AIM2 suppresses human breast cancer cell proliferation <i>in vitro</i> and mammary tumor growth in a mouse model

Chen, I-Fen; Ou‐Yang, Fu; Hung, Jen‐Yu; Liu, Jaw-Ching; Wang, Hongying; Wang, Shao‐Chun; Hou, Ming‐Feng; Hortobágyi, Gabriel N.; Hung, Mien‐Chie

doi:10.1158/1535-7163.mct-05-0310

Cited by 123 publications

(107 citation statements)

References 20 publications

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“…These observations suggest that the loss of AIM2 protein function in cancer cells may provide a growth advantage to the cancer cells. Accordingly, overexpression of the AIM2 protein in certain human cancer cell lines (including the breast and colon cancer cell lines) suppressed cell proliferation (49)(50)(51). Consistent with the above observations, we found that basal levels of the AIM2 mRNA were significantly lower in prostate tumors as compared with normal prostate (Fig.…”

Section: Discussionsupporting

confidence: 87%

AIM2, an IFN-Inducible Cytosolic DNA Sensor, in the Development of Benign Prostate Hyperplasia and Prostate Cancer

Ponomareva

Liu

Duan

et al. 2013

Molecular Cancer Research

104

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Close links have been noted between chronic inflammation of the prostate and the development of human prostatic diseases such as benign prostate hyperplasia (BPH) and prostate cancer. However, the molecular mechanisms that contribute to prostatic inflammation remain largely unexplored. Recent studies have indicated that the IFN-inducible AIM2 protein is a cytosolic DNA sensor in macrophages and keratinocytes. Upon sensing DNA, AIM2 recruits the adaptor ASC and pro-CASP1 to assemble the AIM2 inflammasome. Activation of the AIM2 inflammasome cleaves pro-interleukin (IL)-1b and pro-IL-18 and promotes the secretion of IL-1b and IL-18 proinflammatory cytokines. Given that human prostatic infections are associated with chronic inflammation, the development of BPH is associated with an accumulation of senescent cells with a proinflammatory phenotype, and the development of prostate cancer is associated with the loss of IFN signaling, the role of AIM2 in mediating the formation of prostatic diseases was investigated. It was determined that IFNs (a, b, or g) induced AIM2 expression in human prostate epithelial cells and cytosolic DNA activated the AIM2 inflammasome. Steady-state levels of the AIM2 mRNA were higher in BPH than in normal prostate tissue. However, the levels of AIM2 mRNA were significantly lower in clinical tumor specimens. Accordingly, constitutive levels of AIM2 mRNA and protein were lower in a subset of prostate cancer cells as compared with BPH cells. Further, the cytosolic DNA activated the AIM2 inflammasome in the androgen receptor-negative PC3 prostate cancer cell line, suggesting that AIM2-mediated events are independent of androgen receptor status.

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Section: Discussionsupporting

confidence: 87%

AIM2, an IFN-Inducible Cytosolic DNA Sensor, in the Development of Benign Prostate Hyperplasia and Prostate Cancer

Ponomareva

Liu

Duan

et al. 2013

Molecular Cancer Research

104

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“…56 AIM2 is an IFN-inducible proapoptotic nuclear protein, which suppresses growth of mammary cells in vitro and tumors in vivo. 57 We were unable to observe changes in p21 or p27 CDKIs, but we point to another CDKI -p57Kip2-as a target in HaCat. 21 In normal KCs, this gene is expressed, presumably to counterbalance the pro-growth stimuli of DNp63a and prevent uncontrolled division.…”

Section: Discussioncontrasting

confidence: 55%

Identification of New p63 Targets in Human Keratinocytes

Testoni¹,

Borrelli²,

Tenedini³

et al. 2006

Cell Cycle

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ABSTRACTp63 is a transcription factor involved in the development of ectodermal tissues, including limb, skin and, in general, multilayered epithelia. We identified both activated and repressed genes in human keratinocytes via gene expression profiling of p63-depleted cells and validated 21 new primary targets by RT-PCR and ChIP location analysis. The p63 isoforms differentially activate or repress selected promoters. ChIPs in primary keratinocytes indicate that p63 targets are generally shared with p53, but some are p63-specific. Several growth suppressors are among repressed genes. The newly identified genes belong to pathways of growth and differentiation and are regulated in HaCaT differentiation and in stratification of human skin.

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“…On the other hand, silencing of AIM2 was associated with poor survival in colorectal cancer (Dihlmann et al ., 2014), and promoted colon tumorigenesis via the activation of the Wnt and Akt pathways (Wilson et al ., 2015). Excessive AIM2 expression inhibited cell proliferation and induced apoptosis in breast carcinoma (Chen et al ., 2006; Liu et al ., 2015b). Interestingly, AIM2 expression was elevated in chronic hepatitis B (CHB) patients (Han et al ., 2015) and decreased in HCC patients (Ma et al ., 2016).…”

Section: Introductionmentioning

confidence: 99%

Retracted:HBx‐mediated decrease of AIM2 contributes to hepatocellular carcinoma metastasis

Chen

Liu

et al. 2017

Molecular Oncology

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Tumor metastasis is responsible for the high mortality rates in patients with hepatocellular carcinoma (HCC). Absent in melanoma 2 (AIM2) has been implicated in inflammation and carcinogenesis, although its role in HCC metastasis remains unknown. In the present study, we show that AIM2 protein expression was noticeably reduced in HCC cell lines and clinical samples. A reduction in AIM2 was closely associated with higher serum AFP levels, vascular invasion, poor tumor differentiation, an incomplete tumor capsule and unfavorable postsurgical survival odds. In vitro studies demonstrated that AIM2 expression was modulated by hepatitis B virus X protein (HBx) at transcriptional and post‐translational levels. HBx overexpression markedly blocked the expression of AIM2 at mRNA and protein levels by enhancing the stability of Enhancer of zeste homolog 2 (EZH2). Furthermore, HBx interacted with AIM2, resulting in an increase of AIM2 degradation via ubiquitination induction. Functionally, knockdown of AIM2 enhanced cell migration, formation of cell pseudopodium, wound healing and tumor metastasis, whereas reintroduction of AIM2 attenuated these functions. The loss of AIM2 induced the activation of epithelial‐mesenchymal transition (EMT). Fibronectin 1 (FN1) was found to be a downstream effector of AIM2, with its expression reversely modulated by AIM2. Silencing of FN1 significantly halted cell migration induced by AIM2 depletion. These data demonstrate that HBx‐induced loss of AIM2 is associated with poor outcomes and facilitates HCC metastasis by triggering the EMT process. The results of the present study therefore suggest that AIM2 is a potential prognostic biomarker in hepatitis B virus‐related HCC, as well as a possible therapeutic target for tumor metastasis.

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AIM2 suppresses human breast cancer cell proliferation in vitro and mammary tumor growth in a mouse model

Cited by 123 publications

References 20 publications

AIM2, an IFN-Inducible Cytosolic DNA Sensor, in the Development of Benign Prostate Hyperplasia and Prostate Cancer

AIM2, an IFN-Inducible Cytosolic DNA Sensor, in the Development of Benign Prostate Hyperplasia and Prostate Cancer

Identification of New p63 Targets in Human Keratinocytes

Retracted:HBx‐mediated decrease of AIM2 contributes to hepatocellular carcinoma metastasis

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