Top

Published in:

01-04-2020 | Hepatocellular Carcinoma | Original Article

Overexpression of Pyruvate Kinase M2 in Tumor Tissues Is Associated with Poor Prognosis in Patients with Hepatocellular Carcinoma

Authors: Rui Zhao, Lei Li, Jinbo Yang, Qinfeng Niu, Han Wang, Xiaodong Qin, Ning Zhu, Anchen Shi

Published in: Pathology & Oncology Research | Issue 2/2020

Abstract

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors, with a high degree of malignancy and a poor prognosis. The aim of this study was to investigate the relationship between expression of pyruvate kinase M2 (PKM2) and prognosis in patients with HCC. The expression levels of PKM2 and PKM1 in 86 cases of HCC were detected by immunohistochemistry. An H score was used to evaluate the expression of PKM, and all patients were further divided into PKM high-expression and PKM low-expression groups. The relationship between PKM2 expression and the clinicopathological parameters and prognosis of patients were subsequently analyzed. Our data suggested that the expression level of PKM2 was significantly higher in HCC tissues than in adjacent tissues and the negatively expression of PKM1 in HCC tissues. Kaplan-Meier analysis revealed that PKM2 expression was strongly associated with survival in HCC patients (P = 0.001). The patients in the PKM2 high-expression group had significantly shorter survival times than the patients in the PKM2 low-expression group (hazard ratio for death, 2.358; 95% confidence interval [1.156, 4.812]; P = 0.018). In conclusion, these data indicate that PKM2 expression in HCC tissue samples can be used as a prognostic factor for patients with HCC and that high PKM2 expression is correlated with a poor prognosis in HCC patients.

Altekruse SF, McGlynn KA, Dickie LA, Kleiner DE (2012) Hepatocellular carcinoma confirmation, treatment, and survival in surveillance, epidemiology, and end results registries, 1992-2008. Hepatology 55:476–482. https://doi.org/10.1002/hep.24710 CrossRefPubMed

Li H, Huang W, Luo R (2015) The microRNA-325 inhibits hepatocellular carcinoma progression by targeting high mobility group box 1. Diagn Pathol 10:117. https://doi.org/10.1186/s13000-015-0323-z CrossRefPubMedPubMedCentral

Zeng QA, Qiu J, Zou R, Li Y, Li S, Li B, Huang P, Hong J, Zheng Y, Lao X, Yuan Y (2012) Clinical features and outcome of multiple primary malignancies involving hepatocellular carcinoma: a long-term follow-up study. BMC Cancer 12:148. https://doi.org/10.1186/1471-2407-12-148 CrossRefPubMedPubMedCentral

Chen CJ, Yang HI, Su J, Jen CL, You SL, Lu SN, Huang GT, Iloeje UH, REVEAL-HBV Study Group (2006) Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. Jama 295:65–73. https://doi.org/10.1001/jama.295.1.65 CrossRefPubMed

Bosch FX, Ribes J, Diaz M, Cleries R (2004) Primary liver cancer: worldwide incidence and trends. Gastroenterology 127:S5–S16CrossRef

Ang SF, Ng ES, Li H, Ong YH, Choo SP, Ngeow J, Toh HC, Lim KH, Yap HY, Tan CK, Ooi LL, Cheow PC, Chung AY, Chow PK, Foo KF, Tan MH (2015) The Singapore liver cancer recurrence (SLICER) score for relapse prediction in patients with surgically resected hepatocellular carcinoma. PLoS ONE 10:e0118658. https://doi.org/10.1371/journal.pone.0128058 CrossRefPubMedPubMedCentral

Llovet JM, Burroughs A, Bruix J (2003) Hepatocellular carcinoma. Lancet 362:1907–1917. https://doi.org/10.1016/S0140-6736(03)14964-1 CrossRefPubMed

Yu G, Yu W, Jin G, Xu D, Chen Y, Xia T, Yu A, Fang W, Zhang X, Li Z, Xie K (2015) PKM2 regulates neural invasion of and predicts poor prognosis for human hilar cholangiocarcinoma. Mol Cancer 14:193. https://doi.org/10.1186/s12943-015-0462-6 CrossRefPubMedPubMedCentral

Yamada S, Fuchs BC, Fujii T, Shimoyama Y, Sugimoto H, Nomoto S, Takeda S, Tanabe KK, Kodera Y, Nakao A (2013) Epithelial-to-mesenchymal transition predicts prognosis of pancreatic cancer. Surgery 154:946–954. https://doi.org/10.1016/j.surg.2013.05.004 CrossRefPubMed

10.

