Ornithine decarboxylase and glutamate decarboxylase 65 as prognostic markers of gallbladder malignancy: A clinicopathological study in benign and malignant lesions of the gallbladder

Deng,Xiaofeng; Pei,Dongni

doi:10.3892/mmr.2012.1178

Ornithine decarboxylase and glutamate decarboxylase 65 as prognostic markers of gallbladder malignancy: A clinicopathological study in benign and malignant lesions of the gallbladder

Authors:
- Xiaofeng Deng
- Dongni Pei
View Affiliations

Affiliations: Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
Published online on: November 12, 2012 https://doi.org/10.3892/mmr.2012.1178
Pages: 413-418

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Ornithine decarboxylase (ODC) plays a critical role in cell proliferation and is overexpressed in a variety of cancers. Furthermore, γ-aminobutyric acid (GABA) content and glutamate decarboxylase (GAD) activity are increased in neoplastic tissues in colon and breast cancer. However, few studies have examined these molecules in gallbladder cancer specimens. We observed the expression levels of ODC and GAD65 in benign and malignant lesions of the gallbladder and investigated their clinicopathological significance for the first time. The expression levels of ODC and GAD65 in specimens from gallbladder adenocarcinoma (n=108), peritumoral tissues (n=46), adenomatous polyps (n=15) and chronic cholecystitis (n=35) were detected using immunohistochemical methods. Kaplan-Meier survival and Cox regression analyses were carried out to explore the clinical and pathological correlations. The levels of positive staining of ODC and GAD65 were significantly higher in gallbladder adenocarcinoma than in peritumoral tissues, adenomatous polyps and chronic cholecystitis. The Kaplan‑Meier survival analysis and Cox regression analysis showed that the expression of ODC and GAD65 correlated significantly with the one-year survival rate and the mean survival time of the patients postoperatively. We conclude that the overexpression of ODC and GAD65 are significant in the carcinogenesis and progression of gallbladder adenocarcinoma. They may be important biological markers for the evaluation of biological behaviors and the prognosis of gallbladder adenocarcinoma.

