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Lymph node metastasis is an independent risk factor for survival of gastric cancer, but the underlying mechanism remains unclear. Adenosine (ADO) plays an immune regulation role through binding to adenosine receptors (ARs), especially A2AR. PD-L1 plays a key role in the immune escape of tumor. However, the expression of these two indicators in lymph nodes of gastric cancer has been rarely studied. Lymph node samples of 95 gastric cancer patients, including metastatic lymph nodes and matched non-metastatic lymph nodes were collected. Expression of A2AR and PD-L1 were detected with immunohistochemistry. The relationships among their expression with clinicopathological factors and prognostic parameters were analyzed as well. The expressions of A2AR and PDL-1 were both higher in metastatic lymph node than matched non-metastatic lymph node. The expression of A2AR in metastatic lymph nodes of gastric cancer was positively correlated with PD-L1. Positive expressions of A2AR and PDL-1 were associated with tumor N stage and prognostic parameters. There was no significant relationship with other clinicopathological characteristics. Our obtained data suggested that the high expressions of A2AR and PD-L1 were associated with the lymph node metastasis and a poor prognosis in gastric cancer, which may be a potential diagnostic and a therapeutic target for gastric cancer.

Objective The incidence and mortality of colorectal cancer (CRC) is increasing yearly and CRC patients are becoming younger in global. Evidences have revealed the carcinogenic effect of p53 and DNA damage-regulated gene 1 (PDRG1) in several types of tumors. However, its biological function is yet to be investigated in CRC. This study aimed to unveil the prooncogenic role of PDRG1 in CRC. Methods We detected the expression and clinical pathological features of PDRG1 in CRC tissues and paired non-tumor adjacent tissues. The biological role and molecular mechanism of PDRG1 in CRC were characterized through a range of in vitro and in vivo experiments and datasets analysis. Result We identified the significant up-regulated expression of PDRG1 both in CRC tissues and cell, and higher expression of PDRG1 was associated with worse clinicopathological stage and poorer survival outcome. Cox regression analysis revealed that PDRG1 is an independent prognostic factor for CRC patients. Silencing of PDRG1 significantly retarded CRC cell vitality, invasion and migration, induced cell apoptosis and G0/G1 phase arrest. PDRG1 knockdown also attenuated tumor growth and metastasis as evidencing in vivo experiment. The expression of p21 and apoptosis related protein was enhanced with the knockdown of PDRG1 while cell cycle protein was inhibited. Conclusion PDRG1 function as a novel oncogene and participate in malignant progression of CRC by regulating p21-mediated signal pathway, suggesting that it can serve as a valuable predictive biomarker for diagnosing of CRC patient and a promising target for therapy.

The accumulation of adenosine in the tumor microenvironment is associated with tumor progression in many cancers. However, whether adenosine is involved in gastric cancer (GC) metastasis and progression, and the underlying molecular mechanism, is largely unclear. In this study, we find that GC tissues and cell lines had higher A2aR levels than nontumor gastric tissues and cell lines. A2aR expression correlated positively with TNMstage, and associated with poor outcomes. Adenosine enhanced the expression of the stemness and epithelial–mesenchymal transition-associated genes by binding to A2aR. A2aR expression on GC cells promoted metastasis in vivo. The PI3K-AKT-mTOR signaling pathway was involved in adenosine-stimulated GC cell migration and invasion. Our results indicate that adenosine promotes GC cell invasion and metastasis by interacting with A2aR to enhance PI3K–AKT–mTOR pathway signaling.

The aberrant regulation of circular RNAs (circRNAs), ring structures formed by exon or intron backsplicing, has been identified as a novel characteristic of multiple cancers. However, the role of circRNAs in colorectal carcinoma remains to be elucidated. In the present study, we investigated the mRNA level and the promoting effect of circRNA CSPP1 (circCSPP1) in colorectal carcinoma liver metastasis. By bioinformatic analysis of 10 paired samples of colorectal carcinoma and adjacent mucosal tissues, we identified circCSPP1 as a significantly upregulated circRNA in colorectal carcinoma tissues, and its upregulation was correlated with a higher M stage. The gain- and loss-of-function assays revealed that circCSPP1 promotes the migration and invasion of colorectal carcinoma cells in vitro and in vivo. Mechanistically, similar miRNA response elements are shared between circCSPP1 and COL1A1. We demonstrated that circCSPP1 upregulates the mRNA levels of COL1A1, which plays a pivotal role in the process of epithelial–mesenchymal transition (EMT), by competitively binding to miR-193a-5p and preventing miR-193a-5p from decreasing the expression of COL1A1. In conclusion, this finding indicates that circCSPP1 may act as a promising therapeutic target by regulating the EMT process in colorectal carcinoma via activation of the circCSPP1/miR-193a-5p/COL1A1 axis.

