CircDIDO1 inhibits gastric cancer progression by encoding a novel DIDO1-529aa protein and regulating PRDX2 protein stability.

BACKGROUND: Circular RNAs (circRNAs) play important roles in cancer development and progression. The purpose of this study is to identify aberrantly expressed circRNAs in gastric cancer (GC), unravel their roles in GC progression, and provide new targets for GC diagnosis and therapy. METHODS: Bioinformatic analyses were performed to identify the aberrantly expression of hsa_circ_0061137 (termed as circDIDO1) in GC. Gain- and loss-of-function studies were performed to examine the biological roles of circDIDO1 in GC progression. Tagged RNA affinity purification, mass spectrometry, immunofluorescence, co-immunoprecipitation, and Western blot were used to identify circRNA-interacting and circRNA-encoded proteins. RNA sequencing, qRT-PCR, and Western blot were performed to analyze circRNA-regulated downstream target genes and signaling pathways. Mouse tumor models were used to analyze the effects of circDIDO1 on GC growth and metastasis. RESULTS: CircDIDO1 was transcribed from human DIDO1 (death-inducer obliterator 1) gene and formed by back-splicing of exons 2-6 of the linear transcript. circDIDO1 was down-regulated in GC tissues and its low levels were associated with larger tumor size, distal metastasis, and poor prognosis. CircDIDO1 overexpression inhibited while knockdown promoted GC cell proliferation, migration and invasion. CircDIDO1 overexpression suppressed GC growth and metastasis in mouse tumor models. Mechanistically, circDIDO1 encoded a novel 529aa protein that directly interacted with poly ADP-ribose polymerase 1 (PARP1) and inhibited its activity. CircDIDO1 also specifically bound to peroxiredoxin 2 (PRDX2) and promoted RBX1-mediated ubiquitination and degradation of PRDX2, which led to the inactivation of its downstream signaling pathways. CONCLUSIONS: CircDIDO1 is a new circRNA that has tumor suppressor function in GC and it may serve as a potential prognostic biomarker and therapeutic target for GC.

Vascular Normalization Was Associated with Colorectal Tumor Regression upon Anti-PD-L1 Combinational Therapy.

Anti-PD-L1 therapy exhibits durable efficacy, but only in a small fraction of cancer patients. The immunosuppressive tumor microenvironment (TME) is a crucial obstacle that impedes cancer immunotherapy. Here, we found that anti-PD-L1 therapy coupled with CD4+ T cell depletion induced colorectal tumor regression and vascular normalization, while monotherapy only retarded tumor growth without affecting the tumor vasculature. Moreover, simultaneous PD-L1 blockade and CD4+ T cell depletion eradicated intratumoral PD-L1+ lymphoid and myeloid cell populations, while additively elevating the proportions of CD44+CD69+CD8+, central memory CD44+CD62L+CD8+, and effector memory CD44+CD62L-CD8+ T cells, suggesting a reduction in immunosuppressive cell populations and the activation of CD8+ T cells in the TME. Moreover, anti-PD-L1 therapy reduced the proportions of intratumoral PD-L1+ immune cells and suppressed tumor growth in a CD8+ T cell dependent manner. Together, these results suggest that anti-PD-L1 therapy induces tumor vascular normalization and colorectal tumor regression via CD8+ T cells, which is antagonized by CD4+ T cells. Our findings unveil the positive correlation of tumor regression and vascular normalization in colorectal tumor models upon anti-PD-L1 therapy, providing a potential new strategy to improve its efficacy.

Lack of association of two common polymorphisms rs2910164 and rs11614913 with susceptibility to gastric cancer: A meta-analysis.

BACKGROUND/AIMS: MicroRNAs post-transcriptionally regulate the expression of their target genes and their function in a wide range of physiological pathways. Aberrant expression of microRNAs has been implicated in the development of human malignant tumors. Recent reports showed that two single nucleotide polymorphisms (SNPs), miR-146a rs2910164 and miR-196a2 rs11614913, are associated with increased risk of human gastric cancer. Nevertheless, results from the published reports are still inconsistent and inconclusive. Thus, we conducted this meta-analysis study to further evaluate the effects of these two SNPs on susceptibility to human gastric cancer. MATERIALS AND METHODS: Using specific inclusion and exclusion criteria, we extracted data from selected studies that were identified from electronic databases, such as PubMed, Embase, and Wanfang. Odds ratio (ORs) and 95% CIs were then obtained to determine the impact of the two SNPs on susceptibility to human gastric cancer using the statistical software Stata. RESULTS: We identified six studies on rs2910164 and five reports regarding rs11614913 for our meta-analysis. Our data demonstrated that the two SNPs rs2910164 and rs11614913 do not produce any effects on the risk of human gastric cancer under all genetic models. CONCLUSION: There is no significant association between rs2910164 and rs11614913 and the risk of human gastric cancer. However, future studies with large and homogeneous population of patients with gastric cancer and well-matched controls are needed to validate these findings.

[A multi-team case-control study on the effects of psychosocial stress to overall health].

OBJECTIVE: To explore the quantitative relationship between the intensity of psychosocial stress and the degree of overall health damages. METHODS: A multi-group case-control study was designed and implemented. The cases included two groups of out-patients (177) and in-patients (214) in a hospital in Jianyang city, and controls (587) were from the follow-up cohort in the same city. Three groups were studied on the following contents: general demographic characteristics, psychosocial factors and the degree of health damages including mental, physical, and social status. Major statistical analyses were as follows: ranks test, ANOVA, cluster analysis, multinomial logistic regression and ordered-logit regression. RESULTS: Ordered-logit regression model showed that the odds ratio of negative life-events on degree of health damages was 1.335 (P < 0.01). This result showed that there was a positive dose-effect relationship between the negative life-events score and overall health damages. The utility of social support to overall health had protective effect (OR = 0.513). CONCLUSION: Negative life-events were the major risk factors to overall health, and there was a dose-effect relationship between negative events and health damages. Function of social support played a protective factor for health.