VCAN – A novel prognostic marker for gastric cancer

Abstract Background Versican (VCAN) is a large aggregating extracellular matrix proteoglycan implicated in the pathogenesis of most human cancers but its role in gastric cancer is not yet elucidated. We designed the present study to investigate the expression, prognostic value, relationship between genetic alterations and patient’s outcome, disease associations, as well as genetic and protein interactions of VCAN in gastric cancer. Methods Expression of VCAN in tumor and normal tissues was studied with ONCOMINE, UALCAN, and GEPIA databases and the human protein atlas. UALCAN, GEPIA, OncoLnc and Kaplan-Meier plotter were used to assess the prognostic values of VCAN in gastric cancer. Subgroup analysis of the clinical significance of VCAN in gastric cancer was done using Kaplan-Meier plotter. Genetic alterations of VCAN and their associations with patient’s outcome were studied with cBioPortal. Open targets platform was used to study diseases associated with VCAN, GeneMANIA was used to obtain the neighbor genes interaction network of VCAN, and STRING was used to examine VCAN interaction with other proteins. Results VCAN was upregulated and associated with clinical cancer stages. High VCAN expression predicted unfavorable outcome for all patients; subgroup analysis showed worse outcomes for patients treated with surgery or other adjuvants (other than 5-FU based adjuvant) but better outcome for patients treated with 5-FU based adjuvant, associating VCAN expression with chemosensitivity to 5-FU based adjuvants, but chemoresistance to other adjuvants. Genetic alteration of VCAN correlated with a favorable outcome in terms of disease-free survival for patients. Also, open targets platform showed that VCAN is associated with gastric cancer and is a potential therapeutic target for the disease. Finally, interaction of VCAN with neighbor genes and proteins revealed that VCAN interacts with genes and proteins that drive tumorigenesis and cancer progression. Conclusion The results of this study show that VCAN is an oncogene in gastric cancer whose expression can be applied as a biomarker for prognostic prediction, selection of appropriate chemotherapy drugs/monitoring of treatment response, and is a potential therapeutic target for gastric cancer.

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EPLIN Expression in Gastric Cancer and Impact on Prognosis and Chemoresistance

Biomolecules ◽

10.3390/biom11040547 ◽

2021 ◽

Vol 11 (4) ◽

pp. 547

Author(s):

Wenjing Gong ◽

Jianyuan Zeng ◽

Jiafu Ji ◽

Yongning Jia ◽

Shuqin Jia ◽

...

Keyword(s):

Gastric Cancer ◽

Overall Survival ◽

Prognostic Factor ◽

Cancer Progression ◽

Chemotherapy Resistance ◽

Disease Free Survival ◽

Cancer Group ◽

Kaplan Meier ◽

Kaplan Meier Plotter ◽

Disease Free

Epithelial protein lost in neoplasm (EPLIN) has been implicated as a suppressor of cancer progression. The current study explored EPLIN expression in clinical gastric cancer and its association with chemotherapy resistance. EPLIN transcript expression, in conjunction with patient clinicopathological information and responsiveness to neoadjuvant chemotherapy (NAC), was explored in two gastric cancer cohorts collected from the Beijing Cancer Hospital. Kaplan-Meier survival analysis was undertaken to explore EPLIN association with patient survival. Reduced EPLIN expression was associated with significant or near significant reductions of overall, disease-free, first progression or post-progression survival in the larger host cohort and Kaplan Meier plotter datasets. In the larger cohort EPLIN expression was significantly higher in the combined T1 + T2 gastric cancer group compared to the T3 + T4 group and identified to be an independent prognostic factor of disease-free survival and overall survival by multivariate analysis. In the smaller, NAC cohort, EPLIN expression was found to be significantly lower in tumour tissues than in paratumour tissues. EPLIN expression was significantly associated with responsiveness to chemotherapy which contributes to overall survival. Together, EPLIN appears to be a prognostic factor and may be associated with patient sensitivity to NAC.

