Ubiquitin-specific proteases: From biological functions to potential therapeutic applications in gastric cancer.

Deubiquitination, a post-translational modification regulated by deubiquitinases, is essential for cancer initiation and progression. Ubiquitin-specific proteases (USPs) are essential elements of the deubiquitinase family, and are overexpressed in gastric cancer (GC). Through the regulation of several signaling pathways, such as Wnt/ß-Catenin and nuclear factor-κB signaling, and the promotion of the expression of deubiquitination- and stabilization-associated proteins, USPs promote the proliferation, metastasis, invasion, and epithelial-mesenchymal transition of GC. In addition, the expression of USPs is closely related to clinicopathological features, patient prognosis, and chemotherapy resistance. USPs therefore could be used as prognostic biomarkers. USP targeting small molecule inhibitors have demonstrated strong anticancer activity. However, they have not yet been tested in the clinic. This article provides an overview of the latest fundamental research on USPs in GC, aiming to enhance the understanding of how USPs contribute to GC progression, and identifying possible targets for GC treatment to improve patient survival.

Adherence to the Mediterranean Diet and Risk of Gastric Cancer: A Systematic Review and Meta-Analysis.

Available results on the association between the Mediterranean diet (MD) and gastric cancer (GC) incidence are controversial. The present study aimed to determine the correlation between different subtypes of GC and MD adherence. This meta-analysis was registered on PROSPERO (CRD42021284432). We searched Embase, PubMed, Cochrane Library, and Web of Science from inception through 22 April 2023 to retrieve relevant studies. A random-effects model was used to pool odds ratios (ORs) with 95% confidence intervals (CIs). Eleven studies were included in the meta-analysis. Pooled analyses revealed that adherence to the MD was inversely associated with GC risk (ORcc, 0.43; 95% CI, 0.29 to 0.63; ORcoh, 0.84; 95% CI, 0.77 to 0.92). Higher MD adherence was significantly associated with a reduced GC risk in male (ORcc, 0.78; 95% CI, 0.65 to 0.93; ORcoh, 0.81; 95% CI, 0.65 to 1.01), but not in female (ORcc, 0.83; 95% CI, 0.68 to 1.01; ORcoh, 1.04; 95% CI, 0.82 to 1.31). Furthermore, adherence to the MD possibly decreased the risk of gastric cardia adenocarcinoma (GCA) (ORcc, 0.64; 95% CI, 0.49 to 0.83; ORcoh, 0.88; 95% CI, 0.76 to 1.02) and gastric non-cardia adenocarcinoma (GNCA) (ORcc, 0.68; 95% CI, 0.59 to 0.79; ORcoh, 0.85; 95% CI, 0.78 to 0.94). Our results indicate that adherence to the MD reduces the risk of GC and its subtypes.

Role of N6-methyladenosine RNA modification in gastric cancer.

N6-methyladenosine (m6A) RNA methylation is the most prevalent internal modification of mammalian messenger RNA. The m6A modification affects multiple aspects of RNA metabolism, including processing, splicing, export, stability, and translation through the reversible regulation of methyltransferases (Writers), demethylases (Erasers), and recognition binding proteins (Readers). Accumulating evidence indicates that altered m6A levels are associated with a variety of human cancers. Recently, dysregulation of m6A methylation was shown to be involved in the occurrence and development of gastric cancer (GC) through various pathways. Thus, elucidating the relationship between m6A and the pathogenesis of GC has important clinical implications for the diagnosis, treatment, and prognosis of GC patients. In this review, we evaluate the potential role and clinical significance of m6A-related proteins which function in GC in an m6A-dependent manner. We discuss current issues regarding m6A-targeted inhibition of GC, explore new methods for GC diagnosis and prognosis, consider new targets for GC treatment, and provide a reasonable outlook for the future of GC research.

Exposure to Commonly Used Drugs and the Risk of Gastric Cancer: An Umbrella Review of Meta-Analyses.

