PARP1: A potential biomarker for gastric cancer

Afzal, Hifza; Yousaf, Shahzad; Rahman, Faisal; Ahmed, Malik Waqar; Akram, Zertashia; Kayani, Mahmood Akhtar; Mahjabeen, Ishrat

doi:10.1016/j.prp.2019.152472

Cited by 14 publications

(11 citation statements)

References 40 publications

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“…Subsequently, we also analyzed the associations between PARP1 expression and clinical prognosis, immunotherapy signatures. We found that most tumors had high expression of PARP1 mRNA, compared to corresponding normal tissues, and there was a worse prognosis in patients with high expression for several tumors, suggesting that PAPR1 plays an oncogenic role to some extent in multiple tumors, which is consistent with the findings of previous studies on different tumors, such as colorectal cancer (35), gastric cancer (36) and sarcoma (37). Thus patients with high PARP1 expression are required to be monitored with closer follow-up protocols.…”

Section: Discussionsupporting

confidence: 91%

Pan-Cancer Analysis of PARP1 Alterations as Biomarkers in the Prediction of Immunotherapeutic Effects and the Association of Its Expression Levels and Immunotherapy Signatures

et al. 2021

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BackgroundPoly (ADP-ribose) polymerases-1 (PARP1) alterations are associated with PARP1 inhibitor resistance, regulating the function of Treg cells and PDL1 expression in tumor cells, and high PARP1 expression is significantly associated with aggressive behavior and chemotherapeutic resistance in several tumors. However, a comprehensive analysis of the predictive values of PARP1 alteration for immune checkpoint inhibitor (ICI) effectiveness in tumors remains unclear, and the associations between its expression and immunotherapy signatures also needs to be explored further.MethodsWe performed some analyses with the cBioPortal online database (https://www.cbioportal.org), TIMER2.0 (Tumor Immune Estimation Resource 2.0, http://timer.comp-genomics.org/) and TCGA database (https://xenabrowser.net or https://portal.gdc.cancer.gov/). Survival analysis was conducted using Kaplan–Meier method, and the associations between PARP1 transcription levels and immune checkpoint gene expression, the number of neoantigens, tumor mutation burden (TMB) levels, and microsatellite instability (MSI) event are analyzed by spearman correlation analysis and visualization of those mentioned above is performed using R, version 3.6.3 (http://www.r-project.org/).ResultsWe found that PARP1 was altered in 1338 (2.9%) out of 45604 patients with diverse tumors, which was associated with markedly higher TMB levels in a variety of tumors (P < 0.01). Impressively, patients with PARP1 alterations in advanced tumors showed better overall survival (OS) in the ICI-treated cohort (P = 0.016). PARP1 altered group was substantially correlated with higher immune infiltrates across most tumors, including CD8+ T cells in colorectal adenocarcinoma (P = 0.0061), endometrial carcinoma (P = 0.0033), stomach cancer (P = 0.033), and cervical cancer (P = 0.026), respectively. The PARP1 altered group showed high expression in transcription (P < 0.001), and higher expression of LAG3, PDCD1, CTLA-4, and TIGIT (P < 0.05). Higher PARP1 expression was present in 27 tumor compared the corresponding normal tissues using the GTEx and TCGA databases and it had a worse OS in several tumors (P < 0.05). Further, high PARP1 expression was significantly associated with six immune cells (B cells, CD4+ T cells, CD8+ T cells, macrophages, neutrophils, and dendritic cells) in most tumors, including colon adenocarcinoma (COAD), head and neck squamous cell carcinoma (HNSC), kidney renal clear cell carcinoma (KIRC), and liver hepatocellular carcinoma (LIHC) (P < 0.05). In particular, CD8+T cell infiltration, was also positively correlated with high PARP1 expression in bladder urothelial carcinoma (BLCA), breast invasive carcinoma (BRCA), kidney renal papillary cell carcinoma (KIRP), brain lower grade glioma (LGG), LIHC, pancreatic adenocarcinoma (PAAD), pheochromocytoma and paraganglioma (PCPG), prostate adenocarcinoma (PRAD), rectum adenocarcinoma (READ), testicular germ cell tumors (TGCT), thymoma (THYM), uterine corpus endometrial carcinoma (UCEC), uveal melanoma (UVM) (P < 0.05, no data shown), and PARP1 expression was significantly positively correlated with the transcription levels of some of the 47 immune checkpoint genes, such as CD274, CTLA4, and PDCD1 in several tumors, including PAAD, LIHC, KIRC, HNSC, and BLCA (P < 0.05). A significant positive association between PARP1 expression and the number of immune neoantigen was found within COAD, KIRC, lung adenocarcinoma (LUAD), PAAD and THYM (P < 0.05), and there were also significantly positive correlations between PARP1 expression and TMB in many tumors like adrenocortical carcinoma (ACC), COAD, kidney chromophobe (KICH), LGG, LUAD, READ, skin cutaneous melanoma (SKCM) and stomach adenocarcinoma (STAD) (P < 0.05). In addition, high PARP1 expression was positively associated with microsatellite instability event in COAD, KIRP, BRCA, glioblastoma multiforme (GBM), lung squamous cell carcinoma (LUSC), LGG, READ, UCEC, SKCM and LUAD (P < 0.05).ConclusionsOur results highlight the significance of PARP1 alterations as pan-cancer predictive biomarkers for ICI treatment, and its expression levels seem to be correlated with the status of immunotherapy-associated signatures, thus may be a promising biomarker for predicting ICI response in several tumors.