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Bioinformatics Analysis Identifies CPZ as a Tumor Immunology Biomarker For Gastric Cancer

Current Bioinformatics ◽

10.2174/1574893615999200707145643 ◽

2020 ◽

Vol 15 ◽

Author(s):

Yuan Gu ◽

Ying Gao ◽

Xiaodan Tang ◽

Huizhong Xia ◽

Kunhe Shi

Keyword(s):

Gastric Cancer ◽

T Cells ◽

Signaling Pathway ◽

Tumor Immunology ◽

Bioinformatics Analysis ◽

Human Cancer ◽

Disease Free Survival ◽

Kaplan Meier ◽

Potential Biomarker ◽

Pathway Regulation

Background: Gastric cancer (GC) is one of the most common malignancies worldwide. However, the biomarkers for the prognosis and diagnosis of Gastric cancer were still need. Objective: The present study aimed to evaluate whether CPZ could be a potential biomarker for GC. Method: Kaplan-Meier plotter (http://kmplot.com/analysis/) was used to determine the correlation between CPZ expression and overall survival (OS) and disease-free survival (DFS) time in GC [9]. We analyzed CPZ expression in different types of cancer and the correlation of CPZ expression with the abundance of immune infiltrates, including B cells, CD4+ T cells, CD8+ T cells, neutrophils, macrophages, and dendritic cells, via gene modules using TIMER Database. Results: The present study identified that CPZ was overexpressed in multiple types of human cancer, including Gastric cancer. We found that overexpression of CPZ correlates to the poor prognosis of patients with STAD. Furthermore, our analyses show that immune infiltration levels and diverse immune marker sets are correlated with levels of CPZ expression in STAD. Bioinformatics analysis revealed that CPZ was involved in regulating multiple pathways, including PI3K-Akt signaling pathway, cGMP-PKG signaling pathway, Rap1 signaling pathway, TGF-beta signaling pathway, regulation of cell adhesion, extracellular matrix organization, collagen fibril organization, collagen catabolic process. Conclusion: This study for the first time provides useful information to understand the potential roles of CPZ in tumor immunology and validate it to be a potential biomarker for GC.

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O28: M6A DEMETHYLASE FTO A POTENTIAL TARGET IN BRAIN METASTATIC BREAST CANCER

British Journal of Surgery ◽

10.1093/bjs/znab117.028 ◽

2021 ◽

Vol 108 (Supplement_1) ◽

Author(s):

S Keelan ◽

S Charmsaz ◽

S Purcell ◽

D Varešlija ◽

S Cocchiglia ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Brain Metastasis ◽

Disease Progression ◽

Therapeutic Target ◽

Disease Free Survival ◽

Metastatic Breast ◽

Potential Therapeutic Target ◽

Rna Methylation ◽

Pharmacological Inhibition

Abstract Introduction Brain metastasis (BrM) occurs in 10-30% of patients with advanced breast cancer (BC). BrM is increasing in incidence and confers a poor prognosis. We aimed to investigate the contribution of global epi-transcriptomic alterations in N6-methyladenosine (m6A) RNA-methylation as a therapeutic target in brain metastatic breast cancer. Method In preliminary studies we have demonstrated m6A demethylase – FTO as the main contributor to the progression of ER+ breast cancer. Furthermore an association between FTO and reduced disease-free-survival (n=870, p=0.018) was observed. Here we conducted an epigenetic inhibitor screen using two therapeutic agents, ethyl-ester-meclofenamic acid (MA2) and FB23-2 on matched 2D cell line, 3D organoid cultures and patient-derived xenografts (PDX) explant models of brain metastasis. Result Upon integration of mapped global RNA methylation landscape with matched proteomic analysis, we observed genome-wide RNA hypo-methylation of key pluripotency genes, including SOX2 and KLF4, as key players underlying tumour progression to the brain. Genetic and pharmacological inhibition of FTO in novel ex vivo models of BrM significantly reduced protein expression levels of KLF4 and SOX2. Moreover, pharmacological inhibition of FTO with MA2 and FB23-2, inhibited cell proliferation in endocrine-resistant BC and patient BrM cells. We translate our findings to the clinic by demonstrating the efficacy of anti-FTO therapies in several unique PDX and 3D organoid BrM models. Conclusion Our results reveal epi-transcriptional remodelling events as a key mechanism in BrM. This study establishes an early role for targeting RNA methylation in the management of disease progression and presents FTO as a potential therapeutic target in BrM. Take-home message This study establishes an early role for targeting RNA methylation in the management of disease progression and presents FTO as a potential therapeutic target in brain metastatic breast cancer.