Recently, attention has been paid to some medications and gastric cancer (GC) risk. This review aimed to evaluate associations between commonly used drugs and GC risk and to grade evidence from published systematic reviews and meta-analyses. This umbrella review was registered in PROSPERO (CRD42022320276). The systematic reviews and meta-analyses of observational studies were retrieved by searching Embase, PubMed, and Web of Science. The evidence strength of commonly used drugs and GC risk was categorized into four grades: weak, suggestive, highly suggestive, and strong. Of 19 associations between commonly used drugs and GC risk and its subtypes, none was supported by convincing or highly suggestive evidence. The risk of GC related to non-steroidal anti-inflammatory drugs (NSAIDs), non-aspirin NSAIDs, and acid-suppressive drugs, as well as the risk of non-cardia GC related to NSAIDs and aspirin, was supported by suggestive evidence. The results showed that a reduced GC risk was associated with two drug types (NSAIDs and non-aspirin NSAIDs), and an increased GC risk was associated with acid-suppressing drugs at the suggestive evidence level. Moreover, NSAIDs and aspirin reduced non-cardia GC risk as supported by suggestive evidence. However, the evidence supporting statins or metformin in reducing GC risk was weak, and thus future studies are required to clarify these associations.

Correction to "MicroRNA-596 acts as a tumor suppressor in gastric cancer and is upregulated by promotor demethylation".

[This corrects the article on p. 1224 in vol. 25, PMID: 30886505.].

Exosomal circRNAs: A key factor of tumor angiogenesis and therapeutic intervention.

Over the last few decades, our understanding of the molecular mechanisms underlying tumor angiogenesis has advanced at a significant pace and the clinical translation of these mechanisms has benefited millions of patients. However, limited efficacy and the rapid expansion of drug resistance remain unresolved issues. Recent studies in both preclinical and clinical settings have revealed that circRNAs, as a novel identified non-coding RNA can mediate intercellular communication and regulate the microenvironment within tumors after being selectively packaged, secreted, and transmitted via exosomes. This review aims to provide a comprehensive understanding of how exosomal circRNAs orchestrate inducers and inhibitors of angiogenesis, including their functions, molecular mechanisms, and potential roles as diagnostic biomarkers and therapeutic targets. Finally, we discuss the technological advances in exosome functionalization and exosome-mimetic nanovesicles intending to improve the clinical translation of exosomal circRNAs.

Correction to "Novel long non-coding RNA LINC02532 promotes gastric cancer cell proliferation, migration, and invasion in vitro".

[This corrects the article on p. 91 in vol. 11, PMID: 30788037.].

Correction to "MicroRNA-320a suppresses tumor progression by targeting PBX3 in gastric cancer and is downregulated by DNA methylation".

[This corrects the article on p. 842 in vol. 11, PMID: 31662823.].

Correction to "Aberrant methylation of secreted protein acidic and rich in cysteine gene and its significance in gastric cancer".

[This corrects the article on p. 6713 in vol. 25, PMID: 31857774.].

[Corrigendum] The Pleckstrin and Sec7 domain-containing gene as a novel epigenetic modification marker in human gastric cancer and its clinical significance.

Subsequently to the publication of the above article, an interested reader drew to the authors' attention that a pair of panels in Fig. 6C appeared to contain overlapping data, such that the data, which were intended to show the results from experiments performed under different experimental conditions, may have been derived from the same original source. The authors have re-examined their original data, and have realized that this figure was assembled incorrectly; essentially, the data panel showing the results of the SGC7901-Si-NC experiment in Fig. 6C was incorporated incorrectly during the process of assembling this figure. The corrected version of Fig. 6, showing all the correct data for Fig. 6C, is shown opposite. The authors confirm that this inadvertent error did not have any major impact on the conclusions reported in their paper, and are grateful to the Editor of International Journal of Oncology for allowing them this opportunity to publish a Corrigendum. Furthermore, the authors apologize to the readership for any inconvenience caused. [the original article was published in International Journal of Oncology 46: 195-204, 2015; DOI: 10.3892/ijo.2014.2736].

The functional role of Pescadillo ribosomal biogenesis factor 1 in cancer.

