Ornithine Decarboxylase mRNA Expression in Curatively Resected Non–Small-cell Lung Cancer

Peter P. Grimminger; Paul M. Schneider; Ralf Metzger; Daniel Vallböhmer; Kathleen D. Danenberg; Peter V. Danenberg; Arnulf H. Hölscher; Jan Brabender

Disclosures

Clin Lung Cancer. 2010;11(2):114-119. 

In This Article

Abstract and Introduction

Abstract

Background: The effect of ornithine decarboxylase (ODC) on the pathogenesis of non–small-cell lung cancer (NSCLC) remains poorly investigated. Hence, the aim of this study was to explore the potential role of ODC mRNA expression as a prognostic biomarker in patients with curatively resected NSCLC.
Patients and Methods: A total of 91 tumor and matching nontumorous lung tissue samples from patients with NSCLC were analyzed using a quantitative realtime reverse-transcriptase polymerase chain reaction method. The relative ODC mRNA expression was measured in tumorous and nontumorous lung tissue using β-actin as a reference gene. Squamous cell carcinoma was found in 43 patients (47%), adenocarcinoma in 33 (36%), and large-cell carcinoma in 15 of the patients (17%). All patients' disease was R0 resected.
Results: Ornithine decarboxylase was detected in all 91 tumor and nontumorous lung tissue samples. The median tumorous expression of 9.11 (range, 0.92–155.35) was significantly elevated compared with the median ODC expression of 7.89 (range, 0.0–45.8) in nontumorous lung tissue. Ornithine decarboxylase expression levels were not associated with any clinicopathologic parameters. Using an ODC/β-actin ratio of 10 as a cutoff, tumorous ODC (tODC) expression is a significant prognostic factor in NSCLC. The ODC ratio between tumorous and nontumorous expression was even more prognostic. Moreover, Cox proportional hazards model analysis showed ODC expression to be an independent prognostic factor.
Conclusion: In this study, ODC is shown to have a prognostic potential in NSCLC. Low levels of tODC expression are associated with a more aggressive tumor biology. Also, an increase of ODC mRNA expression during carcinogenesis seems to have a favorable prognostic effect. Measuring the ODC expression in patients with NSCLC could aid in further chemotherapy decisions. Our results suggest that further investigation of ODC mRNA expression in NSCLC may be warranted.

Introduction

Lung cancer is still the leading cause of cancer-related mortality in the United States.[1] Non–small-cell lung cancer (NSCLC) represents approximately 80%–85% of all lung cancers. Each year, in the United States alone, over 160,000 people die of lung cancer. Despite all treatment efforts, the 5-year survival rate remains under 20%.[2] Up to tumor stage IIIA, surgical resection of the tumor is still the main curative treatment. However, in recent years, it has become apparent that the use of predictive and prognostic biomarkers has the potential to markedly improve cancer treatment by allowing the selection of the most suitable therapy for each patient. Most such biomarkers are derived from pathways involved in cell cycle regulation, apoptosis, angiogenesis, growth factor receptors, nucleoside synthesis, DNA repair, or in others such as polyamine biosynthesis.[3–9] In lung cancer, although several proteins and gene expressions have already been analyzed and their prognostic potential has been investigated,[6,10–12] more biomarkers are needed to develop the most effective individualized therapies possible.

Ornithine decarboxylase (ODC) is the first rate-limiting enzyme in the biosynthesis of polyamines,[13,14] which are essential for cell proliferation[15,16] and cell regeneration.[17,18] The regulation of ODC seems to be extremely complex at the levels of transcription, translation, and protein degradation.[19] Aberrant regulation of ODC has been reported to play an important role in neoplastic transformation and tumor growth. While growth factors can increase ODC expression transiently,[20,21] constitutive activation is induced during the cell transformation process by oncogene activation, such as v-SRC, neu, or RAS,[22–25] and also by viral infection.[26] In several cancers such as breast,[27] esophageal,[28] gastric,[29] colon,[30] pancreatic,[31] lung,[32] and prostate cancers[33] as well as precancerous esophageal and gastric lesions,[8,33] elevated ODC levels have been reported and also linked to recurrence.[34] Upregulation of ODC mRNA expression was shown to be an early event in the development and progression of Barrett-associated adenocarcinoma.[35] The role of ODC in tumor development is further supported by observations that reduction of tumor growth occurs in rodent cancer models and cell lines treated with ODC-inhibiting substances, such as α-difluoromethylornithine (DFMO).[36–40]

An elevated tumorous ODC (tODC) expression compared with nontumorous lung tissue in patients with NSCLC has been described in a smaller earlier study.[32] However, the prognostic value of ODC expression in NSCLC has not been studied thus far. Therefore, we undertook this study to assess the prognostic potential of ODC expression in NSCLC.

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