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SAA1 is upregulated in gastric cancer-associated fibroblasts possibly by its enhancer activation

Carcinogenesis ◽

10.1093/carcin/bgaa131 ◽

2020 ◽

Author(s):

Yoshimi Yasukawa ◽

Naoko Hattori ◽

Naoko Iida ◽

Hideyuki Takeshima ◽

Masahiro Maeda ◽

...

Keyword(s):

Gastric Cancer ◽

Cancer Cells ◽

Chromatin Immunoprecipitation ◽

Therapeutic Target ◽

Cancer Associated Fibroblasts ◽

Promoting Effect ◽

Gastric Cancer Cells ◽

Potential Therapeutic Target ◽

Active Enhancer ◽

Serum Amyloid A1

Abstract Cancer-associated fibroblasts (CAFs) tend to have tumor-promoting capacity, and can provide therapeutic targets. Even without cancer cells, CAF phenotypes are stably maintained, and DNA methylation and H3K27me3 changes have been shown to be involved. Here, we searched for a potential therapeutic target in primary CAFs from gastric cancer and a mechanism for its dysregulation. Expression microarray using eight CAFs and seven non-CAFs (NCAFs) revealed that serum amyloid A1 (SAA1), which encodes an acute phase secreted protein, was second most upregulated in CAFs, following IGF2. Conditioned medium (CM) derived from SAA1-overexpressing NCAFs was shown to increase migration of gastric cancer cells compared to that from control NCAFs, and its tumor-promoting effect was comparable to that of CM from CAFs. In addition, increased migration of cancer cells by CM from CAFs was mostly canceled with CM from CAFs with SAA1 knockdown. Chromatin immunoprecipitation (ChIP)-quantitative PCR showed that CAFs had higher levels of H3K27ac, an active enhancer mark, in the promoter and the two far upstream regions of SAA1 than NCAFs. Also, BET bromodomain inhibitors, JQ1 and mivebresib, decreased SAA1 expression and tumor-promoting effects in CAFs, suggesting SAA1 upregulation by enhancer activation in CAFs. Our present data showed that SAA1 is a candidate therapeutic target from gastric CAFs and indicated that increased enhancer acetylation is important for its overexpression.

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Evaluation of the prognostic value of CBXs in gastric cancer patients

Scientific Reports ◽

10.1038/s41598-021-91649-7 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Mengya He ◽

Limin Yue ◽

Haiyan Wang ◽

Feiyan Yu ◽

Mingyang Yu ◽

...

Keyword(s):

Gastric Cancer ◽

Target Genes ◽

Prognostic Significance ◽

Disease Free Survival ◽

Genetic Alterations ◽

Genetic Mutation ◽

The Cancer Genome Atlas ◽

Normal Tissues ◽

Interactive Analysis ◽

Gastric Cancer Patients

AbstractChromobox (CBX) proteins were suggested to exert epigenetic regulatory and transcriptionally repressing effects on target genes and might play key roles in the carcinogenesis of a variety of carcinomas. Nevertheless, the functions and prognostic significance of CBXs in gastric cancer (GC) remain unclear. The current study investigated the roles of CBXs in the prognosis of GC using the Oncomine, The Gene Expression Profiling Interactive Analysis (GEPIA), UALCAN, The Cancer Genome Atlas (TCGA), and cBioPortal databases. CBX1/2/3/4/5 were significantly upregulated in GC tissues compared with normal tissues, and CBX7 was downregulated. Multivariate analysis showed that high mRNA expression levels of CBX3/8 were independent prognostic factors for prolonged OS in GC patients. In addition, the genetic mutation rate of CBXs was 37% in GC patients, and genetic alterations in CBXs showed no association with OS or disease-free survival (DFS) in GC patients. These results indicated that CBX3/8 can be prognostic biomarkers for the survival of GC patients.