Tumors are neogrowths formed by the growth of normal cells or tissues through complex mechanisms under the influence of many factors. The occurrence and development of tumors are affected by many factors. Pescadillo ribosomal biogenesis factor 1 (PES1) has been identified as a cancer-related gene. The study of these genes may open up new avenues for early diagnosis, treatment and prognosis of tumors. As a nucleolar protein and part of the Pes1/Bop1/WDR12 (PeBoW) complex, PES1 is involved in ribosome biogenesis and DNA replication. Many studies have shown that high expression of PES1 is often closely related to the occurrence, proliferation, invasion, metastasis, prognosis and sensitivity to chemotherapeutics of various human malignant tumors through a series of molecular mechanisms and signaling pathways. The molecules that regulate the expression of PES1 include microRNA (miRNA), circular RNA (circRNA), c-Jun, bromodomain-containing protein 4 (BRD4) and nucleolar phosphoprotein B23. However, the detailed pathogenic mechanisms of PES1 overexpression in human malignancies remains unclear. This article summarizes the role of PES1 in the carcinogenesis, prognosis and treatment of multiple tumors, and introduces the molecular mechanisms and signal transduction pathways related to PES1.

Aberrant DNA Methylation-Mediated FOXF2 Dysregulation Is a Prognostic Risk Factor for Gastric Cancer.

Background: The prognosis of gastric cancer (GC) patients is poor. The effect of aberrant DNA methylation on FOXF2 expression and the prognostic role of FOXF2 methylation in GC have not yet been identified. Methods: The RNA-Seq and gene methylation HM450 profile data were used for analyzing FOXF2 expression in GC and its association with methylation level. Bisulfite sequencing PCR (BSP) was performed to measure the methylation level of the FOXF2 promoter region in GC cell lines and normal GES-1 cells. The cells were treated with the demethylation reagent 5-Aza-dC, and the mRNA and protein expression levels of FOXF2 were then measured by qRT-PCR and western blot assays. The risk score system from SurvivalMeth was calculated by integrating the methylation level of the cg locus and the corresponding Cox regression coefficient. Results: FOXF2 was significantly downregulated in GC cells and tissues. On the basis of RNA-Seq and Illumina methylation 450 data, FOXF2 expression was significantly negatively correlated with the FOXF2 methylation level (Pearson's R = -0.42, p < 2.2e-16). The FOXF2 methylation level in the high FOXF2 expression group was lower than that in the low FOXF2 expression group. The BSP assay indicated that the methylation level of the FOXF2 promoter region in GC cell lines was higher than that in GES-1 cells. The qRT-PCR and western blot assay showed that FOXF2 mRNA and protein levels were increased in GC cells following treatment with 5-Aza-Dc. The methylation risk score model indicated that patients in the high risk group had poorer survival probability than those in the low risk group (HR = 1.84 (1.11-3.07) and p = 0.0068). FOXF2 also had a close transcriptional regulation network with four miRNAs and their corresponding target genes. Functional enrichment analysis of the target genes revealed that these genes were significantly related to several important signaling pathways. Conclusion: FOXF2 was downregulated due to aberrant DNA methylation in GC, and the degree of methylation in the promoter region of FOXF2 was related to the prognosis of patients. The FOXF2/miRNAs/target genes axis may play a vital biological regulation role in GC.

Genitourinary function and defecation after colorectal cancer surgery with low- and high-ligation of the inferior mesenteric artery: A meta-analysis.

BACKGROUND: The effect of low ligation (LL) vs high ligation (HL) of the inferior mesenteric artery (IMA) on functional outcomes during sigmoid colon and rectal cancer surgery, including urinary, sexual, and bowel function, is still controversial. AIM: To assess the effect of LL of the IMA on genitourinary function and defecation after colorectal cancer (CRC) surgery. METHODS: EMBASE, PubMed, Web of Science, and the Cochrane Library were systematically searched to retrieve studies describing sigmoid colon and rectal cancer surgery in order to compare outcomes following LL and HL. A total of 14 articles, including 4750 patients, were analyzed using Review Manager 5.3 software. Dichotomous results are expressed as odds ratios (ORs) with 95% confidence intervals (CIs) and continuous outcomes are expressed as weighted mean differences (WMDs) with 95%CIs. RESULTS: LL resulted in a significantly lower incidence of nocturnal bowel movement (OR = 0.73, 95%CI: 0.55 to 0.97, P = 0.03) and anastomotic stenosis (OR = 0.31, 95%CI: 0.16 to 0.62, P = 0.0009) compared with HL. The risk of postoperative urinary dysfunction, however, did not differ significantly between the two techniques. The meta-analysis also showed no significant differences between LL and HL in terms of anastomotic leakage, postoperative complications, total lymph nodes harvested, blood loss, operation time, tumor recurrence, mortality, 5-year overall survival rate, or 5-year disease-free survival rate. CONCLUSION: Since LL may result in better bowel function and a reduced rate of anastomotic stenosis following CRC surgeries, we suggest that LL be preferred over HL.

