Integrating the dysregulated inflammasome-based molecular functionome in the malignant transformation of endometriosis-associated ovarian carcinoma

Chang, Chia‐Ming; Wang, Mong‐Lien; Lu, Kai-Hsi; Yang, Yi‐Ping; Juang, Chi-Mou; Wang, Peng-Hui; Hsu, Ren-Jun; Yu, Mu-Hsien; Chang, Cheng‐Chang

doi:10.18632/oncotarget.23364

Cited by 34 publications

(30 citation statements)

References 30 publications

(33 reference statements)

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“…A recent report analyzed the prevalence of cachexia in 14 different cancer types known to exhibit cachexia or a muscle wasting syndrome within the United States and the European Union, and found that over 1.3 million cancer patients exhibited clinical signs of cachexia in these oncological settings [42]. Reports have shown that cachexia is mediated, at least in part, by canonical NF-κB signaling [39, 43]. As such, a thoughtful examination of this signaling paradigm could pave the way for novel therapeutics to address this current deficit.…”

Section: Discussionmentioning

confidence: 99%

Withaferin A ameliorates ovarian cancer-induced cachexia and proinflammatory signaling

Straughn

Kakar

2019

J Ovarian Res

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BackgroundOvarian cancer is the fifth leading cause of cancer-related deaths amongst women in the United States. Cachexia is the primary cause of death in approximately 30% of cancer patients, and is often evidenced in ovarian cancer patients. We tested the steroidal lactone Withaferin A to examine if it could ameliorate ovarian cancer-induced cachexia.MethodsSix-week-old severely immunodeficient female mice were xenografted with the ovarian cancer cell line A2780 followed by treatment with Withaferin A or vehicle. Changes in functional grip strength were assessed on a weekly basis. Postmortem, H&E staining was performed on skeletal muscle sections and immunofluorescent immunohistochemistry was performed on skeletal muscle and tumor sections. The levels of NF-κB-related proinflammatory cytokines were assessed in the xenografted tumors and in resident host skeletal muscle.ResultsXenografting of the A2780 cell line resulted in a significant rate of mortality, which was attenuated by a therapeutic dosage of Withaferin A. Mice that received vehicle treatment following xenografting exhibited functional muscle decline over the course of the study. The therapeutic dosage Withaferin A treatment attenuated this reduction in grip strength, whereas the supratherapeutic dosage of Withaferin A was found to be toxic/lethal and demonstrated a further decline in functional muscle strength and an increased rate of mortality on par with vehicle treatment. At a histological level, the vehicle treated tumor-bearing mice exhibited a profound reduction in myofibrillar cross-sectional area compared to the vehicle treated tumor-free control group. The atrophic changes induced by the xenografted tumor were significantly ameliorated by treatment with Withaferin A. The combination of functional muscle weakening and induction of myofibrillar atrophy corroborate a cachectic phenotype, which was functionally rescued by Withaferin A. Further, treatment completely abolished the slow-to-fast myofiber type conversion observed in the settings of cancer-induced cachexia. In both host resident skeletal muscle and the xenografted tumors, we report an increase in NF-κB-related proinflammatory cytokines that was reversed by Withaferin A treatment. Finally, we demonstrated that Withaferin A significantly downregulates cytosolic and nuclear levels of phospho-p65, the active canonical NF-κB transcription factor, in xenografted tumors.ConclusionsCumulatively, our results demonstrate a previously overlooked role of Withaferin A in a xenograft model of ovarian cancer. We propose mechanisms by which Withaferin A reduces NF-κB-dependent pro-inflammatory cytokine production leading to an attenuation of the cachectic phenotype in an i.p. xenograft model of ovarian cancer.