Background. Adenosine, derived from the degradation of ATP via ectonucleotidases CD39 and CD73, is a critical immunosuppressive metabolite in the hypoxic microenvironment of tumor tissue. Adenosine signaling via A2aR can inhibit the antitumor immune response of CD8+T cells. CD39 and CD73 high-expressing Tregs play a critical role in tumor immune evasion of gastric cancer (GC). The present study investigated the underlying mechanism by which Tregs suppress antitumor immune responses in GC.Materials and Methods. Fifty-two GC samples were collected, and the frequency of FoxP3+Tregs and CD8+T cells and density ratios of A2aR+/CD8+T cells, CD39+/FoxP3+Tregs, and CD73+/FoxP3+Tregs in GC were assessed with multiplex immunofluorescence. The expression of FoxP3 and A2aR in GC tissues was also detected by the immunoblotting assay. We next investigated the relationship between density of FoxP3+Tregs, ratio of A2aR+/CD8+T cells, and clinicopathological parameters. At the same time, Tregs and CD8+T cells were isolated from peripheral blood of five GC patients, and the antagonists of CD39 and CD73 were used to assess the ability of Tregs to decompose ATP into adenosine. In addition, we cocultured CD8+T cells and Tregs with antagonists of A2aR and A2bR in order to examine the alterations in immune function of CD8+T cells.Results. The density of both FoxP3+Tregs and A2aR+/CD8+T cells was higher in GC tissue compared to peritumoral normal tissue and significantly correlated with the TNM stage, lymph node metastasis, and distant metastasis of GC. The process of Treg hydrolysis of ATP into adenosine was blocked by the antagonists of CD39 and CD73. In addition, Tregs could induce apoptosis and inhibit proliferation of CD8+T cells, while this effect could be obviously reduced by applying the antagonist of A2aR or A2aR+A2bR. Moreover, IFN-γ, TNF-α, and perforin generated by CD8+T cells could also be inhibited through the adenosine A2aR pathway.Conclusions. The FoxP3+Tregs and A2aR+/CD8+T cells were excessively infiltrated in GC tissue. Tregs from GC can decompose ATP to adenosine and in turn induce apoptosis and inhibit the proliferation of CD8+T cells through the A2aR pathway, further leading to immune escape of GC.

Ethnopharmacology relevance Cuscuta chinensis Lam. (Convolvulaceae) had received growing attention as a traditional medicinal herb widely used for treating female impotence, abortion, male reproductive system disease and cardiovascular diseases, respectively. Aim of the study The present study investigated the acute and sub-acute toxicities of C. chinensis water extract (CLW) in the ICR mice model. Materials and methods Various doses of CLW (1250, 2500, and 5000 mg/kg) were administered consecutively for 14 days to evaluate the acute toxicity level with examine mortality, general behavior, body weight, food and water intake of the mice. At the end of treatmet, macroscopic observation of the skin and major internal organs in the abdominal part and organ coefficients were taken. The same doses were administered daily for 28 days to determine the sub-acute toxicity level with examine mortality, general behavior, body weight, food and water intake of the mice. At the end of treatmet, macroscopical examination of organs, tissues, cavities, organ coefficients, pathology, hematological and biochemical parameters were carried out. Results The acute toxicity test results revealed an LD 50 of over 5000 mg/kg for CLW. Similarly, no CLW-related mortality and severe toxicities were experienced in the sub-acute study. However, the treatment of CLW had a reducing effect on body weight of both male and female mice, and feed intake in female mice at the all tested doses (1250, 2500 and 5000 mg/kg). Moreover, significant effects in organ coefficients of brain, liver, lung, testis and thymus became apparent due to CLW mainly at the 2500 and 5000 mg/kg. The hematological analysis result showed a significant decrease in platelets, lymphocytes, and hematocrit. In contrast, a significant increase in the neutrophils was observed in the CLW treated groups (2500 and 5000 mg/kg). Biochemical test results showed a significant increase in aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase levels while decreasing albumin, total cholesterol and triglyceride levels after treatment of CLW mostly at the doses of 2500 and 5000 mg/kg. Mild liver toxicity in both sexes treated with 5000 mg/kg of CLW was recorded in the histopathological analysis. Conclusions Overall, our results suggested that CLW is safe at its dose lower than 1250 mg/kg, although liver toxicity from daily use may be a matter of concern.

Anoikis is a type of programmed cell death induced by detachment from the extracellular matrix. In cancer cells, anoikis resistance is essential for cancer cell survival in blood circulation and distant metastasis. However, the mechanisms behind anoikis resistance of gastric cancer remain largely unknown. Herein, we demonstrate that NADPH oxidase 4 (NOX4) expression and reactive oxygen species (ROS) generation are upregulated in suspension gastric cell cultures compared with adherent cultures. Silencing of NOX4 decreases ROS generation and downregulates EGFR, sensitizing cells to anoikis. NOX4 overexpression upregulates ROS and EGFR levels and promotes anoikis resistance. NOX4 depletion inhibits gastric cancer survival in blood circulation and attenuates distant metastasis. NOX4 expression is correlated with EGFR expression in patients. In conclusion, induction of NOX4 expression by detachment promotes anoikis resistance of gastric cancer through ROS generation and downstream upregulation of EGFR, which is critical for the metastatic progression of gastric cancer.