Systemic Chromosome Instability Resulted in Colonic Transcriptomic Changes in Metabolic, Proliferation, and Stem Cell Regulators in <i>Sgo1</i>
                  <i>−/+</i> Mice

Rao, Chinthalapally V.; Sanghera, Saira; Zhang, Yuting; Biddick, Laura; Reddy, Arun; Lightfoot, Stan; Janakiram, Naveena B.; Mohammed, Altaf; Dai, Wei; Yamada, Hiroshi

doi:10.1158/0008-5472.can-15-0940

Cited by 23 publications

(27 citation statements)

References 54 publications

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“…In particular, the decrease in immune response was an aspect that was not reported previously. Consistent with the pathway analysis, CD8þ T-cells, Nkp46þ NK cells and Nkp1.1þ NK cells isolated from colonic tissues of untreated Sgo1 mice showed significant reduction in g-interferon production compared with control, indicating that Sgo1-CIN mice had partial immune dysfunction [149]. Various immune cell activation markers were downregulated in the lungs of Sgo1 mice [150].…”

Section: Cin Can Enhance Carcinogenesissupporting

confidence: 76%

“…Notably, stem cell markers were also misregulated. Collectively, these findings demonstrate that systemic CIN results in transcriptomic changes in metabolism, proliferation, cell fate, and immune responses in the colon, which may foster a microenvironment amenable to cancer development [149]. Lung RNAseq also indicated downregulations in immune function-related pathways, along with misregulations in other oncogenic pathways [150].…”

Section: Cin Can Enhance Carcinogenesismentioning

confidence: 84%

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Emerging links among Chromosome Instability (CIN), cancer, and aging

Rao

Asch

Yamada

2016

Molecular Carcinogenesis

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Aneuploidy was predicted to cause cancer. To test the prediction, various Chromosome Instability (CIN) mice models that carry transgenic mutations in mitotic regulators have been created. The availability of these mice has aided researchers in discovering connections between CIN, cancer, and aging. This review will focus on recent interdisciplinary findings regarding how CIN and aneuploidy affect carcinogenesis, immune dysfunction, and aging. High CIN can be generated in vivo by various intrinsic alterations (e.g., gene mutation, epigenetic modification) and extrinsic/environmental challenges (e.g., biological, chemical, biophysical), while immune surveillance, cell death, and natural turnover can remove cells with CIN. CIN itself is mutagenic and may cause further cellular mutations, which can be carcinogenic. Mitotically damaged cells can activate senescence-related tumor suppressors (e.g., p21 , p27 , p16 ), which may lead to tissue-level senescence/aging through inflammatory paracrine mechanisms called Senescence-Associated Secretory Phenotype (SASP) and Senescence Inflammatory Response (SIR). Organs with high CIN show altered gene expressions in both organ-specific and non-specific manners. Organ-specific gene expression signatures include activation of oncogenic pathways. Non-organ-specific gene expression signatures include metabolic changes and downregulations in immune functions. Immune surveillance normally targets senescent cells and tetraploid cells, a form of aneuploidy, for elimination. However, with partial immune dysfunction, immune surveillance is weakened with systemic CIN. In this case, more senescent cells and aneuploid cells survive, which further leads to an inflammatory, pro-tumorigenic, and senescent/aging microenvironment. We also discuss how we may intervene in this sequence of events to prevent CIN- or age-related carcinogenesis and/or some aspects of tissue aging. © 2016 Wiley Periodicals, Inc.

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Section: Cin Can Enhance Carcinogenesissupporting

confidence: 76%

Section: Cin Can Enhance Carcinogenesismentioning

confidence: 84%

Emerging links among Chromosome Instability (CIN), cancer, and aging

Rao

Asch

Yamada

2016

Molecular Carcinogenesis

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“…As aneuploidy alone also can modify global gene expression [66], can give proteotoxic stress to cells [67,68] and can modulate autophagy [69], genomic instability can have a broad impact on cellular physiology. The findings also suggest that such a CIN-specific gene expression signature and modulation of carcinogenic pathways can be targeted for cancer prevention purposes [64,65].…”

Section: Shugoshin 1 Haploinsufficient Mice (Sgo1-/+) Showed Cohesinomentioning

confidence: 83%

“…Using comparative RNAseq, we demonstrated that these cancer-prone organs (i.e. colon, liver, lung) differentially expressed genes with demonstrated cancer-association [64,65]. The results suggest that CIN alone can modify global gene expression and introduce local proneness (a field effect) to carcinogenesis.…”

