Overexpression of the M2 Isoform of Pyruvate Kinase is an Adverse Prognostic Factor for Signet Ring Cell Gastric Cancer

Overview

Journal World J Gastroenterol

Publisher Baishideng Publishing Group

Specialty Gastroenterology

Date 2012 Aug 23

PMID 22912555

Citations 50

Authors

Jae Yun Lim

Sun Och Yoon

So Young Seol

Soon Won Hong

Jong Won Kim

Seung Ho Choi

Jae Yong Cho

Affiliations

Soon will be listed here.

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.

Citing Articles

Investigation of target genes and potential mechanisms related to compound Xiao-ai-fei honey ointment based on network pharmacology and bioinformatics analysis.

Abudurousuli K, Talihati Z, Hailati S, Han M, Nuer M, Khan N Medicine (Baltimore). 2023; 102(32):e34629.

PMID: 37565919 PMC: 10419591. DOI: 10.1097/MD.0000000000034629.

Recent Advances on PKM2 Inhibitors and Activators in Cancer Applications.

Chen P, Lou L, Sharma B, Li M, Xie C, Yang F Curr Med Chem. 2023; 31(20):2955-2973.

PMID: 37455458 DOI: 10.2174/0929867331666230714144851.

Pan-Cancer Analysis of the Oncogenic and Prognostic Role of PKM2: A Potential Target for Survival and Immunotherapy.

Liang N, Mi L, Li J, Li T, Chen J, Dionigi G Biomed Res Int. 2023; 2023:3375109.

PMID: 36865483 PMC: 9974260. DOI: 10.1155/2023/3375109.

GTPBP4 promotes hepatocellular carcinoma progression and metastasis via the PKM2 dependent glucose metabolism.

Zhou Q, Yin Y, Yu M, Gao D, Sun J, Yang Z Redox Biol. 2022; 56:102458.

PMID: 36116159 PMC: 9483790. DOI: 10.1016/j.redox.2022.102458.

The C-Terminal Acidic Tail Modulates the Anticancer Properties of HMGB1.

Borde C, Dillard C, Lhonore A, Quignon F, Hamon M, Marchand C Int J Mol Sci. 2022; 23(14).

PMID: 35887213 PMC: 9319070. DOI: 10.3390/ijms23147865.

References

Cerwenka H, Aigner R, Bacher H, Werkgartner G, El-Shabrawi A, Quehenberger F . TUM2-PK (pyruvate kinase type tumor M2), CA19-9 and CEA in patients with benign, malignant and metastasizing pancreatic lesions. Anticancer Res. 1999; 19(1B):849-51. View

Schneider J, Neu K, Grimm H, Velcovsky H, Weisse G, Eigenbrodt E . Tumor M2-pyruvate kinase in lung cancer patients: immunohistochemical detection and disease monitoring. Anticancer Res. 2002; 22(1A):311-8. View

Piessen G, Messager M, Leteurtre E, Jean-Pierre T, Mariette C . Signet ring cell histology is an independent predictor of poor prognosis in gastric adenocarcinoma regardless of tumoral clinical presentation. Ann Surg. 2009; 250(6):878-87. DOI: 10.1097/SLA.0b013e3181b21c7b. View

Schulze G . The tumor marker tumor M2-PK: an application in the diagnosis of gastrointestinal cancer. Anticancer Res. 2001; 20(6D):4961-4. View

Anastasiou D, Poulogiannis G, Asara J, Boxer M, Jiang J, Shen M . Inhibition of pyruvate kinase M2 by reactive oxygen species contributes to cellular antioxidant responses. Science. 2011; 334(6060):1278-83. PMC: 3471535. DOI: 10.1126/science.1211485. View

Peng X, Gong F, Zhao Y, Zhou L, Xie Y, Liao H . Comparative proteomic approach identifies PKM2 and cofilin-1 as potential diagnostic, prognostic and therapeutic targets for pulmonary adenocarcinoma. PLoS One. 2011; 6(11):e27309. PMC: 3210781. DOI: 10.1371/journal.pone.0027309. View

