UBE2L3 expression in human gastric cancer and its clinical significance.

PURPOSE: Gastric cancer (GC) is prevalent as one of the most common malignant tumors globally, with a particularly high incidence in China. The role of UBE2L3 in the initiation and progression of various cancers has been well documented, but its specific significance in GC is not yet fully elucidated. The objective of this study is to examine the expression and importance of UBE2L3 in human gastric cancer tissues. METHODS: Immunohistochemical staining and survival analysis were conducted on 125 cases of GC. Western blot and quantitative real-time polymerase chain reaction (qRT-PCR) were employed to assess the expression of UBE2L3 in GC cell lines. Cell lines with UBE2L3 knockdown and overexpression were cultured through lentivirus transfection and subsequently assessed using Western blot analysis. The involvement of UBE2L3 in the proliferation, invasion, and apoptosis of GC cells was confirmed through in vitro experiments, and its capacity to facilitate tumor growth was also validated in in vivo studies. RESULTS: The up-regulation of UBE2L3 expression was observed in GC, and its high expression was found to be significantly associated with the degree of differentiation (χ2 = 6.153, P = 0.0131), TNM stage (χ2 = 6.216, P = 0.0447), and poor overall survival. In vitro, UBE2L3 has been shown to enhance functions in GC cell lines, such as promoting proliferation and invasion, and inhibiting apoptosis. In vivo experiments have validated the role of UBE2L3 in promoting tumor growth. CONCLUSIONS: The findings of our study demonstrate the significant involvement of UBE2L3 in the pathogenesis and advancement of gastric cancer, suggesting its potential as a therapeutic target.

STAT1 suppresses the transcriptional activity of TRIM21 in gastric cancer.

PURPOSE: Tripartite motif-containing protein 21 (TRIM21) has E3 ubiquitin ligase activity and is involved in the regulation of various biological processes in vivo. TRIM21 has been found to have strong associations with various cancers. However, its role in gastric cancer is unclear. METHODS: The TCGA database was screened to obtain TRIM21 using WGCNA and PPI analyses. The TCGA database was used to evaluate the correlation of TRIM21 expression with patients' clinical characteristics, prognosis, functional enrichment and immune cell infiltration. The role of TRIM21 in cell proliferation, apoptosis and invasion was verified by in vivo and in vitro assays. The UCSC and JASPAR databases were used to evaluate the regulatory role of STAT1 on TRIM21 transcription. Finally, dual-luciferase reporter assay was used to confirm the regulation of TRIM21 transcriptional activity by STAT1. RESULTS: As a key gene, high expression of TRIM21 inhibited the gastric cancer growth and was significantly enriched in apoptosis, cell proliferation, and JAK/STAT signaling pathways. TRIM21 expression was positively correlated with a variety of TICs, including T cells, NK cells, and DCs. In vivo assays, TRIM21 inhibited functions in gastric cancer cell lines, including inhibition of proliferation and migration, and promotion of apoptosis. Database analysis and dual-luciferase reporter assay showed that STAT1 inhibited the transcriptional activity of TRIM21. In vivo assays confirmed that TRIM21 inhibited tumor growth, and STAT1 expression was negatively correlated with STAT1. CONCLUSION: TRIM21 is a tumor-suppressive gene in gastric cancer, and its transcriptional activity is inhibited by STAT1.

Organoids: Construction and Application in Gastric Cancer.

Gastric organoids are biological models constructed in vitro using stem cell culture and 3D cell culture techniques, which are the latest research hotspots. The proliferation of stem cells in vitro is the key to gastric organoid models, making the cell subsets within the models more similar to in vivo tissues. Meanwhile, the 3D culture technology also provides a more suitable microenvironment for the cells. Therefore, the gastric organoid models can largely restore the growth condition of cells in terms of morphology and function in vivo. As the most classic organoid models, patient-derived organoids use the patient's own tissues for in vitro culture. This kind of model is responsive to the 'disease information' of a specific patient and has great effect on evaluating the strategies of individualized treatment. Herein, we review the current literature on the establishment of organoid cultures, and also explore organoid translational applications.

Overcome tumor relapse in CAR T cell therapy

Chimeric antigen receptor (CAR) T cell therapy is a novel therapeutic approach that uses gene editing techniques and lentiviral transduction to engineer T cells so that they can effectively kill tumors. However, CAR T cell therapy still has some drawbacks: many patients who received CAR T cell therapy and achieve remission, still had tumor relapse and treatment resistance, which may be due to tumor immune escape and CAR T cell dysfunction. To overcome tumor relapse, more researches are being done to optimize CAR T cell therapy to make it more precise and personalized, including screening for more specific tumor antigens, developing novel CAR T cells, and combinatorial treatment approaches. In this review, we will discuss the mechanisms as well as the progress of research on overcoming plans. (AU)

MCEMP1 is a potential therapeutic biomarker associated with immune infiltration in advanced gastric cancer microenvironment.