Section: Shugoshin 1 Haploinsufficient Mice (Sgo1-/+) Showed Cohesinomentioning

confidence: 88%

Critical role of mitosis in spontaneous late-onset Alzheimer’s disease; from a Shugoshin 1 cohesinopathy mouse model

et al. 2018

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From early-onset Alzheimer's disease (EOAD) studies, the amyloid-beta hypothesis emerged as the foremost theory of the pathological causes of AD. However, how amyloid-beta accumulation is triggered and progresses toward senile plaques in spontaneous late-onset Alzheimer's disease (LOAD) in humans remains unanswered. Various LOAD facilitators have been proposed, and LOAD is currently considered a complex disease with multiple causes. Mice do not normally develop LOAD. Possibly due to the multiple causes, proposed LOAD facilitators have not been able to replicate spontaneous LOAD in mice, representing a disease modeling issue. Recently, we reported spontaneous late-onset development of amyloid-beta accumulation in brains of Shugoshin 1 (Sgo1) haploinsufficient mice, a cohesinopathy-mediated chromosome instability model. The result for the first time expands disease relevance of mitosis studies to a major disease other than cancers. Reverse-engineering of the model would shed light on the process of late-onset amyloid-beta accumulation in the brain and spontaneous LOAD development, and contribute to development of interventions for LOAD. This review will discuss the Sgo1 model, our current "three-hit hypothesis" regarding LOAD development with an emphasis on critical role of prolonged mitosis in amyloid-beta accumulation, and implications for human LOAD intervention and treatment. Abbreviations: Alzheimer's disease (AD); Late-onset Alzheimer's disease (LOAD); Early-onset Alzheimer's disease (EOAD); Shugoshin-1 (Sgo1); Chromosome Instability (CIN); apolipoprotein (Apoe); Central nervous system (CNS); Amyloid precursor protein (APP); N-methyl-d-aspartate (NMDA); Hazard ratio (HR); Cyclin-dependent kinase (CDK); Chronic Atrial Intestinal Dysrhythmia (CAID); beta-secretase 1 (BACE); phosphor-Histone H3 (p-H3); Research and development (R&D); Non-steroidal anti-inflammatory drugs (NSAIDs); Brain blood barrier (BBB).

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“…20, 37 RAG1 −/− mice were obtained from Dr Naveena Janakiram (OUHSC). All mice were maintained in the OUHSC BRC rodent barrier facility.…”

Section: Methodsmentioning

confidence: 99%

Systemic chromosome instability in Shugoshin-1 mice resulted in compromised glutathione pathway, activation of Wnt signaling and defects in immune system in the lung

et al. 2016

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Mitotic error-mediated chromosome instability (CIN) can lead to aneuploidy, chromothripsis, DNA damage and/or whole chromosome gain/loss. CIN may prompt rapid accumulation of mutations and genomic alterations. Thus, CIN can promote carcinogenesis. This CIN process results from a mutation in certain genes or environmental challenge such as smoking, and is highly prevalent in various cancers, including lung cancer. A better understanding of the effects of CIN on carcinogenesis will lead to novel methods for cancer prevention and treatment. Previously Shugoshin-1 (Sgo1−/+) mice, a transgenic mouse model of CIN, showed mild proneness to spontaneous lung and liver cancers. In this study, adoptive (T/B-cell based) immunity-deficient RAG1−/− Sgo1−/+ double mutant mice developed lung adenocarcinomas more aggressively than did Sgo1−/+ or RAG1−/− mice, suggesting immune system involvement in CIN-mediated lung carcinogenesis. To identify molecular causes of the lung adenocarcinoma, we used systems biology approach, comparative RNAseq, to RAG1−/− and RAG1−/− Sgo1−/+. The comparative RNAseq data and follow-up analyses in the lungs of naive Sgo1−/+ mice demonstrate that, (i) glutathione is depleted, making the tissue vulnerable to oxidative stress, (ii) spontaneous DNA damage is increased, (iii) oncogenic Wnt signaling is activated, (iv) both major branches of the immune system are weakened through misregulations in signal mediators such as CD80 and calreticulin and (v) the actin cytoskeleton is misregulated. Overall, the results show multi-faceted roles of CIN in lung carcinoma development in Sgo1−/+ mice. Our model presents various effects of CIN and will help to identify potential targets to prevent CIN-driven carcinogenesis in the lung.

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Systemic Chromosome Instability Resulted in Colonic Transcriptomic Changes in Metabolic, Proliferation, and Stem Cell Regulators in Sgo1 −/+ Mice

Cited by 23 publications

References 54 publications

Emerging links among Chromosome Instability (CIN), cancer, and aging

Emerging links among Chromosome Instability (CIN), cancer, and aging

Critical role of mitosis in spontaneous late-onset Alzheimer’s disease; from a Shugoshin 1 cohesinopathy mouse model

Systemic chromosome instability in Shugoshin-1 mice resulted in compromised glutathione pathway, activation of Wnt signaling and defects in immune system in the lung

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