Role of cell cycle regulators in lung carcinogenesis

Eymin, Béatrice; Gazzéri, Sylvie

doi:10.4161/cam.4.1.10977

Cited by 76 publications

(76 citation statements)

References 97 publications

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“…However, the important clinical question is whether the overexpression of any of these genes is able to confer a selective advantage on cancer cells and increase their invasive properties. The results of the present study confirm that up-regulation of mitotic spindle genes is a common abnormality in NSCLC and further support a role for the maintenance of a tumorigenic phenotype (5,29). The results of the present study demonstrated that, of the 10 genes examined, only AURKA overexpression was associated with poor prognosis, which suggests that this gene has a particular contribution to a more aggressive phenotype.…”

Section: Discussionsupporting

confidence: 74%

AURKA mRNA expression is an independent predictor of poor prognosis in patients with non-small cell lung cancer

et al. 2017

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Abstract. Deregulation of mitotic spindle genes has been reported to contribute to the development and progression of malignant tumours. The aim of the present study was to explore the association between the expression profiles of Aurora kinases (AURKA, AURKB and AURKC), cytoskeleton-associated protein 5 (CKAP5), discs large-associated protein 5 (DLGAP5), kinesin-like protein 11 (KIF11), microtubule nucleation factor (TPX2), monopolar spindle 1 kinase (TTK), and β-tubulins (TUBB) and (TUBB3) genes and clinicopathological characteristics in human non-small cell lung carcinoma (NSCLC). Reverse transcription-quantitative polymerase chain reaction-based RNA gene expression profiles of 132 NSCLC and 44 adjacent wild-type tissues were generated, and Cox's proportional hazard regression was used to examine associations. With the exception of AURKC, all genes exhibited increased expression in NSCLC tissues. Of the 10 genes examined, only AURKA was significantly associated with prognosis in NSCLC. Multivariate Cox's regression analysis demonstrated that AURKA mRNA expression [hazard ratio (HR), 1.81; 95% confidence interval (CI), 1.16-2.84; P=0.009], age (HR, 1.03; 95% CI, 1.00-1.06; P= 0.020), pathological tumour stage 2 (HR, 2.43; 95% CI, 1.16-5.10; P= 0.019) and involvement of distal nodes (pathological node stage 2) (HR, 3.14; 95% CI, 1.24-7.99; P=0.016) were independent predictors of poor prognosis in patients with NSCLC. Poor prognosis of patients with increased AURKA expression suggests that those patients may benefit from surrogate therapy with AURKA inhibitors.

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Section: Discussionsupporting

confidence: 74%

AURKA mRNA expression is an independent predictor of poor prognosis in patients with non-small cell lung cancer

et al. 2017

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“…In addition, overexpression of distinct cyclins and CDKs also play crucial roles in the development and progression of NSCLC and have been shown to override the inhibitory effect of the above negative regulators (7,15). The underlying mechanism that modulates the abundance of the cyclins and CDKs in NSCLC, however, remains largely unknown.…”

Section: Introductionmentioning

confidence: 99%

“…Disturbed surveillance of cell-cycle progression, such as cellular evasion of multiple cell-cycle checkpoints, which can be driven by abnormal activation of cell-cycle regulators such as cyclins and cyclin-dependent kinases (CDK), represents a hallmark of tumor development and progression (7,8). For example, cyclin D1, which can act to trigger early G 1 entry from quiescence and facilitate G 1 progression by cooperating with CDK4/6, has been shown to be a key driver factor of malignant transformation of NSCLC (9,10).…”

Section: Introductionmentioning

confidence: 99%

miR-186 Downregulation Correlates with Poor Survival in Lung Adenocarcinoma, Where It Interferes with Cell-Cycle Regulation

et al. 2013

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Deeper mechanistic understanding of lung adenocarcinoma (non-small cell lung carcinoma, or NSCLC), a leading cause of cancer-related deaths overall, may lead to more effective therapeutic strategies. In analyzing NSCLC clinical specimens and cell lines, we discovered a uniform decrease in miR-186 (MIR186) expression in comparison with normal lung tissue or epithelial cell lines. miR-186 expression correlated with patient survival, with median overall survival time of 63.0 or 21.5 months in cases exhibiting high or low levels of miR-186, respectively. Enforced overexpression of miR-186 in NSCLC cells inhibited proliferation by inducing G 1 -S checkpoint arrest. Conversely, RNA interference-mediated silencing miR-186 expression promoted cell-cycle progression and accelerated the proliferation of NSCLC cells. Cyclin D1 (CCND1), cyclin-dependent kinase (CDK)2, and CDK6 were each directly targeted for inhibition by miR-186 and restoring their expression reversed miR-186-mediated inhibition of cell-cycle progression. The inverse relationship between expression of miR-186 and its targets was confirmed in NSCLC tumor xenografts and clinical specimens. Taken together, our findings established a tumorsuppressive role for miR-186 in the progression of NSCLC. Cancer Res; 73(2); 756-66. Ó2012 AACR.

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“…The activity of the CDK1‐cyclin B1 complex depends on the phosphorylation/dephosphorylation status of CDK1. The phosphorylation of CDK1 at Thr‐161 is required for the activation of the CDK1‐cyclin B1 kinase complex, whereas the phosphorylation of CDK1 at Thr‐14/Tyr‐15 inhibits CDK1 kinase activity 20, 21. Our studies indicated that STIP knockdown in NSCLC cells led to cell cycle arrest at the G2/M phase.…”

Section: Discussionmentioning

confidence: 61%

STIP overexpression confers oncogenic potential to human non‐small cell lung cancer cells by regulating cell cycle and apoptosis

Tang

Yan

Song

et al. 2015

J Cellular Molecular Medi

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Sip1/tuftelin‐interacting protein (STIP), a multidomain nuclear protein, is a novel factor associated with the spliceosome, yet its role and molecular function in cancer remain unknown. In this study, we show, for the first time, that STIP is overexpressed in non‐small cell lung cancer (NSCLC) tissues compared to adjacent normal lung tissues. The depletion of endogenous STIP inhibited NSCLC cell proliferation in vitro and in vivo, caused cell cycle arrest and induced apoptosis. Cell cycle arrest at the G2/M phase was associated with the expression and activity of the cyclin B1‐CDK1 (cyclin‐dependent kinase 1) complex. We also provide evidence that STIP knockdown induced apoptosis by activating both caspase‐9 and caspase‐3 and by altering the Bcl‐2/Bax expression ratio. RNA sequencing data indicated that the MAPK mitogen‐activated protein kinases, Wnt, PI3K/AKT, and NF‐κB (nuclear factor kappa‐light‐chain‐enhancer of activated B cells) signalling pathways might be involved in STIP‐mediated tumour regulation. Collectively, these results suggest that STIP may be a novel potential diagnostic and therapeutic target for NSCLC.

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Role of cell cycle regulators in lung carcinogenesis

Cited by 76 publications

References 97 publications

AURKA mRNA expression is an independent predictor of poor prognosis in patients with non-small cell lung cancer

AURKA mRNA expression is an independent predictor of poor prognosis in patients with non-small cell lung cancer

miR-186 Downregulation Correlates with Poor Survival in Lung Adenocarcinoma, Where It Interferes with Cell-Cycle Regulation

STIP overexpression confers oncogenic potential to human non‐small cell lung cancer cells by regulating cell cycle and apoptosis

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