AIM2 promotes the development of non-small cell lung cancer by modulating mitochondrial dynamics

Miao, Qi; Dang, Dai; Liu, Jin; Li, Zhongqi; Liang, Panpan; Wang, Yue; Lu, Cheng Hsien; Zhan, Yihong; An, Zhifeng; Song, Yaoyao; Yang, Ya-Na; Yan, Xiaohui; Xiao, Hui; Shao, Huanjie

doi:10.1038/s41388-020-1176-9

Cited by 68 publications

(73 citation statements)

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“…The morphology of mitochondrial is dynamically regulated by the balance between fusion and ssion events to maintain energy and metabolic homeostasis [12] . During recent years, a series of studies have revealed the close links between the unbalanced mitochondrial dynamics and various human cancers [15] , including liver [16,17] , breast [18,19] , lung [20,21] and colon [22] cancers. MIEF2 (mitochondrial elongation factor 2) is a outer mitochondrial membrane protein involved in the regulation of mitochondrial ssion [23] .…”

Section: Discussionmentioning

confidence: 99%

“…During the lifetime of a cell, the morphology and function of mitochondrial is continuously remodeled by the balance between ssion and fusion events [12][13][14] . During recent years, the close links between fragmented mitochondrial networks and cancer has been revealed in various types of human cancers [15] , including liver [16,17] , breast [18,19] , lung [20,21] and colon [22] cancers. In addition, abnormal expressions of mitochondria ssion and fusion proteins such as DRP1 (dynamin related protein 1) and MFN1 (mitofusion 1) have also been observed.…”

Section: Introductionmentioning

confidence: 99%

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MIEF2 over-expression promotes tumor growth and metastasis through reprogramming of glucose metabolism in ovarian cancer

Zhao

Shi

Zhang

et al. 2020

Preprint

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Background: Increasing evidence has revealed the close link between mitochondrial dynamic dysfunction and cancer. MIEF2 (mitochondrial elongation factor 2) is mitochondrial outer membrane protein that functions in the regulation of mitochondrial fission. However, the expression, clinical significance and biological functions of MIEF2 are still largely unclear in human cancers, especially in ovarian cancer (OC). Methods: The expression and clinical significance of MIEF2 were determined by qRT-PCR, western blot and immunohistochemistry analyses in tissues and cell lines of OC. The biological functions of MIEF2 in OC were determined by in vitro and in vivo cell growth and metastasis assays. Furthermore, the effect of MIEF2 on metabolic reprogramming of OC was determined by metabolomics and glucose metabolism analyses. Results: MIEF2 expression was significantly increased in OC mainly due to the down-regulation of miR-424-5p, which predictes poor survival for patients with OC. Knockdown of MIEF2 significantly suppressed OC cell growth and metastasis both in vitro and in vivo by inhibiting G1-S cell transition, epithelial-to -mesenchymal transition (EMT) and inducing cell apoptosis, while forced expression of MIEF2 had the opposite effects. Mechanistically, mitochondrial fragmentation-suppressed cristae formation and thus glucose metabolism switch from oxidative phosphorylation to glycolysis was found to be involved in the promotion of growth and metastasis by MIEF2 in OC cells. Conclusions: MIEF2 play a critical role in the promotion of OC progression and may serve as a valuable prognostic biomarker and therapeutic target in treatment of this malignancy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

MIEF2 over-expression promotes tumor growth and metastasis through reprogramming of glucose metabolism in ovarian cancer

Zhao

Shi

Zhang

et al. 2020

Preprint

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“…AIM2 is a dsDNA sensor that is mainly activated in monocytes and macrophages by cytoplasmic DNA, derived from pathogens or neighboring necrotic cells (Briard et al, 2020). In addition, there is accumulating evidence for AIM2 to be involved in sustaining mitochondrial function by detecting mitochondrial DNA (mtDNA) in various human diseases, including cancer and diabetes type 2 (Bae et al, 2019;Qi et al, 2020), as well as in detecting virus-induced oxidized DNA (Moriyama et al, 2020). In neurodevelopment, AIM2 was recently shown to be involved in surveillance of DNA damage of neurons (Lammert et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Deficiency in Aim2 affects viability and calcification of vascular smooth muscle cells from murine aortas and Angiotensin-II induced aortic aneurysms

