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

Abstract

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.

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

“…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]. In addition to increased generation of senescent cells, CIN model mice may accumulate senescent cells because immune surveillance is partly dysfunctional.…”

“…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]. Thus, systemic CIN affects gene expressions in organ-specific and non-specific manners and can influence cancer development.…”

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

“…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].…”

“…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.…”

“…With colonic carcinogen azoxymethane challenge, the Sgo1 −/+ mouse also showed enhanced initial development of colonic precancerous lesions and adenocarcinomas compared with wild type [56]. These mice were prone to spontaneous cancers in the liver and lung at middle age [57,58,64]. Using comparative RNAseq, we demonstrated that these cancer-prone organs (i.e.…”