Overexpression of the M2 isoform of pyruvate kinase is an adverse prognostic factor for signet ring cell gastric cancer

doi:10.3748/wjg.v18.i30.4037

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World Journal of Gastroenterology

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1007-9327

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Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA

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World J Gastroenterol. Aug 14, 2012; 18(30): 4037-4043
Published online Aug 14, 2012. doi: 10.3748/wjg.v18.i30.4037

Overexpression of the M2 isoform of pyruvate kinase is an adverse prognostic factor for signet ring cell gastric cancer

Jae Yun Lim, Sun Och Yoon, So Young Seol, Soon Won Hong, Jong Won Kim, Seung Ho Choi, Jae Yong Cho

Jae Yun Lim, So Young Seol, Jae Yong Cho, Department of Medical Oncology, Gangnam Severance Cancer Hospital, Yonsei University College of Medicine, Seoul 135-720, South Korea

Sun Och Yoon, Soon Won Hong, Department of Pathology, Gangnam Severance Cancer Hospital, Yonsei University College of Medicine, Seoul 135-720, South Korea

Jong Won Kim, Seung Ho Choi, Department of Surgery, Gangnam Severance Cancer Hospital, Yonsei University College of Medicine, Seoul 135-720, South Korea

Author contributions: Lim JY and Cho JY designed the study; Lim JY, Yoon SO, Seol SY, Hong SW, Kim JW and Choi SH contributed to performing experiment and acquisition of data; Lim JY, Yoon SO and Cho JY analyzed and interpreted the data; and Lim JY and Cho JY wrote the paper.

Supported by Faculty Research Grant of Yonsei University College of Medicine for 2011, 6-2011-0113, 6-2011-0146; A Faculty Research Grant of Department of Internal Medicine, Yonsei University College of Medicine for 2010; and Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology, No. 2010-0024248

Correspondence to: Dr. Jae Yong Cho, Department of Medical Oncology, Gangnam Severance Cancer Hospital, Yonsei University College of Medicine, 712 Eonjuro, Gangnam-gu, Seoul 135-720, South Korea. chojy@yuhs.ac

Telephone: +82-2-20194363 Fax: +82-2-34633882

Received: February 7, 2012
Revised: April 11, 2012
Accepted: April 18, 2012
Published online: August 14, 2012

Abstract

AIM: To investigate M2 isoform of pyruvate kinase (PKM2) expression in gastric cancers and evaluate its potential as a prognostic biomarker and an anticancer target.

METHODS: All tissue samples were derived from gastric cancer patients underwent curative gastrectomy as a primary treatment. Clinical and pathological information were obtained from the medical records. Gene expression microarray data from 60 cancer and 19 non-cancer gastric tissues were analyzed to evaluate the expression level of PKM2 mRNA. Tissue microarrays were constructed from 368 gastric cancer patients. Immunohistochemistry was used to measure PKM2 expression and PKM2 positivity of cancer was determined by proportion of PKM2-positive tumor cells and staining intensity. Association between PKM2 expression and the clinicopathological factors was evaluated and the correlation between PKM2 and cancer prognosis was evaluated.

RESULTS: PKM2 mRNA levels were increased more than 2-fold in primary gastric cancers compared to adjacent normal tissues from the same patients (log transformed expression level: 7.6 ± 0.65 vs 6.3 ± 0.51, P < 0.001). Moreover, differentiated type cancers had significantly higher PKM2 mRNA compared to undifferentiated type cancers (log transformed expression level: 7.8 ± 0.70 vs 6.7 ± 0.71, P < 0.001). PKM2 protein was mainly localized in the cytoplasm of primary cancer cells and detected in 144 of 368 (39.1%) human gastric cancer cases. PKM2 expression was not related with stage (P = 0.811), but strongly correlated with gastric cancer differentiation (P < 0.001). Differentiated type cancers expressed more PKM2 protein than did the undifferentiated ones. Well differentiated adenocarcinoma showed 63.6% PKM2-positive cells; in contrast, signet-ring cell cancers showed only 17.7% PKM2-positive cells. Importantly, PKM2 expression was correlated with shorter overall survival (P < 0.05) independent of stage only in signet-ring cell cancers.

CONCLUSION: PKM2 expression might be an adverse prognostic factor for signet-ring cell carcinomas. Its function and potential as a prognostic marker should be further verified in gastric cancer.

Keywords: Gastric cancer, M2 isoform of pyruvate kinase, Biomarker, Signet ring cell carcinoma, Prognosis