Wortmann

Arshad

Hakimi

et al. 2020

Preprint

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Background: Phenotypic transformation of vascular smooth muscle cells is a key element in vascular remodeling and aortic aneurysm growth. Previously, deletion of several inflammasome components decreased formation of aortic aneurysm (AA) in the Angiotensin II (AngII) -induced mouse model. We hypothesized that the inflammasome sensor Absent in melanoma 2 (Aim2) might affect the phenotype of vascular smooth muscle cells (VSMC), thereby reducing AA formation. Methods : Aim2-/- mice and wild-type (WT) C57Bl/6J mice were used as an animal model. VSMC were isolated from 6 months old mice and grown in vitro . Young (passage 3-5) and senescent (passage 7-12) cells were analyzed in vitro for calcification in mineralization medium by Alizarin Red S staining. Expression of calcification and inflammatory markers were studied by real-time RT-PCR and Western blotting, release of cytokines was determined by ELISA. To induce AA, osmotic mini-pumps loaded with AngII (1500 ng/kg bodyweight/min) were implanted for 28 days in male mice at 6 months of age. Results : Compared with VSMC from WT mice, VSMC isolated from Aim2-/- mice were larger, less viable, and underwent stronger calcification in mineralization medium, along with induction of Bmp4 and repression of Tnfsf11/Rankl gene expression. In addition, Aim2 deficiency was associated with reduced inflammasome gene expression and release of Interleukin-6. Using the mouse model of AngII induced AA, Aim2 deficiency reduced AA incidence to 48.4% (15/31) in Aim2-/- mice versus 76.5% (13/17) in WT mice. In contrast to Aim2-/- mice, AA from WT mice expressed significantly increased levels of alpha-smooth muscle actin/ Acta2 , indicating tissue remodeling. Reduced cell proliferation in Aim2-/- mice was indicated by significantly increased p16ink4a/ Cdkn2a expression in untreated and AngII-infused aortas, and by significantly lower amounts of proliferating (Ki67 positive) VSMC in AngII-infused Aim2-/- mice. Conclusions: Our results suggest a role for Aim2 in regulating VSMC proliferation and transition to an osteoblast-like or osteoclast-like phenotype, thereby modulating the response of VSMC in aortic remodeling and AA Formation.

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“…148 Furthermore, it has been recently reported that AIM2 expression positively correlates with the growth and proliferation of NSCLC cells in vitro and in vivo and that AIM2 expression in NSCLC tumors is associated with poor prognosis in patient. 91 AIM2 promotion of cell proliferation was independent of its inflammasome function; AIM2 has been found to colocalize with mitochondria in NSCLC cells and modulate mitochondrial fission and fusion dynamics to facilitate growth and proliferation of cancer cells.…”

Section: Infl Amma Some-independent Fun C Ti On S Of Aim2mentioning

confidence: 94%

“…High expression of AIM2 is observed in non-small cell lung cancer (NSCLC), and AIM2 plays both inflammasome-dependent and inflammasome-independent roles in NSCLC. [90][91][92] In an in vitro study with lung cancer epithelial cell lines A549 and H460, the depletion of AIM2 and ASC with shRNA and siRNA, respectively, as well as inhibition of caspase-1 with VX765, inhibited cell growth and metastasis. Furthermore, the depletion of AIM2 and ASC and the inhibition of caspase-1 promoted cell-cycle arrest at G2/M phase, which paralleled with cyclin B1 reduction in these cell lines.…”

Section: Cancermentioning

confidence: 99%

AIM2 in health and disease: Inflammasome and beyond

Kumari

Russo

Shivcharan

et al. 2020

Immunological Reviews

155

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Nucleic acid sensing is a critical mechanism by which the immune system monitors for pathogen invasion. A set of germline‐encoded innate immune receptors detect microbial DNA in various compartments of the cell, such as endosomes, the cytosol, and the nucleus. Sensing of microbial DNA through these receptors stimulates, in most cases, interferon regulatory factor‐dependent type I IFN synthesis followed by JAK/STAT‐dependent interferon‐stimulated gene expression. In contrast, the detection of DNA in the cytosol by AIM2 assembles a macromolecular complex called the inflammasome, which unleashes the proteolytic activity of a cysteine protease caspase‐1. Caspase‐1 cleaves and activates the pro‐inflammatory cytokines such as IL‐1β and IL‐18 and a pore‐forming protein, gasdermin D, which triggers pyroptosis, an inflammatory form of cell death. Research over the past decade has revealed that AIM2 plays essential roles not only in host defense against pathogens but also in inflammatory diseases, autoimmunity, and cancer in inflammasome‐dependent and inflammasome‐independent manners. This review discusses the latest advancements in our understanding of AIM2 biology and its functions in health and disease.

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AIM2 promotes the development of non-small cell lung cancer by modulating mitochondrial dynamics

Cited by 68 publications

References 44 publications

MIEF2 over-expression promotes tumor growth and metastasis through reprogramming of glucose metabolism in ovarian cancer

MIEF2 over-expression promotes tumor growth and metastasis through reprogramming of glucose metabolism in ovarian cancer

Deficiency in Aim2 affects viability and calcification of vascular smooth muscle cells from murine aortas and Angiotensin-II induced aortic aneurysms

AIM2 in health and disease: Inflammasome and beyond

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