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Section: Discussionsupporting

confidence: 91%

Pan-Cancer Analysis of PARP1 Alterations as Biomarkers in the Prediction of Immunotherapeutic Effects and the Association of Its Expression Levels and Immunotherapy Signatures

et al. 2021

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“…Hence, these PARP1-mediated effects are thought to aid tumour initiation in gastric cancer. This is supported by the increased PARP1 mRNA expression demonstrated in tumour samples, compared to surrounding matched normal tissue [59]. Furthermore, increasing PARP1 levels positively correlate with advanced gastric tumour stage, metastases and poorer survival rates, supporting a role for PARP1 in disease progression [58].…”

Section: Gastric Cancermentioning

confidence: 83%

“…The Helicobacter pylori (H. pylori) bacterium is a leading global cancer-causing pathogen, primarily associated with gastric cancer [57]. Gastric cancer patients with H. pylori infection were demonstrated to express higher levels of PARP1 when compared to H. pylori negative gastric cancer patients [58,59]. H. pylori releases an unidentified factor that stimulates PARylation by the PARP1 enzyme [60].…”

Section: Gastric Cancermentioning

confidence: 99%

Therapeutic Potential of PARP Inhibitors in the Treatment of Gastrointestinal Cancers

et al. 2021

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Gastrointestinal (GI) malignancies are a major global health burden, with high mortality rates. The identification of novel therapeutic strategies is crucial to improve treatment and survival of patients. The poly (ADP-ribose) polymerase (PARP) enzymes involved in the DNA damage response (DDR) play major roles in the development, progression and treatment response of cancer, with PARP inhibitors (PARPi) currently used in the clinic for breast, ovarian, fallopian, primary peritoneal, pancreatic and prostate cancers with deficiencies in homologous recombination (HR) DNA repair. This article examines the current evidence for the role of the DDR PARP enzymes (PARP1, 2, 3 and 4) in the development, progression and treatment response of GI cancers. Furthermore, we discuss the role of HR status as a predictive biomarker of PARPi efficacy in GI cancer patients and examine the pre-clinical and clinical evidence for PARPi and cytotoxic therapy combination strategies in GI cancer. We also include an analysis of the genomic and transcriptomic landscape of the DDR PARP genes and key HR genes (BRCA1, BRCA2, ATM, RAD51, MRE11, PALB2) in GI patient tumours (n = 1744) using publicly available datasets to identify patients that may benefit from PARPi therapeutic approaches.

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“…These changes in the cell cycle could also be related to the DNA damage response[ 32 ], leading cells to early apoptosis, as seen in our results. Recent studies have shown increased expression of genes related to the response to DNA damage and repair, such as APE1, H2AX and PARP-1, in GC samples, thus possibly influencing the survival of tumour cells[ 33 , 34 ]. Yang et al [ 35 ] demonstrated that TNFR2 enhances DNA damage repair by regulating PARP expression in breast cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of TNFR2 decreases survival gene expression, promotes apoptosis and affects the cell cycle of gastric cancer cells

Rossi¹,

Manoel-Caetano²,

Biselli³

et al. 2022

WJG

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BACKGROUND Chronic inflammation due to Helicobacter pylori ( H. pylori ) infection promotes gastric carcinogenesis. Tumour necrosis factor-α (TNF-α), a key mediator of inflammation, induces cell survival or apoptosis by binding to two receptors (TNFR1 and TNFR2). TNFR1 can induce both survival and apoptosis, while TNFR2 results only in cell survival. The dysregulation of these processes may contribute to carcinogenesis. AIM To evaluate the effects of TNFR1 and TNFR2 downregulation in AGS cells treated with H. pylori extract on the TNF-α pathway. METHODS AGS cell lines containing TNFR1 and TNFR2 receptors downregulated by specific shRNAs and nonsilenced AGS cells were treated with H. pylori extract for 6 h. Subsequently, quantitative polymerase chain reaction with TaqMan ® assays was used for the relative quantification of the mRNAs ( TNFA, TNFR1, TNFR2, TRADD, TRAF2, CFLIP, NFKB1, NFKB2, CASP8, CASP3 ) and miRNAs (miR-19a, miR-34a, miR-103a, miR-130a, miR-181c) related to the TNF-α signalling pathway. Flow cytometry was employed for cell cycle analysis and apoptosis assays. RESULTS In nonsilenced AGS cells, H. pylori extract treatment increased the expression of genes involved in cell survival and inhibited both apoptosis ( NFKB1, NFKB2 and CFLIP ) and the TNFR1 receptor. TNFR1 downregulation significantly decreased the expression of the TRADD and CFLIP genes, although no change was observed in the cellular process or miRNA expression. In contrast, TNFR2 downregulation decreased the expression of the TRADD and TRAF2 genes, which are both important downstream mediators of the TNFR1-mediated pathway, as well as that of the NFKB1 and CFLIP genes, while upregulating the expression of miR-19a and miR-34a . Consequently, a reduction in the number of cells in the G0/G1 phase and an increase in the number of cells in the S phase were observed, as well as the promotion of early apoptosis. CONCLUSION Our findings mainly highlight the important role of TNFR2 in the TNF-α pathway in gastric cancer, indicating that silencing it can reduce the expression of survival and anti-apoptotic genes.

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PARP1: A potential biomarker for gastric cancer

Cited by 14 publications

References 40 publications

Pan-Cancer Analysis of PARP1 Alterations as Biomarkers in the Prediction of Immunotherapeutic Effects and the Association of Its Expression Levels and Immunotherapy Signatures

Pan-Cancer Analysis of PARP1 Alterations as Biomarkers in the Prediction of Immunotherapeutic Effects and the Association of Its Expression Levels and Immunotherapy Signatures

Therapeutic Potential of PARP Inhibitors in the Treatment of Gastrointestinal Cancers

Downregulation of TNFR2 decreases survival gene expression, promotes apoptosis and affects the cell cycle of gastric cancer cells

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