BACKGROUND: Over the last decade, breakthroughs have been made in cancer immunotherapy. However, for advanced gastric cancer (AGC), the complexity and heterogeneity of the tumor microenvironment (TME) has been the biggest challenge for immunotherapy. Therefore, an intensive study on TME of AGC is necessary. METHODS: ESTIMATE and CIBERSORT algorithms were applied to analyze the transcriptome data of AGC using TCGA database systematically. We identified mast cell-expressed membrane protein 1 (MCEMP1) as a potential prognostic marker by protein-protein interaction (PPI) and Univariate Cox regression. The expression of MCEMP1 was evaluated by immunohistochemistry (IHC) and quantitative real time PCR. We assessed prognostic values of MCEMP1 with use of Kaplan-Meier and Multivariate Cox regression analysis. Gene set enrichment analysis (GSEA) was used to analyze the molecular mechanism of MCEMP1. The correlation between MCEMP1 expression and tumor immune infiltration was analyzed by the TIMER database and CIBERSORT algorithm, which was confirmed by IHC. RESULTS: The mRNA and protein expression of MCEMP1 was up-regulated substantially and related to poor survival in AGC. GSEA analysis revealed that MCEMP1 was involved in the immune-related signaling pathways. We further demonstrated that the expression of MCEMP1 was correlated with multiple immune cells and immune checkpoints. The results of IHC indicated that there was a positive correlation between PD-L1 expression and MCEMP1, suggesting that MCEMP1 may affect the prognosis of AGC patients by regulating immune infiltration and the function of immune cells. CONCLUSION: MCEMP1 may serve as a biomarker associated with immune infiltration in TME and could be a potential therapeutic target for AGC patients.

Overcome tumor relapse in CAR T cell therapy.

Chimeric antigen receptor (CAR) T cell therapy is a novel therapeutic approach that uses gene editing techniques and lentiviral transduction to engineer T cells so that they can effectively kill tumors. However, CAR T cell therapy still has some drawbacks: many patients who received CAR T cell therapy and achieve remission, still had tumor relapse and treatment resistance, which may be due to tumor immune escape and CAR T cell dysfunction. To overcome tumor relapse, more researches are being done to optimize CAR T cell therapy to make it more precise and personalized, including screening for more specific tumor antigens, developing novel CAR T cells, and combinatorial treatment approaches. In this review, we will discuss the mechanisms as well as the progress of research on overcoming plans.

Role of CD155/TIGIT in Digestive Cancers: Promising Cancer Target for Immunotherapy.

The tumor microenvironment restricts the function and survival of various immune cells by up-regulating inhibitory immune checkpoints, and participates in the immune escape of tumors. The development of immunotherapies targeting immune checkpoints, such as programmed cell death receptor 1 antibody and anti-cytotoxic T lymphocyte-associated antigen 4 antibody, has provided many options for cancer treatment. The efficacy of other immune checkpoint inhibitors is also under development and research. Among them, T cell immunoreceptor with Ig and ITIM domains (TIGIT) has shown excellent clinical application prospects. Correspondingly, poliovirus receptor (PVR, CD155), one of the main ligands of TIGIT, is mainly expressed in various human malignant tumors and myeloid cells. CD155 interacts with TIGIT on natural killer cells and T cells, mediating inhibitory immunomodulatory regulation. This study summarized the mechanism of CD155/TIGIT in regulating immune cells and its role in the occurrence and development of digestive system tumors, aiming to provide a new perspective for immunotherapy of digestive cancers.

Mechanism and Disease Association With a Ubiquitin Conjugating E2 Enzyme: UBE2L3.

Ubiquitin conjugating enzyme E2 is an important component of the post-translational protein ubiquitination pathway, which mediates the transfer of activated ubiquitin to substrate proteins. UBE2L3, also called UBcH7, is one of many E2 ubiquitin conjugating enzymes that participate in the ubiquitination of many substrate proteins and regulate many signaling pathways, such as the NF-κB, GSK3ß/p65, and DSB repair pathways. Studies on UBE2L3 have found that it has an abnormal expression in many diseases, mainly immune diseases, tumors and Parkinson's disease. It can also promote the occurrence and development of these diseases. Resultantly, UBE2L3 may become an important target for some diseases. Herein, we review the structure of UBE2L3, and its mechanism in diseases, as well as diseases related to UBE2L3 and discuss the related challenges.