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

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.

Keywords: lung cancer; mRNA expression; mitotic spindle genes; prognosis.

Figure 1.

Comparative mRNA expression of the examined genes in NSCLC tissues and adjacent normal tissues. The mRNA expression levels of the genes in NSCLC tumours are significantly higher than those in adjacent normal tissues, with the exception of AURKC. P-values were calculated using a Mann-Whitney U test and adjusted for multiple comparisons by Bonferroni correction. RQ values were calculated using RNA from the non-tumorigenic immortalised human bronchial epithelial cell line HBEC-3KT as a calibrator. Larger circles represent outlier values (>1.5x interquartile range); smaller circles represent extreme values (>3x interquartile range). NSCLC, non-small cell lung cancer; RQ, relative quantification; AURK, Aurora kinase; DLGAP5, discs large-associated protein 5; CKAP5, cytoskeleton-associated protein 5; KIF11, kinesin-like protein 11; TPX2, microtubule nucleation factor TPX2; TTK, TTK protein kinase; TUBB, tubulin β.

Figure 2.

mRNA expression of AURKA, AURKB, AURKC, DLGAP5, CKAP5, KIF11, TPX2, TTK, TUBB and TUBB3 genes in SqCCL and AdC of the lung. Comparison between histology types demonstrated that the mRNA expression levels of the AURKA, AURKB, DLGAP5, KIF11, TPX2, TTK and TUBB genes in SqCCL tumours are significantly higher than those in AdC tumours. P-values were calculated using a Mann-Whitney U test and adjusted for multiple comparisons by Bonferroni correction. RQ values were calculated using RNA from the non-tumorigenic immortalised human bronchial epithelial cell line HBEC-3KT as a calibrator. Larger circles represent outlier values (>1.5x interquartile range); smaller circles represent extreme values (>3x interquartile range). AURK, Aurora kinase; DLGAP5, discs large-associated protein 5; CKAP5, cytoskeleton-associated protein 5; KIF11, kinesin-like protein 11; TPX2, microtubule nucleation factor TPX2; TTK, TTK protein kinase; TUBB, tubulin β; SqCCL, squamous cell carcinoma of the lung; AdC, adenocarcinoma; RQ, relative quantification.

Figure 3.

Kaplan-Meier estimator curves of cumulative survival of patients with NSCLC dichotomised by 95% reference interval of AURKA mRNA expression in wild-type tissues. The P-values were calculated using a log-rank (Mantel-Cox) test. Increased AURKA expression (unbroken line) is associated with decreased survival time. The correlation between AURKA expression and cumulative survival is significant in AdC and SqCCL. Decreased AURKA expression (broken line) is associated with increased survival time. NSCLC, non-small cell lung cancer; AdC, adenocarcinoma; SqCCL, squamous cell carcinoma of the lung.