Luftner D, Mesterharm J, Akrivakis C, Geppert R, Petrides P, Wernecke K . Tumor type M2 pyruvate kinase expression in advanced breast cancer. Anticancer Res. 2001; 20(6D):5077-82. View

Chen X, Leung S, Yuen S, Chu K, Ji J, Li R . Variation in gene expression patterns in human gastric cancers. Mol Biol Cell. 2003; 14(8):3208-15. PMC: 181561. DOI: 10.1091/mbc.e02-12-0833. View

Tay S, Leong S, Yu K, Aggarwal A, Tan S, Lee C . A combined comparative genomic hybridization and expression microarray analysis of gastric cancer reveals novel molecular subtypes. Cancer Res. 2003; 63(12):3309-16. View

10.

Pak K, Yun M, Cheong J, Hyung W, Choi S, Noh S . Clinical implication of FDG-PET in advanced gastric cancer with signet ring cell histology. J Surg Oncol. 2011; 104(6):566-70. DOI: 10.1002/jso.21997. View

11.

Cho J, Lim J, Cheong J, Park Y, Yoon S, Kim S . Gene expression signature-based prognostic risk score in gastric cancer. Clin Cancer Res. 2011; 17(7):1850-7. PMC: 3078023. DOI: 10.1158/1078-0432.CCR-10-2180. View

12.

Kim B, Bang S, Lee S, Kim S, Jung Y, Lee C . Expression profiling and subtype-specific expression of stomach cancer. Cancer Res. 2003; 63(23):8248-55. View

13.

Warburg O . On the origin of cancer cells. Science. 1956; 123(3191):309-14. DOI: 10.1126/science.123.3191.309. View

14.

Wechsel H, Petri E, Bichler K, Feil G . Marker for renal cell carcinoma (RCC): the dimeric form of pyruvate kinase type M2 (Tu M2-PK). Anticancer Res. 1999; 19(4A):2583-90. View

15.

Vander Heiden M, Christofk H, Schuman E, Subtelny A, Sharfi H, Harlow E . Identification of small molecule inhibitors of pyruvate kinase M2. Biochem Pharmacol. 2009; 79(8):1118-24. PMC: 2823991. DOI: 10.1016/j.bcp.2009.12.003. View

16.

Zhang B, Chen J, Chen D, Wang G, Shen P . Tumor type M2 pyruvate kinase expression in gastric cancer, colorectal cancer and controls. World J Gastroenterol. 2004; 10(11):1643-6. PMC: 4572770. DOI: 10.3748/wjg.v10.i11.1643. View

17.

Tan I, Ivanova T, Lim K, Ong C, Deng N, Lee J . Intrinsic subtypes of gastric cancer, based on gene expression pattern, predict survival and respond differently to chemotherapy. Gastroenterology. 2011; 141(2):476-85, 485.e1-11. PMC: 3152688. DOI: 10.1053/j.gastro.2011.04.042. View

18.

Wong T, Liu X, Ho A, Yuen A, Ng R, Wei W . Identification of pyruvate kinase type M2 as potential oncoprotein in squamous cell carcinoma of tongue through microRNA profiling. Int J Cancer. 2008; 123(2):251-257. DOI: 10.1002/ijc.23583. View

19.

Yoo B, Ku J, Hong S, Shin Y, Park S, Kim H . Decreased pyruvate kinase M2 activity linked to cisplatin resistance in human gastric carcinoma cell lines. Int J Cancer. 2003; 108(4):532-9. DOI: 10.1002/ijc.11604. View

20.

Chen J, Xie J, Jiang Z, Wang B, Wang Y, Hu X . Shikonin and its analogs inhibit cancer cell glycolysis by targeting tumor pyruvate kinase-M2. Oncogene. 2011; 30(42):4297-306. DOI: 10.1038/onc.2011.137. View