Decreased expression of prenyl diphosphate synthase subunit 2 correlates with reduced survival of patients with gastric cancer

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Abstract

Background

Identification of novel molecular biomarkers will improve the management of patients with gastric cancer (GC). Prenyl diphosphate synthase subunit 2 (PDSS2) is required for coenzyme Q10 biosynthesis and acts as a tumor suppressor; however, the role and regulatory mechanisms of PDSS2 in GC are not understood. The aim of this study was to determine expression status and regulatory mechanisms of PDSS2 in GC.

Methods

Associations between expression and methylation of PDSS2 were evaluated using GC cell lines. The clinical significance of PDSS2 expression was evaluated using 238 pairs of surgically resected gastric tissues with subgroup analysis based on GC subtypes.

Results

The expression of PDSS2 mRNA was decreased in 73% of GC cell lines compared with the control non-cancerous cell. The PDSS2 promoter was hypermethylated in cells with decreased PDSS2 expression, and treating these cells with a methylation inhibitor reactivated PDSS2 expression. GC tissues expressed significantly lower mean levels of PDSS2 mRNA compared with adjacent normal tissues ( P <0.001). The expression pattern of PDSS2 protein was consistent with that of its mRNA. The decrease of PDSS2 mRNA expression in GC tissues (less than half the level of expression detected in the corresponding normal adjacent tissues) correlated significantly with elevated levels of carbohydrate antigen 19-9 ( P = 0.015), lymph node metastasis ( P = 0.022), and shorter recurrence-free survival after curative resection ( P = 0.022). Further, multivariate analysis identified PDSS2 mRNA expression as an independent prognostic factor (hazard ratio 1.95, 95% confidence interval 1.22–3.09, P = 0.005), and its expression pattern and prognostic significance were similar among three GC subtypes.

Conclusions

PDSS2 encodes a putative tumor suppressor, and we show here that its expression was regulated by hypermethylation of its promoter in GC cells. Inhibition of PDSS2 mRNA expression may serve as a novel biomarker of all types of GC.

Electronic supplementary material

The online version of this article (doi:10.1186/s13046-014-0088-3) contains supplementary material, which is available to authorized users.

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Most cited references 23

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Metabolism and function of coenzyme Q.

Mikael J. Turunen, Jerker M. Olsson, Gustav Dallner (2004)

Coenzyme Q (CoQ) is present in all cells and membranes and in addition to be a member of the mitochondrial respiratory chain it has also several other functions of great importance for the cellular metabolism. This review summarizes the findings available to day concerning CoQ distribution, biosynthesis, regulatory modifications and its participation in cellular metabolism. There are a number of indications that this lipid is not always functioning by its direct presence at the site of action but also using e.g. receptor expression modifications, signal transduction mechanisms and action through its metabolites. The biosynthesis of CoQ is studied in great detail in bacteria and yeast but only to a limited extent in animal tissues and therefore the informations available is restricted. However, it is known that the CoQ is compartmentalized in the cell with multiple sites of biosynthesis, breakdown and regulation which is the basis of functional specialization. Some regulatory mechanisms concerning amount and biosynthesis are established and nuclear transcription factors are partly identified in this process. Using appropriate ligands of nuclear receptors the biosynthetic rate can be increased in experimental system which raises the possibility of drug-induced upregulation of the lipid in deficiency. During aging and pathophysiological conditions the tissue concentration of CoQ is modified which influences cellular functions. In this case the extent of disturbances is dependent on the localization and the modified distribution of the lipid at cellular and membrane levels.

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Human Coenzyme Q10 Deficiency

Catarina Quinzii, Salvatore DiMauro, Michio Hirano (2006)

Ubiquinone (coenzyme Q10 or CoQ10) is a lipid-soluble component of virtually all cell membranes and has multiple metabolic functions. Deficiency of CoQ10 (MIM 607426) has been associated with five different clinical presentations that suggest genetic heterogeneity, which may be related to the multiple steps in CoQ10 biosynthesis. Patients with all forms of CoQ10 deficiency have shown clinical improvements after initiating oral CoQ10 supplementation. Thus, early diagnosis is of critical importance in the management of these patients. This year, the first molecular defect causing the infantile form of primary human CoQ10 deficiency has been reported. The availability of genetic testing will allow for a better understanding of the pathogenesis of this disease and early initiation of therapy (even presymptomatically in siblings of patients) in this otherwise life-threatening infantile encephalomyopathy.

