Inflammation-Induced Oxidative Stress Mediates Gene Fusion Formation in Prostate Cancer

Mani, Ram S.; Amin, M. Asif; Li, Xiangyi; Kalyana-Sundaram, Shanker; Veeneman, Brendan; Wang, Lei; Ghosh, A. K.; Aslam, Adam J.; Ramanand, Susmita G.; Rabquer, Bradley J.; Kimura, Wataru; Tran, Maxwell; Cao, Xuhong; Roychowdhury, Sameek; Dhanasekaran, Saravana M.; Palanisamy, Nallasivam; Sadek, Hesham A.; Kapur, Payal; Koch, Alisa E.; Chinnaiyan, Arul M.

doi:10.1016/j.celrep.2016.11.019

Cited by 75 publications

(65 citation statements)

References 39 publications

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“…9-11 Indeed, several recent studies highlight a mechanistic role for inflammation induced by infection or bacterial components (eg lipopolysaccharides) in the formation of hallmark prostate cancer ETS gene fusions 12 and in the expansion of intermediate cells, 13 the hypothesized cells where neoplastic transformation in prostate cancer may commence. 14 Given this recent experimental evidence linking bacterial infections to prostate cancer development, there is a pressing need to understand how, when and what microorganisms may be introduced in the prostate.…”

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confidence: 99%

Profiling the Urinary Microbiome in Men with Positive versus Negative Biopsies for Prostate Cancer

et al. 2018

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Purpose Studies demonstrating bacterial DNA and cultivable bacteria in urine samples have challenged the clinical dogma that urine is sterile. Furthermore, studies now indicate that dysbiosis of the urinary microbiome is associated with pathological conditions. We propose that the urinary microbiome may influence chronic inflammation observed in the prostate, leading to prostate cancer development and progression. Therefore, we profiled the urinary microbiome in men with positive vs negative biopsies for prostate cancer. Materials and Methods Urine was collected from men prior to biopsy for prostate cancer. DNA was extracted from urine pellet samples and subjected to bacterial 16S rDNA Illumina® sequencing and 16S rDNA quantitative polymerase chain reaction. We determined the association between bacterial species and the presence or absence of cancer, cancer grade, and type and degree of prostate inflammation. Results Urine samples revealed diverse bacterial populations. There were no significant differences in α or β diversity and no clear hierarchical clustering of benign or cancer samples. We identified a cluster of pro-inflammatory bacteria previously implicated in urogenital infections in a subset of samples. Many species, including known uropathogens, were significantly and differentially abundant among cancer and benign samples, in low vs higher grade cancers and in relation to prostate inflammation type and degree. Conclusions To our knowledge we report the most comprehensive study to date of the male urinary microbiome and its relationship to prostate cancer. Our results suggest a prevalence of pro-inflammatory bacteria and uropathogens in the urinary tract of men with prostate cancer.

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confidence: 99%

Profiling the Urinary Microbiome in Men with Positive versus Negative Biopsies for Prostate Cancer

et al. 2018

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“…Our data suggest that this increase in androgen signaling, possibly combined with inflammatory signaling could promote the chromosomal breaks necessary for EWSR1/FLI1 formation. The origins of the most common fusion in prostate cancer, TMPRSS2/ERG is accredited to intronic AR binding in combination with DNA damage or inflammatory signaling (Lin et al, 2009;Mani et al, 2016). Our current study suggests a similar mechanism could lead to EWSR1 breakpoint formation followed by EWSR1/FLI1 fusion.…”

Section: Discussionmentioning

confidence: 59%

“…Because high levels of androgen can cause DNA damage (Chatterjee et al, 2019), we asked if lower levels of androgen signaling could also promote high frequency breakage of EWSR1. Mani et al reports that inflammation induced oxidative stress mediated by TNFa combined with androgen signaling promotes formation of the TMPRSS2/ERG fusion in prostate cells (Mani et al, 2016). We found that VCaP cells treated with TNFa alone did not show significantly increased EWSR1 breakpoint frequency, however the combination of low dose (1 nM) R1881 with TNFa increased breakpoint frequency to near that of cells treated with high dose (100 nM) R1881 ( Figure 5E).…”