Screening and Validation of the Hypoxia-Related Signature of Evaluating Tumor Immune Microenvironment and Predicting Prognosis in Gastric Cancer.

Background: Hypoxia is one driving factor of gastric cancer. It causes a series of immunosuppressive processes and malignant cell responses, leading to a poor prognosis. It is clinically important to identify the molecular markers related to hypoxia. Methods: We screened the prognostic markers related to hypoxia in The Cancer Genome Atlas database, and a risk score model was developed based on these markers. The relationships between the risk score and tumor immune microenvironment were investigated. An independent validation cohort from Gene Expression Omnibus was applied to validate the results. A nomogram of risk score model and clinicopathological factor was developed to individually predict the prognosis. Results: We developed a hypoxia risk score model based on SERPINE1 and EFNA3. Quantified real-time PCR was further applied to verified gene expressions of SERPINE1 and EFNA3 in gastric cancer patients and cell lines. A high-risk score is associated with a poor prognosis through the immunosuppressive microenvironment and immune escape mechanisms, including infiltration of immunosuppressive cells, expression of immune checkpoint molecules, and enrichment of signal pathways related to cancer and immunosuppression. The nomogram basing on the hypoxia-related risk score model showed a good ability to predict prognosis and high clinical net benefits. Conclusions: The hypoxia risk score model revealed a close relationship between hypoxia and tumor immune microenvironment. The current study potentially provides new insights of how hypoxia affects the prognosis, and may provide a new therapeutic target for patients with gastric cancer.

A Novel TNM Classification for Colorectal Cancers based on the Metro-ticket Paradigm.

Background: Several revisions of the TNM classifications for colorectal cancer (CRC) have acknowledged that the oncological outcomes of stage IIB/IIC CRC are worse than those of stage IIIA. We aimed to develop a novel TNM (nTNM) classification based on the metro-ticket paradigm. Methods: We identified eligible CRC patients from the Surveillance, Epidemiology, and End Results database. The nTNM was developed using distance from the origin on a Cartesian plane incorporating the pN (x-axis) and pT (y-axis) stages, and was compared with the AJCC TNM classification. The areas under the curves (AUCs), calibration curves, and Akaike's information criterion (AIC) were used to evaluate the predictive performances of the two classifications. Clinical benefits were further estimated by decision curve analyses. The validation cohort was applied to validate these findings. Results: A total of 58,192 CRC patients (40,736 training cohort, 17,456 validation cohort) were finally included. In the training cohort, 18,476 patients (45.4%) experienced upstaging and 15,907 patients (39.0%) experienced downstaging in the nTNM classification compared with the TNM classification. Taking the prognosis of stage I as the reference, survival decreased with increasing nTNM stage. The nTNM classification showed better discrimination (AUC, 0.678 vs. 0.667, P<0.001), model-fitting (AIC, 236,525 vs. 237,741), and clinical benefits than the TNM classification. Similar results were found in the validation cohort. Conclusions: The nTNM classification for CRC has better predictive performances and superior accuracy for predicting prognosis compared with the TNM classification. The nTNM classification should therefore be considered in future revisions of the TNM classification.

The novel role and function of LINC01235 in metastasis of gastric cancer cells by inducing epithelial-mesenchymal transition.