View Figures

View References

1	Ito H, Matros E, Brooks DC, Osteen RT, Zinner MJ, Swanson RS, Ashley SW and Whang EE: Treatment outcomes associated with surgery for gallbladder cancer: a 20-year experience. J Gastrointest Surg. 8:183–190. 2004.PubMed/NCBI
2	Randi G, Franceschi S and La Vecchia C: Gallbladder cancer worldwide: geographical distribution and risk factors. Int J Cancer. 118:1591–1602. 2006. View Article : Google Scholar : PubMed/NCBI
3	Shukla PJ and Barreto SG: Gallbladder cancer: we need to do better! Ann Surg Oncol. 16:2084–2085. 2009.
4	Gerner EW and Meyskens FL Jr: Polyamines and cancer: old molecules, new understanding. Nat Rev Cancer. 4:781–792. 2004. View Article : Google Scholar : PubMed/NCBI
5	Miao XP, Li JS, Li HY, Zeng SP, Zhao Y and Zeng JZ: Expression of ornithine decarboxylase in precancerous and cancerous gastric lesions. World J Gastroenterol. 13:2867–2871. 2007.PubMed/NCBI
6	Subhi AL, Tang B, Balsara BR, et al: Loss of methylthioadenosine phosphorylase and elevated ornithine decarboxylase is common in pancreatic cancer. Clin Cancer Res. 10:7290–7296. 2004. View Article : Google Scholar : PubMed/NCBI
7	Love RR, Astrow SH, Cheeks AM and Havighurst TC: Ornithine decarboxylase (ODC) as a prognostic factor in operable breast cancer. Breast Cancer Res Treat. 79:329–334. 2003. View Article : Google Scholar : PubMed/NCBI
8	Young L, Salomon R, Au W, Allan C, Russell P and Dong Q: Ornithine decarboxylase (ODC) expression pattern in human prostate tissues and ODC transgenic mice. J Histochem Cytochem. 54:223–229. 2006. View Article : Google Scholar : PubMed/NCBI
9	Matsuba T, Yano M, Abiru N, Takino H, Akazawa S, Nagataki S and Yasukawa K: Expression of recombinant human glutamic acid decarboxylase (GAD) in myeloma cells and enzyme-linked immunosorbent assay (ELISA) for autoantibodies to GAD. J Biochem. 121:20–24. 1997. View Article : Google Scholar : PubMed/NCBI
10	Pinal CS, Cortessis V and Tobin AJ: Multiple elements regulate GAD65 transcription. Dev Neurosci. 19:465–475. 1997. View Article : Google Scholar : PubMed/NCBI
11	Matuszek M, Jesipowicz M and Kleinrok Z: GABA content and GAD activity in gastric cancer. Med Sci Monit. 7:377–381. 2001.PubMed/NCBI
12	Opolski A, Mazurkiewicz M, Wietrzyk J, Kleinrok Z and Radzikowski C: The role of GABA-ergic system in human mammary gland pathology and in growth of transplantable murine mammary cancer. J Exp Clin Cancer Res. 19:383–390. 2000.PubMed/NCBI
13	Kleinrok Z, Matuszek M, Jesipowicz J, Matuszek B, Opolski A and Radzikowski C: GABA content and GAD activity in colon tumors taken from patients with colon cancer or from xenografted human colon cancer cells growing as s. c tumors in athymic nu/nu mice. J Physiol Pharmacol. 49:303–310. 1998.PubMed/NCBI
14	Kumar KN, Raja SB, Vidhya N and Devaraj SN: Ellagic acid modulates antioxidant status, ornithine decarboxylase expression, and aberrant crypt foci progression in 1,2-dimethylhydrazine-instigated colon preneoplastic lesions in rats. J Agric Food Chem. 60:3665–3672. 2012. View Article : Google Scholar
15	Arisan ED, Obakan P, Coker A and Palavan-Unsal N: Inhibition of ornithine decarboxylase alters the roscovitine-induced mitochondrial-mediated apoptosis in MCF-7 breast cancer cells. Mol Med Rep. 5:1323–1329. 2012.
16	Manni A, Washington S, Griffith JW, et al: Influence of polyamines on in vitro and in vivo features of aggressive and metastatic behavior by human breast cancer cells. Clin Exp Metastasis. 19:95–105. 2002. View Article : Google Scholar : PubMed/NCBI
17	Kubo S, Tamori A, Tanaka H, et al: Polyamine metabolism and recurrence after resection for hepatocellular carcinoma. Hepatogastroenterology. 51:208–210. 2004.PubMed/NCBI
18	Smirnova OA, Isaguliants MG, Hyvonen MT, et al: Chemically induced oxidative stress increases polyamine levels by activating the transcription of ornithine decarboxylase and spermidine/spermine-N(1)-acetyltransferase in human hepatoma HUH7 cells. Biochimie. 94:1876–1883. 2012. View Article : Google Scholar
19	Barry EL, Mott LA, Sandler RS, Ahnen DJ and Baron JA: Variants downstream of the ornithine decarboxylase gene influence risk of colorectal adenoma and aspirin chemoprevention. Cancer Prev Res (Philadelphia). 4:2072–2082. 2011. View Article : Google Scholar : PubMed/NCBI
20	Wolf C, Brüss M, Hänisch B, Göthert M, von Kügelgen I and Molderings GJ: Molecular basis for the antiproliferative effect of agmatine in tumor cells of colonic, hepatic, and neuronal origin. Mol Pharmacol. 71:276–283. 2007. View Article : Google Scholar : PubMed/NCBI
21	Xu X, Liu Z, Fang M, et al: CagA induces ornithine decarboxylase upregulation via Src/MEK/ERK/c-Myc pathway: implication for progression of gastric diseases Helicobacter pylori. Exp Biol Med (Maywood). 237:435–441. 2012. View Article : Google Scholar : PubMed/NCBI
22	Jaraj SJ, Augsten M, Häggarth L, Wester K, Pontén F, Ostman A and Egevad L: GAD1 is a biomarker for benign and malignant prostatic tissue. Scand J Urol Nephrol. 45:39–45. 2011. View Article : Google Scholar : PubMed/NCBI
23	Takehara A, Hosokawa M, Eguchi H, Ohigashi H, Ishikawa O, Nakamura Y and Nakagawa H: Gamma-aminobutyric acid (GABA) stimulates pancreatic cancer growth through overexpressing GABAA receptor pi subunit. Cancer Res. 67:9704–9712. 2007. View Article : Google Scholar
24	Maemura K, Shiraishi N, Sakagami K, et al: Proliferative effects of gamma-aminobutyric acid on the gastric cancer cell line are associated with extracellular signal-regulated kinase 1/2 activation. J Gastroenterol Hepatol. 24:688–696. 2009. View Article : Google Scholar
25	Walls AB, Nilsen LH, Eyjolfsson EM, et al: GAD65 is essential for synthesis of GABA destined for tonic inhibition regulating epileptiform activity. J Neurochem. 115:1398–1408. 2010. View Article : Google Scholar : PubMed/NCBI
26	Moon MS, Cho EW, Byun HS, Jung IL and Kim IG: GAD 67KD antisense in colon cancer cells inhibits cell growth and sensitizes to butyrate and pH reduction and H₂O₂ and gamma-radiation. Arch Biochem Biophys. 430:229–236. 2004. View Article : Google Scholar : PubMed/NCBI
27	Mazurkiewicz M, Opolski A, Wietrzyk J, Radzikowski C and Kleinrok Z: GABA level and GAD activity in human and mouse normal and neoplastic mammary gland. J Exp Clin Cancer Res. 18:247–253. 1999.PubMed/NCBI