Mediating immunosuppressive functions: a new perspective on the complex immunological properties of SEMA4D in the tumor microenvironment.

Semaphorin 4D (SEMA4D) is considered a new antitumor target closely related to immune cells. However, understanding the role of SEMA4D in the tumor microenvironment (TME) is limited. In this study, we explored the expression and immune cell infiltration patterns of SEMA4D using multiple bioinformatics datasets and analyzed the relationship between SEMA4D expression with immune checkpoints, tumor mutational load (TMB), microsatellite instability (MSI) and immune function. We detected that SEMA4D is overexpressed in many tumors types, widely enriched in immune cells, and closely associated with TILs, MSI, TMB, as well as T-cell exhaustion-associated immune checkpoints, and thus can broadly affect the immune microenvironment. We further verified the overexpression of SEMA4D in tumor and its distribution in TME by immunohistochemistry, RT-qPCR and flow cytometry, and confirmed that decreased expression of SEMA4D can lead to recovery of T cell exhaustion. In conlusion, this study provides a more comprehensive perspective of SEMA4D regulation of tumor immunity, which provide a new option for cancer immunotherapy.

A novel 3'tRNA-derived fragment tRF-Val promotes proliferation and inhibits apoptosis by targeting EEF1A1 in gastric cancer.

At present, it is commonly believed that tRFs and tiRNAs are formed by the specific and selective shear of tRNAs under certain pressure stimulation, rather than by random degradation of tRNA. tRFs and tiRNAs have been reported to contribute to the biological process of a variety of human cancers. However, the evidence for the mechanisms of tRFs and tiRNAs in the occurrence and development of gastric cancer (GC) is still insufficient. Here, we aimed to explore the carcinogenic roles of tRFs and tiRNAs in GC with RNA-sequencing technique, and found a novel 3'tRNA-derived fragment tRF-Val was significantly upregulated in GC tissues and cell lines. tRF-Val expression was positively correlated with tumor size and the depth of tumor invasion in GC tissues. Functionally, tRF-Val promoted proliferation and invasion, and inhibited apoptosis in GC cells. Mechanistically, tRF-Val directly bound to the chaperone molecule EEF1A1, mediated its transport into the nucleus and promoted its interaction with MDM2 (a specific p53 E3 ubiquitin ligase), thus inhibiting the downstream molecular pathway of p53 and promoting GC progression. These findings provided a new potential therapeutic target for GC and a new explanation for the occurrence of GC.

A new candidate oncogenic lncRNA derived from pseudogene WFDC21P promotes tumor progression in gastric cancer.

As oncogenes and tumor suppressor genes, long non-coding RNAs (lncRNAs) regulate the biological behavior of gastric cancer (GC) cells such as proliferation, invasion, and metastasis through various signal pathways. At present, although numerous lncRNAs that significantly influence the development and progression of GC have been identified, a considerable number of them have not been found and studied yet. In this study, we identified a new lncRNA derived from pseudogenes WFDC21P, which have not been reported in any previous GC study. LncRNA WFDC21P was significantly upregulated in GC cells and tissues, and clinically associated with the pathological stages of advanced GC. WFDC21P promoted proliferation and metastasis of GC cells both in vitro and in vivo. LncRNA WFDC21P was directly bound to GTPase Ran and it promoted the activity of the Akt/GSK3ß/ß-catenin pathway. Forkhead Box P3 (FOXP3), as a transcription factor of WFDC21P, was directly bound to the promoter region and it positively regulated the transcription of WFDC21P. This finding may provide a novel biomarker and therapeutic target for GC.

miR-885-5p Inhibits Invasion and Metastasis in Gastric Cancer by Targeting Malic Enzyme 1.

Several studies have reported that miR-885-5p was dysregulated in a variety of cancers. However, there are few studies on the biological function of miR-885-5p in gastric cancer (GC). In this study, we investigated the biological function and underlying mechanism of miR-885-5p in GC. Quantitative real-time PCR was used to examine the expression of miR-885-5p in GC. Bioinformatics analysis was used to predict the target of miR-885-5p and confirmed using the luciferase reporter assay. Wound-healing and Transwell assay were conducted to evaluate the biological function of miR-885-5p and malic enzyme 1 (ME1). Western blotting was used to assess molecular changes. Hepatic and lung metastasis models were constructed and used to verify the role of miR-885-5p. We found that the expression of miR-885-5p was significantly downregulated in GC. Overexpression of miR-885-5p inhibited invasion and metastasis of GC in vivo and in vitro, while inhibition of miR-885-5p has the opposite result in vitro. ME1 is a direct target of miR-885-5p, overexpressed in GC, associated with poor prognosis. Overexpression of miR-885-5p negatively regulates ME1 and causes changes in downstream molecules Vimentin and Fibronectin. Our research found that miR-885-5p plays a tumor suppressor gene and could potentially serve as a biomarker and therapeutic target in GC.