Fast track — ArticlesExpression of choline kinase alpha to predict outcome in patients with early-stage non-small-cell lung cancer: a retrospective study
Introduction
Lung cancer is the leading cause of cancer-related death, accounting for one-third of all deaths from cancer worldwide.1 Lung cancer consists of a number of diseases of diverse aetiology, divided broadly into small-cell lung cancer (SCLC), which comprises 20% of all lung cancers, and non-small-cell lung cancer (NSCLC), which accounts for the remaining 80%.2 NSCLC is thought to originate in lung epithelial cells and includes diverse histological subtypes, including adenocarcinoma, bronchioloalveolar, squamous, anaplastic and large-cell carcinoma.2 Despite intensive research over the past decades, 5-year survival of patients with lung cancer is less than 15%.3 Currently, the most accurate prognostic factor for patients with NSCLC is tumour, node, metastasis (TNM) staging.3, 4 However, patients with early-stage NSCLC have a broad spectrum of survival, which indicates the need for additional prognostic parameters to better predict disease outcome.3 In the past decade, efforts have focused on the identification of molecular markers that could identify patients with a high risk of relapse after curative surgical resection.5
To improve global survival, several immunohistochemical markers have been proposed as prognostic indicators, including KRAS, P53, PRb, Ki-67, and the excision repair cross-complementation protein ERCC1.6, 7, 8, 9 Additionally, other molecules, such as cyclooxygenase-2, E-cadherin, vascular endothelial growth factor (VEGF), and epidermal-growth-factor receptor (EGFR), have been analysed at the mRNA level for their prognostic usefulness.10, 11, 12 These developments validate the use of techniques based on mRNA measurements as useful and highly reproducible methods for the classification and prognosis of various types of cancers.13, 14, 15, 16 However, given that the 5-year overall survival of patients with lung cancer is still poor, a better understanding of the molecular biology of tumours, new biological prognostic markers, and new approaches for treatment are still needed to improve clinical diagnosis, therapeutic treatment and, consequently, patient outcome.
Choline kinase alpha (ChoKα), the enzyme responsible for the generation of phosphorylcholine, is involved in metabolic processes and cell proliferation.17, 18 Studies have shown a role for ChoKα in oncogene-mediated transformation19, 20 and in the generation of human tumours, including lung cancer.21, 22, 23, 24, 25 Also, ChoKα has been described as a new oncogene that mediates human cell transformation and induces in-vivo tumorigenesis.26 Furthermore, ChoKα-specific inhibitors have been shown to have in-vitro antiproliferative and in-vivo antitumoral activity against human xenografts.27, 28, 29, 30, 31, 32
In this study, we aimed to assess whether ChoKα gene expression could identify patients with different prognoses.
Section snippets
Patients
60 patients were enrolled initially in the training group and we analysed frozen specimens of cancer tissue from 53 patients for whom we had tissue, who had NSCLC, and who had undergone surgical resection for NSCLC between February, 2001, and December, 2004, and who were followed up by the Medical Oncology Division at La Paz University Hospital, Madrid, Spain. Inclusion criteria were: age 18 years or older; completely resected NSCLC; intraoperative mediastinal-node dissection for reliable
Results
ChoKα expression and activity were first established in different cell lines derived from human lung cancer. ChoKα mRNA levels, in terms of their corresponding normal human primary BEC, were increased in all the tumour cell lines analysed in this study (figure 1). The noted increase in mRNA levels resulted in an increase in protein expression and ChoK enzymatic activity (figure 1). Therefore, protein concentrations and enzymatic activity correlated well with mRNA concentrations. These results
Discussion
In our study, an overall analysis of the training and validation groups showed that patients with NSCLC who had ChoKα overexpression had worse survival than those without overexpression. We also noted that the cut-off point for ChoKα expression should be 1·91-times higher than concentrations noted in healthy tissues.
We used different human cell lines from patients with NSCLC to analyse ChoKα expression and assess the correlation between mRNA levels, protein expression, and enzymatic activity of
References (37)
Revisions in the International System for Staging Lung Cancer
Chest
(1997)- et al.
Prognostic significance of Ki-67 immunostaining and symptoms in resected stage I and II non-small cell lung cancer
Lung Cancer
(1998) - et al.
The angiopoietins, tie2 and vascular endothelial growth factor are differentially expressed in the transformation of normal lung to non-small cell lung carcinomas
Lung Cancer
(2000) - et al.
Cancer statistics, 2005
CA Cancer J Clin
(2005) - et al.
The new World Health Organization classification of lung tumours
Eur Respir J
(2001) - et al.
Lung cancer
- et al.
A genomic strategy to refine prognosis in early-stage non-small-cell lung cancer
N Engl J Med
(2006) - et al.
Prognostic value of genetically diagnosed lymph node micrometastasis in non-small cell lung carcinoma cases
Cancer Res
(2000) - et al.
Rb and p16INK4a expression in resected non-small cell lung tumors
Cancer Res
(1996) - et al.
DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy
N Engl J Med
(2006)
Differential expression of E-cadherin and type IV collagenase genes predicts outcome in patients with stage I non-small cell lung carcinoma
Clin Cancer Res
Epidermal growth factor receptor and HER2-neu mRNA expression in non-small cell lung cancer Is correlated with survival
Clin Cancer Res
Gene-expression profiles predict survival of patients with lung adenocarcinoma
Nat Med
A molecular signature of metastasis in primary solid tumors
Nat Genet
Erlotinib in lung cancer—molecular and clinical predictors of outcome
N Engl J Med
A five-gene signature and clinical outcome in non-small-cell lung cancer
N Engl J Med
Choline kinase: a novel target for antitumor drugs
Drugs
Phospholipid metabolites, prognosis and proliferation in human breast carcinoma
NMR Biomed
Cited by (135)
Circulating metabolites as a concept beyond tumor biology determining disease recurrence after resection of colorectal liver metastasis
2022, HPBCitation Excerpt :Interestingly, some tumor cells themselves can exert direct effects on phopshatidylcholines and lysophosphatidylcholines. In breast,46 ovarian47 or lung48 cancer choline kinase α, an established oncogene, can be overexpressed in those tumor cells thereby increasing PC and total choline concentrations. Further, many cancer cells exhibit overexpression of phospholipase D (PLD) which is an enzyme degrading PCs into choline and phosphatidic acid (PA).
Identification of unprecedented ATP-competitive choline kinase inhibitors
2021, Bioorganic and Medicinal Chemistry LettersCholine kinase alpha 2 acts as a protein kinase to promote lipolysis of lipid droplets
2021, Molecular CellCitation Excerpt :CHKα promotes tumor cell proliferation and survival. Its overexpression has been detected in 40%–60% of human tumors and is correlated with prognosis in early-stage non-small cell lung cancer, hepatocellular carcinoma (HCC), and prostate cancer (Challapalli et al., 2015; Chen et al., 2017; Kwee et al., 2012; Ramírez de Molina et al., 2007). However, the mechanisms underlying CHKα-enhanced tumor progression still need to be elucidated.
Epigenetic footprint enables molecular risk stratification of hepatoblastoma with clinical implications
2020, Journal of HepatologyCholine Uptake and Metabolism Modulate Macrophage IL-1β and IL-18 Production
2019, Cell Metabolism