Analysis of key genes and signaling pathways involved in <i>Helicobacter pylori</i>‐associated gastric cancer based on The Cancer Genome Atlas database and <scp>RNA</scp> sequencing data

Hu, Yi; He, Cong; Liu, Jianping; Li, Nianshuang; Peng, Chao; Yang-Ou, Yao-Bin; Yang, Xiaoyu; Lü, Nonghua; Zhu, Yin

doi:10.1111/hel.12530

Cited by 33 publications

(26 citation statements)

References 49 publications

(49 reference statements)

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“…And the expression of IGFBP1 is positively associated with tumor invasion, lymph node metastasis and vascular invasion ( Sato et al, 2019 ). VSTM2L is reported to be downregulated in the H. pylori -positive GC samples ( Hu et al, 2018 ). However, the role of VSTM2L in tumors is rarely reported, and its role requires further studies.…”

Section: Discussionmentioning

confidence: 99%

Genome‐wide identification of CpG island methylator phenotype related gene signature as a novel prognostic biomarker of gastric cancer

Zeng

Xie

Gong

2020

PeerJ

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Background Gastric cancer (GC) is one of the most fatal cancers in the world. Results of previous studies on the association of the CpG island methylator phenotype (CIMP) with GC prognosis are conflicting and mainly based on selected CIMP markers. The current study attempted to comprehensively assess the association between CIMP status and GC survival and to develop a CIMP-related prognostic gene signature of GC. Methods We used a hierarchical clustering method based on 2,082 GC-related methylation sites to stratify GC patients from the cancer genome atlas into three different CIMP subgroups according to the CIMP status. Gene set enrichment analysis, tumor-infiltrating immune cells, and DNA somatic mutations analysis were conducted to reveal the genomic characteristics in different CIMP-related patients. Cox regression analysis and the least absolute shrinkage and selection operator were performed to develop a CIMP-related prognostic signature. Analyses involving a time-dependent receiver operating characteristic (ROC) curve and calibration plot were adopted to assess the performance of the prognostic signature. Results We found a positive relationship between CIMP and prognosis in GC. Gene set enrichment analysis indicated that cancer-progression-related pathways were enriched in the CIMP-L group. High abundances of CD8+ T cells and M1 macrophages were found in the CIMP-H group, meanwhile more plasma cells, regulatory T cells and CD4+ memory resting T cells were detected in the CIMP-L group. The CIMP-H group showed higher tumor mutation burden, more microsatellite instability-H, less lymph node metastasis, and more somatic mutations favoring survival. We then established a CIMP-related prognostic gene signature comprising six genes (CST6, SLC7A2, RAB3B, IGFBP1, VSTM2L and EVX2). The signature was capable of classifying patients into high‐and low‐risk groups with significant difference in overall survival (OS; p < 0.0001). To assess performance of the prognostic signature, the area under the ROC curve (AUC) for OS was calculated as 0.664 at 1 year, 0.704 at 3 years and 0.667 at 5 years. When compared with previously published gene-based signatures, our CIMP-related signature was comparable or better at predicting prognosis. A multivariate Cox regression analysis indicated the CIMP-related prognostic gene signature was an independent prognostic indicator of GC. In addition, Gene ontology analysis indicated that keratinocyte differentiation and epidermis development were enriched in the high-risk group. Conclusion Collectively, we described a positive association between CIMP status and prognosis in GC and proposed a CIMP-related gene signature as a promising prognostic biomarker for GC.

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Section: Discussionmentioning

confidence: 99%

Genome‐wide identification of CpG island methylator phenotype related gene signature as a novel prognostic biomarker of gastric cancer

Zeng

Xie

Gong

2020

PeerJ

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“…However, this gene's functional role and mechanism are still unclear, especially in cancer. In recent years, there are a few studies that described the expression and clinical relevance of VSTM2L in cancer; the mRNA level of VSTM2L is lower in gastric cancer tissues than in adjacent normal tissues and was downregulated in the H. pylori-positive gastric cancer [ 16 ]. Moreover, the VSTM2L gene was considered a novel CIMP-related prognostic marker to classify gastric cancer patients into high- and low-risk groups with significant difference in overall survival time [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

High Expression of VSTM2L Induced Resistance to Chemoradiotherapy in Rectal Cancer through Downstream IL-4 Signaling