MacDonald MJ, Chang CM (1985) Pancreatic islets contain the M2 isoenzyme of pyruvate kinase. Its phosphorylation has no effect on enzyme activity. Mol Cell Biochem 68:115–120PubMed

11.

Dombrauckas JD, Santarsiero BD, Mesecar AD (2005) Structural basis for tumor pyruvate kinase M2 allosteric regulation and catalysis. Biochemistry 44:9417–9429. https://doi.org/10.1021/bi0474923 CrossRefPubMed

12.

Vaupel P, Harrison L (2004) Tumor hypoxia: causative factors, compensatory mechanisms, and cellular response. Oncologist 9:4–9. https://doi.org/10.1634/theoncologist.9-90005-4 CrossRefPubMed

13.

Wong N, De Melo J, Tang D (2013) PKM2, a central point of regulation in cancer metabolism. Int J Cell Biol 2013:242513:1–11. https://doi.org/10.1155/2013/242513 CrossRef

14.

Noguchi T, Inoue H, Tanaka T (1986) The M1- and M2-type isozymes of rat pyruvate kinase are produced from the same gene by alternative RNA splicing. J Biol Chem 261:13807–13812PubMed

15.

Eigenbrodt E, Reinacher M, Scheefers-Borchel U, Scheefers H, Friis R (1992) Double role for pyruvate kinase type M2 in the expansion of phosphometabolite pools found in tumor cells. Crit Rev Oncog 3:91–115PubMed

16.

Mazurek S, Boschek CB, Hugo F, Eigenbrodt E (2005) Pyruvate kinase type M2 and its role in tumor growth and spreading. Semin Cancer Biol 15:300–308. https://doi.org/10.1016/j.semcancer.2005.04.009 CrossRefPubMed

17.

Steinberg P, Klingelhoffer A, Schafer A, Wust G, Weisse G, Oesch F, Eigenbrodt E (1999) Expression of pyruvate kinase M2 in preneoplastic hepatic foci of N-nitrosomorpholine-treated rats. Virchows Arch 434:213–220. https://doi.org/10.1007/s004280050330 CrossRefPubMed

18.

David CJ, Chen M, Assanah M, Canoll P, Manley JL (2010) HnRNP proteins controlled by c-Myc deregulate pyruvate kinase mRNA splicing in cancer. Nature 63:364–368. https://doi.org/10.1038/nature08697 CrossRef

19.

Dong G, Mao Q, Xia W, Xu Y, Wang J, Xu L, Jiang F (2016) PKM2 and cancer: the function of PKM2 beyond glycolysis. Oncol Lett 11:1980–1986. https://doi.org/10.1038/nature08697 CrossRefPubMedPubMedCentral

20.

Li Z, Yang P, Li Z (2014) The multifaceted regulation and functions of PKM2 in tumor progression. Biochim Biophys Acta 1846:285–296. https://doi.org/10.1016/j.bbcan.2014.07.008 CrossRefPubMed

21.

Christofk HR, Vander Heiden MG, Harris MH, Ramanathan A, Gerszten RE, Wei R, Fleming MD, Schreiber SL, Cantley LC (2008) The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature 452:230–233. https://doi.org/10.1038/nature06734 CrossRefPubMed

22.

Tamada M, Suematsu M, Saya H (2012) Pyruvate kinase M2: multiple faces for conferring benefits on cancer cells. Clin Cancer Res 18:5554–5561. https://doi.org/10.1158/1078-0432.CCR-12-0859 CrossRefPubMed

23.

Schulze G (2000) The tumor marker tumor M2-PK: an application in the diagnosis of gastrointestinal cancer. Anticancer Res 20:4961–4964PubMed

24.

Wong N, Yan J, Ojo D, De Melo J, Cutz JC, Tang D (2014) Changes in PKM2 associate with prostate cancer progression. Cancer Investig 32:330–338. https://doi.org/10.3109/07357907.2014.919306 CrossRef

25.

