation, cell apoptosis and cycle. Materials and methods The expression of miR-524-5p was detected in 48 paired of GC tissue samples and matched adjacent tissues, and also detected in GC cell lines by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Using miR-524-5p mimics, we analyzed the effects of overexpressed miR-524-5p on cell proliferation, cell apoptosis and cycle. Bioinformatics analysis, dual-luciferase activity assay and Western blot were recruited to validate the potential target gene of miR-524-5p. Results The expression of miR-524-5p was significantly decreased in GC tissue samples and cell lines. Increased miR-524-5p in GC cells significantly decreased cell proliferation capacity, promoted cell apoptosis and induced cell cycle arrest at G0/G1 phase, while decreased miR-524-5p exerted the opposite effects. Dual-luciferase, qRT-PCR and Western blot confirmed CASP3 as a target gene of miR-524-5p. Furthermore, recovery of CASP3 expression attenuated the suppressive effect of miR-524-5p on cell growth. Conclusions MiR-524-5p participates in the development of GC via regulating CASP3, which might provide a new prospect for GC diagnosis and therapy.

MicroRNA-524-5p suppresses cell proliferation and promotes cell apoptosis in gastric cancer by regulating CASP3.

Our previous study has identified intratumoral CD103+CD8+ T cells as a favorable prognostic factor in gastric cancer. However, the significance of CD103+CD4+ T cells in gastric cancer hasn't yet been elucidated. Here, we aimed to investigate the clinical significance and phenotype characteristics of intratumoral CD103+CD4+ T cells in gastric cancer. In our study, 469 formalin-fixed and paraffin-embedded samples and 24 fresh tissue specimens of patients with gastric cancer from Zhongshan Hospital were included. We manifested that intratumoral CD103+CD4+ T cells in gastric cancer predicted poor overall survival and inferior responsiveness to fluorouracil-based ACT. The density and phenotypic characteristics of CD103+CD4+ T cells in gastric cancer were detected by immunohistochemistry and flow cytometry, which showed that CD103+CD4+ T cells exhibited an immunosuppressive phenotype and higher retention capacity in tumor tissues. Furthermore, increased CD103+CD4+ T cells contributed to CD8+T cell dysfunction with decreased granzyme B (GZMB), interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α) and perforin (PRF-1) expression in gastric cancer. Overall, this study revealed that intratumoral CD103+CD4+T cell infiltration defined immunoevasive contexture and predicted poor prognosis and inferior responsiveness to fluorouracil-based ACT. Therefore, we recommended that CD103+CD4+ T cells might be a potential immunotherapeutic target for gastric cancer.

https://www.tandfonline.com/doi/pdf/10.1080/2162402X.2020.1844402

Intratumoral CD103+CD4+ T cell infiltration defines immunoevasive contexture and poor clinical outcomes in gastric cancer patients

Although the association between H. pylori and gastric cancer has been well described, the alterations studies are scarce in the humoral immune response in specific anatomical areas of stomach and during the stages of gastric cancer. The aim in this study was to determine the influence of humoral immune responses against H. pylori infection on gastric carcinoma. We selected 16 gastric cancer cases and approximately one matched control per case at the National Institute of Medical Sciences and Nutrition Salvador Zubiran (INCMNSZ); all the cases met the inclusion criteria for the study. We obtained three biopsies from each patient and from each of the predetermined regions of the stomach: antrum, angular portion, corpus, and fundus. From the patients with gastric cancer, additional biopsy specimens were obtained from tumor mid-lesion and tumor margin, and additional specimens were collected at least 2 and 5 cm from the tumor margin. We compared IgA levels against H. pylori in each area of stomach between cases and controls as well as between early and advanced stages of gastric cancer. IgA values were strikingly elevated in cancer cases compared with control subjects; a value that was even higher in the distant periphery of tumor but was remarkably decreased toward the carcinoma lesion. The advanced stages of gastric cancer demonstrated the relapse of the humoral immune response in the mid-lesion region of the tumor compared with the tumor margins and adjacent non-tumor tissue. Gastric cancer is characterized by progressive accumulation of a concentrated, specific IgA response against H. pylori, beginning with an abnormal increase in the entire stomach but particularly in the adjacent non-tumor tissue. Thus, it is possible that this strong immune response also participates in some degree in the damage and in the development of gastric cancer to some extent.

/pdf/gastric-cancer-progression-associated-with-local-humoral-3okm1qgxnz.pdf

Gastric cancer progression associated with local humoral immune responses

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Gastric cancer progression associated with local humoral immune responses