Líu

Zhang

Zhen

et al. 2021

Journal of Immunology Research

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Background. Preoperative chemoradiotherapy (pCRT) is a common and essential therapeutic strategy for patients with locally advanced rectal cancer (LARC), but poor tumor response and therapeutic resistance to chemoradiotherapy have appeared usually among persons and affected those patients’ survival prognosis. The resistance to chemoradiotherapy in rectal cancer is difficult to predict. This study was aimed at evaluating the role of V-set and transmembrane domain containing 2 like protein (VSTM2L) in resistance to chemoradiotherapy in rectal cancer. Methods. Analysis of the GEO profiling datasets of rectal cancer patients receiving pCRT disclosed that VSTM2L as a candidate gene was significantly upregulated in nonresponders of rectal cancer with pCRT. The mRNA and protein expression of VSTM2L was detected by quantitate real-time PCR, western blotting, and immunohistochemistry in six rectal cancer biopsy tissues before pCRT. Furthermore, the rectal cancer patient-derived organoids were cultured to evaluate the association of VSTM2L expression and tumor response to CRT. Overexpression of VSTM2L in cancer cells treated with CRT was analyzed for the function of cell proliferation and viability, clone formation, DNA damage repair, and apoptosis ability. The GSEA and RNA-sequence analysis were used to find the downstream mechanism of VSTM2L overexpression in cells treated with CRT. Results. The mRNA levels of VSTM2L were significantly downregulated in normal rectal tissues compared to tumor tissues and were upregulated in nonresponders of rectal cancer patients receiving pCRT and positively correlated with poor survival prognosis from GEO datasets. High expression of VSTM2L was significantly associated with tumor regression after pCRT ( P = 0.030 ). Moreover, high expression of VSTM2L reduced γ-H2AX expression in rectal cancer patient-derived organoids treated with CRT. The overexpression of VSTM2L in colorectal cancer cells induced resistance to CRT via promoting cell proliferation and inhibiting apoptosis. The molecular mechanism revealed that the overexpression of VSTM2L induced resistance to CRT through downstream IL-4 signaling affecting the progress of cell proliferation and apoptosis. Conclusion. The high expression of VSTM2L induced resistance to CRT, and adverse survival outcomes served as a prognostic factor in patients with rectal cancer receiving pCRT, suggesting that VSTM2L high expression may be a potential resistant predictable biomarker for LARC patients receiving pCRT.

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“…In our study, they showed a trend of increasing in NAG and then decreasing in AG and GC, which may be closely associated with the occurrence of GC. Hu, et al screened genes involved in the Hp + -GC group than in the H. pylori --GC group, furthermore verified the results in TCGA database (Hu et al 2018). They did not analyze differential expressed genes during the dynamic progression from NAG, AG-IM and GC.…”

Section: Discussion：mentioning

confidence: 98%

Peer Review #2 of "Identification of DEGs and transcription factors involved in H. pylori-associated inflammation and their relevance with gastric cancer (v0.2)"

2020

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Background: Previous studies have indicated that chronic inflammation linked to H. pylori infection is the leading causes for gastric cancer (GC). However, the exact mechanism is not entirely clear until now. Purpose: To identify the key molecules and TFs involved in H. pylori infection and to provide new insights into H. pylori-associated carcinogenesis and lay the groundwork for the prevention of GC. Results: GO and KEGG analysis revealed that the DEGs of Hp +-NAG were mainly associated with the immune response, chemokine activity, extracellular region and rheumatoid arthritis pathway. The DEGs of Hp +-AG-IM were related to the apical plasma membrane, intestinal cholesterol absorption, transporter activity and fat digestion and absorption pathway. In Hp +-NAG network, the expression of TNF, CXCL8, MMP9, CXCL9, CXCL1, CCL20, CTLA4, CXCL2, C3, SAA1 and FOXP3, JUN had statistical significance between normal and cancer in TCGA database. In Hp +-AG-IM network the expression of APOA4, GCG, CYP3A4, XPNPEP2 and FOXP3, JUN were statistically different in the comparison of normal and cancer in TCGA database. FOXP3 were negatively associated with overall survival, and the association for JUN was positive. Conclusion: The current study identified key DEGs and their transcriptional regulatory networks involved in H. pylori-associated NAG, AG-IM and GC and found that patients with higher expressed FOXP3 or lower expressed JUN had shorter overall survival time. Our study provided new directions for inflammationassociated oncogenic transformation involved in H. pylori infection.

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Analysis of key genes and signaling pathways involved in Helicobacter pylori‐associated gastric cancer based on The Cancer Genome Atlas database and RNA sequencing data

Abstract: These results indicate that some genes (TP53, CCDC151, CHRNB2, GMPR2, HDGFRP2, VSTM2L) and previously unidentified signaling pathways (eg, the Hippo signaling pathway) might play an important role in H. pylori-associated GC.

Cited by 33 publications

References 49 publications

Genome‐wide identification of CpG island methylator phenotype related gene signature as a novel prognostic biomarker of gastric cancer

Genome‐wide identification of CpG island methylator phenotype related gene signature as a novel prognostic biomarker of gastric cancer

High Expression of VSTM2L Induced Resistance to Chemoradiotherapy in Rectal Cancer through Downstream IL-4 Signaling

Peer Review #2 of "Identification of DEGs and transcription factors involved in H. pylori-associated inflammation and their relevance with gastric cancer (v0.2)"

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