Downregulation of LKB1 promotes tumor progression and predicts unfavorable prognosis in patients with glioma

Abstract

The liver kinase B1 (LKB1)/5'-adenosine monophosphate-activated protein kinase pathway has been reported to facilitate glioma cell growth by improving growth conditions. To investigate the clinical significance of LKB1 in human gliomas western blot analysis and quantitative polymerase chain reaction experiments were performed. The present study demonstrated that LKB1 expression was markedly decreased at the messenger RNA and protein levels in 30 freshly prepared glioma tissues, compared with non-neoplastic brain tissues (P<0.001). Subsequently, immunohistochemical analysis demonstrated that LKB1 immunostaining in 180 glioma tissues was significantly decreased compared with that in the corresponding non-neoplastic brain tissues (P<0.001). Notably, this downregulation frequently occurred in high-grade gliomas, and statistical analysis revealed that low LKB1 expression was significantly associated with large tumor size (P=0.02), advanced World Health Organization grade (P=0.006) and low Karnofsky performance scale (P=0.01). The prognostic value of LKB1 expression in patients with glioma was additionally evaluated using Kaplan-Meier survival curves and Cox proportional hazards regression models. As a result, the overall survival time of patients with glioma with low LKB1 expression was shorter compared with that of patients with high LKB1 expression (P<0.001), and low LKB1 expression also indicated decreased survival time in patients with high-grade glioma (P<0.001). Collectively, the present data indicated that the downregulation of LKB1 was closely associated with the malignant degree of human gliomas, exhibiting lower expression at a higher grade. Notably, LKB1 may serve as a potential prognostic biomarker for patients with glioma following surgery.

Keywords: clinicopathological features; glioma; liver kinase B1; prognosis.

Figure 1.

Downregulation of LKB1 mRNA and protein expression in glioma tissues. LKB1 expression was markedly decreased at (A) mRNA (tumor vs. normal, 1.96±0.59 vs. 3.66±0.92; P<0.001), and (B) protein (tumor vs. normal, 1.89±0.54 vs. 3.71±0.87; P<0.001) levels in 30 freshly prepared glioma tissues, compared with that in non-neoplastic brain tissues. (C) Spearman's rank correlation analysis revealed that the expression levels of LKB1 mRNA in glioma tissues were closely correlated with those of LKB1 protein in gliomas (r=0.32; P=0.02). (D) Relatively lower expression levels of LKB1 mRNA and protein were observed in freshly prepared high-grade glioma tissue samples (WHO grades III–IV) compared with those in low-grade glioma samples (WHO grades I–II). *P<0.05. LKB1, liver kinase B1; WHO, World Health Organization; mRNA, messenger RNA.

Figure 2.

Immunostaining of LKB1 protein in glioma tissues. (A) Weak immunostaining of LKB1 protein in glioma tissues (magnification, ×200). (B) Strong immunostaining of LKB1 protein in non-neoplastic brain tissue samples (magnification, ×200). (C) Statistically, the IRS of LKB1 protein in gliomas was significantly decreased compared with that in the corresponding non-neoplastic brain tissues (tumor vs. normal, 2.38±1.00 vs. 4.38±1.19; ***P<0.001). (D) The expression of LKB1 in high-grade glioma was decreased compared with that in low-grade glioma (**P<0.01). LKB1, liver kinase B1; IRS, immunoreactive scoring.

Figure 3.

Kaplan-Meier survival curves of glioma patients. (A) Overall survival of all 180 glioma patients with LKB1 protein expression: High vs. low. (B) Overall survival of high-grade glioma patients with LKB1 protein expression: High vs. low. (C) Overall survival of low-grade glioma patients with LKB1 protein expression: High vs. low. LKB1, liver kinase B1.