Section: Androgen Signaling Promotes Ewsr1 Breakpoint Formation Via Rmentioning

confidence: 53%

Androgen signaling connects short isoform production to breakpoint formation at Ewing sarcoma breakpoint region 1 via an R-loop-dependent mechanism

Nicholas

Hollenhorst

2020

Preprint

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Ewing's sarcoma is most prevalent in adolescent males and is almost always the result of a chromosomal rearrangement that creases a fusion gene with EWSR1 as the 5' fusion partner.Why EWSR1 is more commonly rearranged than other, similar genes and why Ewing's sarcoma is predisposed to adolescent males is not known. We found that in prostate cancer, androgen signaling upregulated a 5' EWSR1 isoform by promoting usage of an intronic polyadenylation site proximal to the Ewing's sarcoma breakpoint hotspot. An intronic Androgen Receptor (AR) binding site was necessary for this upregulation. Strikingly, androgen signaling drove high levels of breakpoint formation in EWSR1. Androgen signaling also promoted R-loop formation and Rloops were necessary for breakpoint formation. These data suggest that aberrant androgen signaling leads to R-loop-mediated DNA damage at the EWSR1 breakpoint hotspot and subsequent misrepair could promote EWSR1 gene fusions in Ewing's sarcoma.

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“…Almost half of all PCs possess the TMPRSS2-ERG gene fusion, and this phenomenon predominantly occurs because of inflammation-induced oxidative stress that promotes DNA breaks and, thus, fusion genes. 99 The TMPRSS2-ERG fusion in cancer cells regulates CXCR4 gene expression through the binding and activation of ERG to upstream elements in the CXCR4 gene. 70,71 CXCR4 further leads to regulation of PI4KIIIa activity and mediates metastatic activity.…”

Section: Pten Nf-kb and Other Signaling Moleculesmentioning

confidence: 99%

Prostate Cancer

Rani

Dasgupta

Murphy

2019

The American Journal of Pathology

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Prostate cancer (PC) is a leading cause of death in men. Inflammation is one of the initiating processes whereby cells are trafficked into the tumor microenvironment by specific cytokines termed chemokines. This recruitment is complex and involves diverse leukocyte subsets with procancer and anticancer functions. Chemokines promote/abrogate proliferation of cancerous cells, block/aid apoptosis, and are instrumental/ detrimental in cancer cell migration required for metastasis. Chemokines guide the release/transport of immune cells that serve as chaperones at sites of inflammation, and after subsequent activation, they lead to an immune response. The variety of immune cells recruited at the site of tumor initiation possess unique functions, and the plethora of chemokines released by each cell derived from a progenitor cell activated under a defined set of conditions dictates its specific role in cancer progression/regression. Geographic consequences that govern the climate and endemic diseases, along with the associated evolutionary effects that at times protect populations from one disease, could lead to genetic variations that determine a role for ethnicity and race in PC risk and susceptibility. Dysregulated expression or an imbalance in the homeostatic mechanisms associated with chemokines is implicated in PC. This review discusses the role of inflammation and chemokines in PC.

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Inflammation-Induced Oxidative Stress Mediates Gene Fusion Formation in Prostate Cancer

Cited by 75 publications

References 39 publications

Profiling the Urinary Microbiome in Men with Positive versus Negative Biopsies for Prostate Cancer

Profiling the Urinary Microbiome in Men with Positive versus Negative Biopsies for Prostate Cancer

Androgen signaling connects short isoform production to breakpoint formation at Ewing sarcoma breakpoint region 1 via an R-loop-dependent mechanism

Prostate Cancer

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