Chromosomal instability is a risk factor for poor prognosis of adenocarcinoma of the lung: Fluorescence in situ hybridization analysis of paraffin-embedded tissue from Korean patients

Choi, Chang‐Min; Seo, Kwang Won; Jang, Se Jin; Oh, Yeon‐Mok; Shim, Tae-Sun; Kim, Woo Sung; Lee, Dong-Soon; Lee, Sang‐Do

doi:10.1016/j.lungcan.2008.07.016

Cited by 58 publications

(67 citation statements)

References 26 publications

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“…Emerging evidence suggests the involvement of CIN in cancer progression. CIN is associated with a poor prognosis in patients with lung and colon cancer (16,17). Furthermore, overactivation of the mitotic checkpoint, a major mechanism for CIN acquisition, has been shown to inhibit certain tumor suppressive signal pathways (15).…”

Section: Introductionmentioning

confidence: 99%

Chromosome Instability Modulated by BMI1–AURKA Signaling Drives Progression in Head and Neck Cancer

et al. 2013

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Chromosomal instability (CIN) is widely considered a hallmark of cancer, but its precise roles in cancer stem cells (CSC) and malignant progression remain uncertain. BMI1 is a member of the Polycomb group of chromatinmodifier proteins that is essential for stem cell self-renewal. In human cancers, BMI1 overexpression drives stemlike properties associated with induction of epithelial-mesenchymal transition (EMT) that promotes invasion, metastasis, and poor prognosis. Here, we report that BMI1 mediates its diverse effects through upregulation of the mitotic kinase Aurora A, which is encoded by the AURKA gene. Two mechanisms were found to be responsible for BMI1-induced AURKA expression. First, BMI1 activated the Akt pathway, thereby upregulating AURKA expression through activation of the b-catenin/TCF4 transcription factor complex. Second, BMI1 repressed miRNA let-7i through a Polycomb complex-dependent mechanism, thereby relieving AURKA expression from let7i suppression. AURKA upregulation by BMI1 exerts several effects, including centrosomal amplification and aneuploidy, antiapoptosis, and cell-cycle progression through p53 degradation and EMT through stabilization of Snail. Inhibiting Aurora A kinase activity attenuated BMI1-induced tumor growth in vivo. In clinical specimens of head and neck cancer, we found that coamplification of BMI1 and AURKA correlated with poorer prognosis. Together, our results link CSCs, EMT, and CIN through the BMI1-AURKA axis and suggest therapeutic use from inhibiting Aurora A in head and neck cancers, which overexpress BMI1. Cancer Res; 73(2); 953-66. Ó2012 AACR.

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Section: Introductionmentioning

confidence: 99%

Chromosome Instability Modulated by BMI1–AURKA Signaling Drives Progression in Head and Neck Cancer

et al. 2013

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“…This provides a straight-forward explanation for why tumors that have loss-of-function mutations in STAG2 are often aneuploid and display CIN. CIN generates intra-tumor genetic heterogeneity and correlates with tumor aggressiveness, drug-resistance and tumor recurrence (Choi et al, 2009;Heilig et al, 2010;Bakhoum et al, 2011;Bakhoum and Compton, 2012). Our data provide insight into strategies to suppress CIN caused by loss of STAG2 and, perhaps, alter the aggressiveness of tumors.…”

Section: Resultsmentioning

confidence: 76%

“…In addition to a state of aneuploidy, many solid tumors continuously missegregate chromosomes at high rates in a phenomenon called chromosomal instability (CIN) (Lengauer et al, 1998;Holland and Cleveland, 2009;. This high rate of missegregation has been clinically correlated with metastasis, drug resistance and poor patient prognosis (Walther et al, 2008;Choi et al, 2009;Heilig et al, 2010;Lee et al, 2011;Bakhoum et al, 2011;Bakhoum and Compton, 2012). Direct analysis of CIN cancer cells has shown that the most common cause of whole chromosome missegregation is the persistence of errors in the attachment of chromosomes to spindle microtubules (Thompson and Compton, 2008).…”

Section: Introductionmentioning

confidence: 99%

STAG2 promotes error correction in mitosis by regulating kinetochore-microtubule attachments

Kleyman

Kabeche

Compton

2014

Journal of Cell Science

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Mutations in the STAG2 gene are present in ,20% of tumors from different tissues of origin. STAG2 encodes a subunit of the cohesin complex, and tumors with loss-of-function mutations are usually aneuploid and display elevated frequencies of lagging chromosomes during anaphase. Lagging chromosomes are a hallmark of chromosomal instability (CIN) arising from persistent errors in kinetochore-microtubule (kMT) attachment. To determine whether the loss of STAG2 increases the rate of formation of kMT attachment errors or decreases the rate of their correction, we examined mitosis in STAG2-deficient cells. STAG2 depletion does not impair bipolar spindle formation or delay mitotic progression. Instead, loss of STAG2 permits excessive centromere stretch along with hyperstabilization of kMT attachments. STAG2-deficient cells display mislocalization of Bub1 kinase, Bub3 and the chromosome passenger complex. Importantly, strategically destabilizing kMT attachments in tumor cells harboring STAG2 mutations by overexpression of the microtubule-destabilizing enzymes MCAK (also known as KIF2C) and Kif2B decreased the rate of lagging chromosomes and reduced the rate of chromosome missegregation. These data demonstrate that STAG2 promotes the correction of kMT attachment errors to ensure faithful chromosome segregation during mitosis.

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“…Several reports describe the correlation between global hypomethylation and genomic instability [21,22], which are known to indicate poor prognosis of NSCLC [23][24][25]. Transcriptional dysregulation might be another possible mechanism, and activation of proto-oncogenes might affect the aggressiveness of the tumor.…”

Section: Commentmentioning

confidence: 99%

Long Interspersed Nucleotide Element 1 Hypomethylation Is Associated With Poor Prognosis of Lung Adenocarcinoma

Ikeda

Shiraishi

Eguchi

et al. 2013

The Annals of Thoracic Surgery

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Chromosomal instability is a risk factor for poor prognosis of adenocarcinoma of the lung: Fluorescence in situ hybridization analysis of paraffin-embedded tissue from Korean patients

Cited by 58 publications

References 26 publications

Chromosome Instability Modulated by BMI1–AURKA Signaling Drives Progression in Head and Neck Cancer

Chromosome Instability Modulated by BMI1–AURKA Signaling Drives Progression in Head and Neck Cancer

STAG2 promotes error correction in mitosis by regulating kinetochore-microtubule attachments

Long Interspersed Nucleotide Element 1 Hypomethylation Is Associated With Poor Prognosis of Lung Adenocarcinoma

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