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Expression and prognostic roles of PRDXs gene family in hepatocellular carcinoma

Journal of Translational Medicine ◽

10.1186/s12967-021-02792-8 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Mingxing Xu ◽

Jianliang Xu ◽

Dun Zhu ◽

Rishun Su ◽

Baoding Zhuang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Acid Metabolism ◽

Family Members ◽

Interaction Network ◽

Genetic Alterations ◽

Database Analysis ◽

Kaplan Meier ◽

Canonical Pathways ◽

Human Protein Atlas ◽

Kaplan Meier Plotter

Abstract Background As the fourth leading cause of cancer-related death in the world, the therapeutic effect and 5-year overall survival of hepatocellular carcinoma (HCC) are not optimistic. Previous researches indicated that the disorder of PRDXs was related to the occurrence and development of cancers. Methods In this study, PRDXs were found in various tumor cell lines by CCLE database analysis. The analysis results of UALCAN, HCCDB and Human Protein Atlas databases showed the expression of PRDXs mRNA and protein in HCC tissues was dysregulated. Besides, UALCAN was used to assess the correlations between PRDXs mRNA as well as methylation levels and clinical characterization. Results High expression of PRDX1 or low expression of PRDX2/3 suggested poor prognosis for HCC patients which was demonstrated by Kaplan–Meier Plotter. The genetic alterations and biological interaction network of PRDXs in HCC samples were obtained from c-Bioportal. In addition, LinkedOmics was employed to analyze PRDXs related differentially expressed genes, and on this basis, enrichment of KEGG pathway and miRNAs targets of PRDXs were conducted. The results indicated that these genes were involved in several canonical pathways and certain amino acid metabolism, some of which may effect on the progression of HCC. Conclusions In conclusion, the disordered expression of some PRDX family members was associated with the prognosis of HCC patients, suggesting that these PRDX family members may become new molecular targets for the treatment and prognosis prediction of HCC.

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Amplification and expression of c-MET correlate with poor prognosis of patients with gastric cancer and upregulate the expression of PDL1

Acta Biochimica et Biophysica Sinica ◽

10.1093/abbs/gmab026 ◽

2021 ◽

Vol 53 (5) ◽

pp. 547-557

Author(s):

Ya’nan Yang ◽

Chenchen Wang ◽

Congqi Dai ◽

Xinyang Liu ◽

Wenhua Li ◽

...

Keyword(s):

Gastric Cancer ◽

Prognostic Significance ◽

Growth Factor Receptor ◽

Disease Free Survival ◽

Positive Association ◽

Her2 Positive ◽

Kaplan Meier ◽

Met Amplification ◽

Amplification Rate ◽

Cox Proportional Hazard Regression

Abstract The prognostic significance of c-MET in gastric cancer (GC) remains uncertain. In the present study, we examined the amplification, expression, and the prognostic value of c-MET, human epidermal growth factor receptor 2 (HER2), and programmed cell death 1 ligand 1 (PDL1), together with the correlations among them in a large cohort of Chinese samples. A total of 444 patients were included. The immunohistochemistry (IHC) and the dual-color silver in situ hybridization (SISH) were performed to examine their expression and amplification. Univariate and multivariate analyses were performed by the Cox proportional hazard regression model, and survival curves were estimated by the Kaplan–Meier method. The positivity determined by IHC of c-MET was 24.8%, and the MET amplification rate was 2.3%. The positivity rates of HER2 and PDL1 were 8% and 34.7%, respectively. PDL1 expression had a significantly positive association with c-MET expression. c-MET positivity played a significant prognostic role in disease-free survival (DFS) (P = 0.032). Patients with mesenchymal-epithelial transition (MET) amplification had significantly poorer prognosis on both DFS and overall survival (OS). Subgroup analysis showed that in HER2-negative patients, but not in HER2-positive patients, MET-positive patients had significantly worse DFS (P = 0.000) and OS (P = 0.006). c-MET regulated the expression of PDL1 through an AKT-dependent pathway. c-MET inhibitor enhanced the T-cell killing ability and increased the efficacy of PD1 antibody. c-MET was found to be an independent prognostic factor for DFS of GC patients. A combination of c-MET inhibitors and PD1 antibodies could enhance the killing capacity of T cells, providing a preliminary basis for the clinical research on the same combination in GC treatment.

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