A potential mechanism of tumor immune escape: Regulation and application of soluble natural killer group 2 member D ligands (Review).

The immune system is integral to the surveillance and eradication of tumor cells. Interactions between the natural killer group 2 member D (NKG2D) receptor and its ligands (NKG2DLs) are vital for activating NKG2D receptor­positive immune cells, such as natural killer cells. This activation enables these cells to identify and destroy tumor cells presenting with NKG2DLs, which is an essential aspect of tumor immunity. However, tumor immune escape is facilitated by soluble NKG2DL (sNKG2DL) shed from the surface of tumor cells. The production of sNKG2DL is predominantly regulated by metalloproteinases [a disintegrin and metalloproteinases (ADAM) and matrix metalloproteinase (MMP) families] and exosomes. sNKG2DL not only diminish immune recognition on the tumor cell surface but also suppress the function of immune cells, such as NK cells, and reduce the expression of the NKG2D receptor. This process promotes immune evasion, progression, and metastasis of tumors. In this review, an in­depth summary of the mechanisms and factors that influence sNKG2DL production and their contribution to immune suppression within the tumor microenvironment are provided. Furthermore, due to the significant link between sNKG2DLs and tumor progression and metastasis, they have great potential as novel biomarkers. Detectable via liquid biopsies, sNKG2DLs could assess tumor malignancy and prognosis, and act as pivotal targets for immunotherapy. This could lead to the discovery of new drugs or the enhancement of existing treatments. Thus, the application of sNKG2DLs in clinical oncology was explored, offering substantial theoretical support for the development of innovative immunotherapeutic strategies for sNKG2DLs.

Polyphenol Compound 18a Modulates UCP1-Dependent Thermogenesis to Counteract Obesity.

Recent studies increasingly suggest that targeting brown/beige adipose tissues to enhance energy expenditure offers a novel therapeutic approach for treating metabolic diseases. Brown/beige adipocytes exhibit elevated expression of uncoupling protein 1 (UCP1), which is a thermogenic protein that efficiently converts energy into heat, particularly in response to cold stimulation. Polyphenols possess potential anti-obesity properties, but their pharmacological effects are limited by their bioavailability and distribution within tissue. This study discovered 18a, a polyphenol compound with a favorable distribution within adipose tissues, which transcriptionally activates UCP1, thereby promoting thermogenesis and enhancing mitochondrial respiration in brown adipocytes. Furthermore, in vivo studies demonstrated that 18a prevents high-fat-diet-induced weight gain and improves insulin sensitivity. Our research provides strong mechanistic evidence that UCP1 is a complex mediator of 18a-induced thermogenesis, which is a critical process in obesity mitigation. Brown adipose thermogenesis is triggered by 18a via the AMPK-PGC-1α pathway. As a result, our research highlights a thermogenic controlled polyphenol compound 18a and clarifies its underlying mechanisms, thus offering a potential strategy for the thermogenic targeting of adipose tissue to reduce the incidence of obesity and its related metabolic problems.

Identification of Key Carcinogenic Genes in Colon Adenocarcinoma.

Background: We aimed to probe carcinogenic genes associated with colon adenocarcinoma (COAD) development. Methods: The gene expression profile of COAD were downloaded from TCGA. Differentially expressed genes (DEGs) were identified; GO and KEGG pathway enrichment were analyzed. Applying the up-mRNA-and-down-miRNA pairs and the down-mRNA-and-up-miRNA pairs, the miRNA target network was generated. The important genes were further analyzed towards the influence on overall survival and immune infiltration. In addition, essential miRNAs were selected for expression validation using real-time qPCR. Results: Together, from 2020-2021, in Central Laboratory of the Second Affiliated Hospital of Fujian Medical University, we found 3060 up-regulated transcripts and 2254 down-regulated transcripts in mRNA expression, with 235 up-regulated and 263 down-regulated miRNAs. We discovered 98 enriched GO terms using the up-regulated DEGs and 315 enriched GO terms using downregulated DEGs. There were 14 enriched KEGG pathways based on the down-regulated DEGs and only one pathway based on the up-regulated DEGs. There were 61 up-mRNA-and-down-miRNA pairs, including 7 miRNAs and 41 carcinogenic targets, among which HOXC13, FOXL2NB, ALOXE3, and ZIC2 were found related to a poorer OS. ZIC2 located at the subnet with the most targets (the miR-129-5p subnet). ZIC2 expression was correlated with immune-cell infiltration. Conclusion: These risk genes, interaction networks, and enrichments may provide a better understanding of the complex molecular mechanisms in COAD development and potential therapeutic targets for clinical treatment of COAD.

Combination of gemcitabine and erlotinib inhibits recurrent pancreatic cancer growth in mice via the JAK-STAT pathway.

Compared to single gemcitabine treatment, the combination of gemcitabine and erlotinib has shown effective response in patients with locally advanced or metastatic pancreatic cancer. However, the combination therapy has not proven effective in patients with pancreatic cancer after R0 or R1 resection. In the present study, a nude mice model of orthotopic xenotransplantation after tumor resection was established using pancreatic cancer cell lines, BxPC-3 and PANC­1. Mice were divided in four groups (each with n=12) and were treated as follows: the control group received a placebo via intraperitoneal injection (i.p.), while the other three groups were treated with gemcitabine (50 mg/kg i.p., twice a week), erlotinib (50 mg/kg oral gavage, once every three days), and combined treatment of gemcitabine and erlotinib, respectively. The treatment lasted for 21 days, after which all mice were sacrificed and tumors were examined ex vivo. We determined that the combination of gemcitabine and erlotinib inhibited recurrent tumor growth and induced apoptosis in vivo by downregulating phosphorylation levels of JAKs and STATs, which in turn downregulated the downstream proteins HIF­1α and cyclin D1, and upregulated caspase­9 and caspase­3 expression. To sum up, the combination of gemcitabine with erlotinib was effective in treating patients with pancreatic cancer after R0 or R1 resection.