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Section: Discussionmentioning

confidence: 99%

Withaferin A ameliorates ovarian cancer-induced cachexia and proinflammatory signaling

Straughn

Kakar

2019

J Ovarian Res

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“…AIM2 is a member of innate immune sensors that initiate inflammasomes and trigger secretion of proinflammatory cytokines [ 66 ]. Although it has displayed both tumor suppression and promotion roles across cancer types, its upregulation in ovarian cancers suggests it could promote EOC progression [ 67 , 68 ]. STAB1 is a transmembrane receptor expressed on macrophages and lymphatic endothelial cells that acts as an inhibitor of antitumor immunity [ 69 ].…”

Section: Genetic Susceptibility Mediated By Dna Methylationmentioning

confidence: 99%

DNA Methylation in Ovarian Cancer Susceptibility

Reid

Fridley

2020

Cancers

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Epigenetic alterations are somatically acquired over the lifetime and during neoplastic transformation but may also be inherited as widespread ‘constitutional’ alterations in normal tissues that can cause cancer predisposition. Epithelial ovarian cancer (EOC) has an established genetic susceptibility and mounting epidemiological evidence demonstrates that DNA methylation (DNAm) intermediates as well as independently contributes to risk. Targeted studies of known EOC susceptibility genes (CSGs) indicate rare, constitutional BRCA1 promoter methylation increases familial and sporadic EOC risk. Blood-based epigenome-wide association studies (EWAS) for EOC have detected a total of 2846 differentially methylated probes (DMPs) with 71 genes replicated across studies despite significant heterogeneity. While EWAS detect both symptomatic and etiologic DMPs, adjustments and analytic techniques may enrich risk associations, as evidenced by the detection of dysregulated methylation of BNC2—a known CSG identified by genome-wide associations studies (GWAS). Integrative genetic–epigenetic approaches have mapped methylation quantitative trait loci (meQTL) to EOC risk, revealing DNAm variations that are associated with nine GWAS loci and, further, one novel risk locus. Increasing efforts to mapping epigenome variation across populations and cell types will be key to decoding both the genomic and epigenomic causal pathways to EOC.

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“…Further work has been done by Chang et al [41], who documented the crucial role of inflammation in the malignant transformation of endometriosis by analyzing microarray data. They observed that 7 genes of inflammasome complex ( Caspase-4 , Caspase-7 , Caspase-8 , NLRP3 , AIM2 , PYCARD , NAIP ) and 11 genes of the inflammasome-related pathway ( IL-1B , IL1RL1 , IL-18 , TLR1 , TLR7 , TOLLIP , NFKBIA , TNF , TNFAIP3 , INFGR2 , P2RX7 ) were highly expressed in endometriosis-associated ovarian carcinoma and demonstrated a tendency to correlate with poor survival.…”

Section: Genome Profile Of Endometriosis and Associated Cancermentioning

confidence: 99%

Genes’ Interactions: A Major Contributor to the Malignant Transformation of Endometriosis

Sapalidis

Machairiotis

Vasilakaki

et al. 2019

IJMS

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The genetic and epigenetic factors that contribute to the malignant transformation of endometriosis are still under investigation. The objective of the present study was to investigate the genetic link between endometriosis and cancer by examining and correlating the latest clinical observations with biological experimental data. We collected updated evidence about the genetic relationship between endometriosis and cancers by conducting a comprehensive search of PubMed and Scopus databases, focusing on the papers published between January 2018 and January 2019. New insights into the mechanism of the malignant transformation of endometriosis have been published recently. The use of state-of-the-art techniques and methods, such as the genome-wide association study analysis and the weighted gene co-expression analysis, have significantly altered our understanding of the association between endometriosis and endometriosis-associated cancer development. Interestingly, the interactions formed between genes seem to play a pivotal role in the phenotypic expression of mutations. Therefore, the effect of single nucleotide polymorphisms and the function of the expression quantitative trait loci on genes’ expression have been the subject of many recent works. In addition, it has been discovered that genes, the mutations of which have been related to the development of endometriosis, play a role as hub genes. This may lead to new areas of research for understanding the mechanism of malignant transformation of the disease. Significant steps forward have been made towards the identification of factors that control the malignant transformation of endometriosis. Still, due to rarity of the event, a better-organized scheme for sampling on a global level should be adopted.

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Integrating the dysregulated inflammasome-based molecular functionome in the malignant transformation of endometriosis-associated ovarian carcinoma

Cited by 34 publications

References 30 publications

Withaferin A ameliorates ovarian cancer-induced cachexia and proinflammatory signaling

Withaferin A ameliorates ovarian cancer-induced cachexia and proinflammatory signaling

DNA Methylation in Ovarian Cancer Susceptibility

Genes’ Interactions: A Major Contributor to the Malignant Transformation of Endometriosis

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