LncRNAs play a vital role in the tumorigenesis of gastric cancer (GC). This study determined that LINC01235 expression has greater fold changes by analyzing TCGA RNA-Seq data. The qRT-PCR assay confirmed that LINC01235 is significantly over-expressed in GC cells and tissues. Additionally, the overall survival analysis showed that patients with a higher LINC01235 expression had a poorer prognosis than those with a lower LINC01235 expression. Univariate Cox regression analysis indicated that high LINC01235 expression is positively correlated with poor prognosis. Moreover, LINC01235 was an independent poor prognostic marker for GC in multivariate Cox analysis. Invitro assays suggested that LINC01235 knockdown suppresses GC cell migration and invasion. GSEA revealed that high LINC01235 expression is strongly enriched in the EMT pathway. Western blotting results revealed that LINC01235 silencing decreases the expression of EMT-induced proteins. In conclusion, LINC01235 can promote GC cell metastasis via EMT and function as a prognostic biomarker.

A Modified Pathological N Stage Including Status of Tumor Deposits in Colorectal Cancer With Nodal Metastasis.

BACKGROUND: The American Joint Committee on Cancer 8th classification states that colorectal cancer (CRC) is classified as N1c stage when regional lymph nodes (LNs) are negative and tumor deposits (TDs) are positive. However, how to classify TDs when regional LNs are positive remains unclear. The current study aimed to investigate the possibility of combining positive LNs and positive TDs to develop a modified pathological N (mpN) stage for CRC. METHODS: We retrospectively analyzed 9,198 patients with stage III CRC from the Surveillance, Epidemiology, and End Results program who underwent surgery (6,440 in the training cohort and 2,758 the validation cohort). The combination of positive LNs and TD status was defined as mpN stage. Overall survival (OS) according to mpN and pathological N (pN) stages was analyzed by the Kaplan-Meier method. The area under the curves (AUCs) and Akaike's information criterion (AIC) were applied to assess the predictive discrimination abilities and goodness-of-fit of the model. The clinical benefits were measured using decision curve analyses. The validation cohort was used to validate the results. RESULTS: AUC analysis showed that the prognostic discrimination of mpN stage (AUC = 0.628, 95% confidence interval (CI), 0.616-0.640) was better than that of pN stage (AUC = 0.618, 95% CI, 0.606-0.630, p = 0.006) for OS. The AIC demonstrated that mpN stage (AIC = 30,217) also showed superior model-fitting compared with pN stage (AIC = 30,257) and decision curve analyses revealed that mpN stage had better clinical benefits than pN stage. Similar results were found in the validation cohort. CONCLUSIONS: Among patients with CRC and LN metastasis, mpN stage might be superior to pN stage for assessing prognosis and survival, suggesting that TD status should be included in the pN stage.

A Modified Tumor-Node-Metastasis Classification for Stage III Colorectal Cancers Based on Treating Tumor Deposits as Positive Lymph Nodes.

Background: The tumor-node-metastasis classification of the American Joint Committee on Cancer classified tumor deposits (TDs) in patients with colorectal cancer (CRC) without lymph node (LN) metastasis as N1c, but the classification of TDs in patients with LN metastases remains controversial. This study investigated the probability of regarding TDs as positive LNs (pLNs) in pN stage and estimated its prognostic ability in CRC. Methods: We used the Surveillance, Epidemiology, and End Results program to analyze CRC patients who underwent surgical therapy (14,906 training cohort, 6,384 validation cohort). A modified pN stage (mpN) was identified using the number of pLNs plus TDs. Overall survival (OS) was analyzed using the Kaplan-Meier survival curves, and significant prognostic factors were identified by univariate and multivariate analyses. Prognostic ability was estimated using the area under the curve (AUC), calibration curve, and the Akaike's information criterion (AIC). Clinical benefit was measured by the decision curve analyses (DCA). The results were validated using the validation cohort. Results: Both the pN and mpN stages were independent prognostic factors in CRC according to univariate and multivariate analyses. The AUC analysis showed that the mpN stage had better prognostic discrimination for OS than the pN stage (0.612 vs. 0.605, P < 0.001). The AIC demonstrated that the mpN stage also showed superior model-fitting compared with the pN stage (49,756 vs. 49,841). The DCA further revealed that the mpN stage had better clinical benefits than the pN stage. The validation cohort showed similar findings. Conclusions: We concluded that counting TDs as pLNs may be superior to the pN stage when assessing the prognosis of CRC patients.