Hardt PD, Ngoumou BK, Rupp J, Schnell-Kretschmer H, Kloer HU (2000) Tumor M2-pyruvate kinase: a promising tumor marker in the diagnosis of gastro-intestinal cancer. Anticancer Res 20:4965–4968PubMed

26.

Fan F, Wu H, Liu Z, Hou X, Chen W, Wang A, Lu Y (2016) Nuclear PKM2 expression, an independent risk factor for ER after curative resection of hepatocellular carcinoma. Biomed Pharmacother 84:1858–1864. https://doi.org/10.1016/j.biopha.2016.10.108 CrossRefPubMed

27.

Chen Z, Lu X, Wang Z, Jin G, Wang Q, Chen D, Chen T, Li J, Fan J, Cong W, Gao Q, He X (2015) Co-expression of PKM2 and TRIM35 predicts survival and recurrence in hepatocellular carcinoma. Oncotarget 6:2538–2548. https://doi.org/10.18632/oncotarget.2991 CrossRefPubMed

28.

Xu Q, Liu X, Zheng X, Yao Y, Liu Q (2014) PKM2 regulates Gli1 expression in hepatocellular carcinoma. Oncol Lett 8:1973–1979. https://doi.org/10.3892/ol.2014.2441 CrossRefPubMedPubMedCentral

29.

Fan FT, Shen CS, Tao L, Tian C, Liu ZG, Zhu ZJ, Liu YP, Pei CS, Wu HY, Zhang L, Wang AY, Zheng SZ, Huang SL, Lu Y (2014) PKM2 regulates hepatocellular carcinoma cell epithelial-mesenchymal transition and migration upon EGFR activation. Asian Pac J Cancer Prev 15:1961–1970CrossRef

30.

Liu WR, Tian MX, Yang LX, Lin YL, Jin L, Ding ZB, Shen YH, Peng YF, Gao DM, Zhou J, Qiu SJ, Dai Z, He R, Fan J, Shi YH (2015) PKM2 promotes metastasis by recruiting myeloid-derived suppressor cells and indicates poor prognosis for hepatocellular carcinoma. Oncotarget 6:846–861. https://doi.org/10.18632/oncotarget.2749 CrossRefPubMed

31.

Liu Y, Wu H, Mei Y, Ding X, Yang X, Li C, Deng M, Gong J (2017) Clinicopathological and prognostic significance of PKM2 protein expression in cirrhotic hepatocellular carcinoma and non-cirrhotic hepatocellular carcinoma. Sci Rep 7:15294. https://doi.org/10.1038/s41598-017-14813-y CrossRefPubMedPubMedCentral

Title: Overexpression of Pyruvate Kinase M2 in Tumor Tissues Is Associated with Poor Prognosis in Patients with Hepatocellular Carcinoma
Authors: Rui Zhao
Lei Li
Jinbo Yang
Qinfeng Niu
Han Wang
Xiaodong Qin
Ning Zhu
Anchen Shi
Publication date: 01-04-2020
Publisher: Springer Netherlands
Keywords: Hepatocellular Carcinoma
Hepatocellular Carcinoma
Published in: Pathology & Oncology Research / Issue 2/2020
Print ISSN: 1219-4956
Electronic ISSN: 1532-2807
DOI: https://doi.org/10.1007/s12253-019-00630-3

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 2/2020

p63 Expression and its Relation to Epithelial Cells Proliferation in Dentigerous Cyst, Odontogenic Keratocyst, and Ameloblastoma

MicroRNA-182-5p Modulates Oral Squamous Cell Carcinoma Migration and Invasion Via Targeting MTSS1 Gene

Real-World Data of the Correlation between EGFR Determination by Liquid Biopsy in Non-squamous Non-small Cell Lung Cancer (NSCLC) and the EGFR Profile in Tumor Biopsy

Regulation of PD-1/PD-L1 Pathway in Cancer by Noncoding RNAs

Role of Peritoneal Cytology in Patients with Early Stage Colorectal Cancer

ACTN4 Promotes the Proliferation, Migration, Metastasis of Osteosarcoma and Enhances its Invasive Ability through the NF-κB Pathway

Keynote webinar | Spotlight on antibody–drug conjugates in cancer