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Molecular Pathology of Gastric Carcinoma

Bo-Gun Jang, B.-G. Jang, Woo Ho Kim (2011)

Gastric carcinoma (GC) is a biologically heterogeneous disease involving numerous genetic and epigenetic alterations. A very small proportion of GCs can be caused by a specific germ-line mutation of the E-cadherin gene (CDH1) . Sporadic GC is developed through multistep processes that begin with Helicobacter pylori -induced atrophic gastritis. Epstein-Barr virus is another infectious cause of GC, and the above two infection-associated GCs are characterized by global CpG island methylation in the promoter region of cancer-related genes. Mutations of tumor protein p53 (TP53) and β-catenin (CTNNB1) genes occur early in the development of GC and contribute to gastric carcinogenesis. Furthermore, significant numbers of GCs show loss of Runx3 due to hemizygous deletion and hypermethylation of the promoter region. Aberrant Cdx2 expression has been shown in precancerous lesions as well as GC. However, it remains unclear whether Cdx2 plays an oncogenic role in gastric carcinogenesis. GC with microsatellite instability is also a well-defined subset exhibiting distinctive clinicopathologic features. Targeted therapy against GC with ERBB2 amplification recently improved the prognosis of patients with advanced GC. In addition, epigenetic changes in GC could be attractive targets for cancer treatment with modulators. A genome-wide search has been undertaken to identify novel methylation-silenced genes in GC, which will help us understand the overall molecular features of GC and further provide novel opportunities in the treatment of GC.

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Author and article information

Contributors

Mitsuro Kanda: m-kanda@med.nagoya-u.ac.jp

Shuji Nomoto: snomoto@med.nagoya-u.ac.jp

Hisaharu Oya: hohya@med.nagoya-u.ac.jp

Ryoji Hashimoto: hashi64@med.nagoya-u.ac.jp

Hideki Takami: takamihideki@med.nagoya-u.ac.jp

Dai Shimizu: d-shimizu@med.nagoya-u.ac.jp

Fuminori Sonohara: fsonohara@med.nagoya-u.ac.jp

Daisuke Kobayashi: kobadai@med.nagoya-u.ac.jp

Chie Tanaka: chtanaka@med.nagoya-u.ac.jp

Suguru Yamada: suguru@med.nagoya-u.ac.jp

Tsutomu Fujii: fjt@med.nagoya-u.ac.jp

Goro Nakayama: goro@med.nagoya-u.ac.jp

Hiroyuki Sugimoto: sugi@med.nagoya-u.ac.jp

Masahiko Koike: dockoike@med.nagoya-u.ac.jp

Kenta Murotani: kmurotani@med.nagoya-u.ac.jp

Michitaka Fujiwara: mfuji@med.nagoya-u.ac.jp

Yasuhiro Kodera: ykodera@med.nagoya-u.ac.jp

Journal

Journal ID (nlm-ta): J Exp Clin Cancer Res

Journal ID (iso-abbrev): J. Exp. Clin. Cancer Res

Title: Journal of Experimental & Clinical Cancer Research : CR

Publisher: BioMed Central (London )

ISSN (Print): 0392-9078

ISSN (Electronic): 1756-9966

Publication date (Electronic): 22 October 2014

Publication date PMC-release: 22 October 2014

Publication date Collection: 2014

Volume: 33

Issue: 1

Electronic Location Identifier: 88

Affiliations

[ ]Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550 Japan

[ ]Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya, Japan

Article

Publisher ID: 88

DOI: 10.1186/s13046-014-0088-3

PMC ID: 4209044

PubMed ID: 25330808

SO-VID: 0c40b13c-e542-492a-abad-759f5882b820

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 27 July 2014

Date accepted : 3 October 2014

Custom metadata

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: gastric cancer,prenyl diphosphate synthase subunit 2,expression,methylation,subtype

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: gastric cancer, prenyl diphosphate synthase subunit 2, expression, methylation, subtype

Decreased expression of prenyl diphosphate synthase subunit 2 correlates with reduced survival of patients with gastric cancer

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Abstract

Background

Methods

Results

Conclusions

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Karger: Oncology

Most cited references 23

Metabolism and function of coenzyme Q.

Human Coenzyme Q10 Deficiency

Molecular Pathology of Gastric Carcinoma

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