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Molecular Cancer
Published in: Molecular Cancer 1/2015

Open Access 01-12-2015 | Research

PKM2 regulates neural invasion of and predicts poor prognosis for human hilar cholangiocarcinoma

Authors: Guanzhen Yu, Wenlong Yu, Guangzhi Jin, Dongyun Xu, Ying Chen, Tian Xia, Allan Yu, Wenzheng Fang, Xiaoli Zhang, Zhaosheng Li, Keping Xie

Published in: Molecular Cancer | Issue 1/2015

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Abstract

Background

The therapeutic and prognostic value of the glycolytic enzymes hexokinase, phosphofructokinase, and pyruvate kinase (PK) has been implicated in a variety of cancers, while their roles in treatment of and prognosis for hilar cholangiocarcinoma (HC) remain unclear. In this study, we determined the expression of PKM2 in and its impact on biology and clinical outcome of human HC.

Methods

The regulation and function of PKM2 in HC pathogenesis was evaluated using human tissues, molecular and cell biology, and animal models, and its prognostic significance was determined according to its impact on patient survival.

Results

We found that expression of hexokinase 1 and the M2 splice isoform of PK (PKM2) was upregulated in HC tissues and that this expression correlated with tumor recurrence and outcome. PKM2 expression was increased in HC cases with chronic cholangitis as demonstrated by isobaric tags for relative and absolute quantification. High PKM2 expression was highly correlated with high syndecan 2 (SDC2) expression and neural invasion. PKM2 downregulation led to a decrease in SDC2 expression. Treatment with metformin markedly suppressed PKM2 and SDC2 expression at both the transcriptional and posttranscriptional levels and inhibited HC cell proliferation and tumor growth.

Conclusions

PKM2 regulates neural invasion of HC cells at least in part via regulation of SDC2. Inhibition of PKM2 and SDC2 expression contributes to the therapeutic effect of metformin on HC. Therefore, PKM2 is an independent prognostic factor and potential therapeutic target for human HC.
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Literature
1.
Soares KC, Kamel I, Cosgrove DP, Herman JM, Pawlik TM. Hilar cholangiocarcinoma: diagnosis, treatment options, and management. Hepatobil Surg Nutr. 2014;3(1):18–34.
2.
Berardi R, Mocchegiani F, Pierantoni C, Federici A, Nicolini D, Morgese F, et al. Resected biliary tract cancers: a novel clinical-pathological score correlates with global outcome. Dig Liver Dis. 2013;45(1):70–4.CrossRefPubMed
3.
Juntermanns B, Radunz S, Heuer M, Hertel S, Reis H, Neuhaus JP, et al. Tumor markers as a diagnostic key for hilar cholangiocarcinoma. Eur J Med Res. 2010;15(8):357–61.PubMedCentralCrossRefPubMed
4.
Chen Y, Cha Z, Fang W, Qian B, Yu W, Li W, et al. The prognostic potential and oncogenic effects of PRR11 expression in hilar cholangiocarcinoma. Oncotarget. 2015;6(24):20419–33.CrossRefPubMed
5.
Bensinger SJ, Christofk HR. New aspects of the Warburg effect in cancer cell biology. Semin Cell Dev Biol. 2012;23(4):352–61.CrossRefPubMed
6.
Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324(5930):1029–33.PubMedCentralCrossRefPubMed
7.
Altenberg B, Greulich KO. Genes of glycolysis are ubiquitously overexpressed in 24 cancer classes. Genomics. 2004;84(6):1014–20.CrossRefPubMed
8.
Patra KC, Wang Q, Bhaskar PT, Miller L, Wang Z, Wheaton W, et al. Hexokinase 2 is required for tumor initiation and maintenance and its systemic deletion is therapeutic in mouse models of cancer. Cancer Cell. 2013;24(2):213–28.PubMedCentralCrossRefPubMed
9.
Marini C, Salani B, Massollo M, Amaro A, Esposito A, Orengo AM, et al. Direct inhibition of hexokinase activity by metformin at least partially impairs glucose metabolism and tumor growth in experimental breast cancer. Cell Cycle. 2013;12(22):3490–9.PubMedCentralCrossRefPubMed
10.
Jiang L, Ren J, Xiao X, Tang YY, Weng HQ, Yang Q, et al. Proteomic analysis of bladder cancer by iTRAQ after Bifidobacterium infantis-mediated HSV-TK/GCV suicide gene treatment. Biol Chem. 2013;394(10):1333–42.CrossRefPubMed
11.
Iqbal MA, Gupta V, Gopinath P, Mazurek S, Bamezai RN. Pyruvate kinase M2 and cancer: an updated assessment. FEBS Lett. 2014;588(16):2685–92.CrossRefPubMed
12.
Wong N, Ojo D, Yan J, Tang D. PKM2 contributes to cancer metabolism. Cancer Lett. 2014;356(2 Pt A):184–91.PubMed
13.
Yun SJ, Jo SW, Ha YS, Lee OJ, Kim WT, Kim YJ, et al. PFKFB4 as a prognostic marker in non-muscle-invasive bladder cancer. Urol Oncol. 2012;30(6):893–9.CrossRefPubMed
14.
15.
Shen FZ, Zhang BY, Feng YJ, Jia ZX, An B, Liu CC, et al. Current research in perineural invasion of cholangiocarcinoma. J Exp Clin Cancer Res. 2010;29:24.PubMedCentralCrossRefPubMed
16.
Chen J, Zhang S, Li Y, Tang Z, Kong W. Hexokinase 2 overexpression promotes the proliferation and survival of laryngeal squamous cell carcinoma. Tumour Biol. 2014;35(4):3743–53.CrossRefPubMed
17.
Suh DH, Kim MA, Kim H, Kim MK, Kim HS, Chung HH, et al. Association of overexpression of hexokinase II with chemoresistance in epithelial ovarian cancer. Clin Exp Med. 2013;14(3):345–53.CrossRefPubMed
18.
Li J, Yang Z, Zou Q, Yuan Y, Li J, Liang L, et al. PKM2 and ACVR 1C are prognostic markers for poor prognosis of gallbladder cancer. Clin Transl Oncol. 2014;16(2):200–7.CrossRefPubMed
19.
Zhang X, He C, He C, Chen B, Liu Y, Kong M, et al. Nuclear PKM2 expression predicts poor prognosis in patients with esophageal squamous cell carcinoma. Pathol Res Pract. 2013;209(8):510–5.CrossRefPubMed
20.
Pastor MD, Nogal A, Molina-Pinelo S, Melendez R, Salinas A, Gonzalez De la Pena M, et al. Identification of proteomic signatures associated with lung cancer and COPD. J Proteomics. 2013;89:227–37.CrossRefPubMed
21.
Zhu Z, Kleeff J, Kayed H, Wang L, Korc M, Buchler MW, et al. Nerve growth factor and enhancement of proliferation, invasion, and tumorigenicity of pancreatic cancer cells. Mol Carcinog. 2002;35(3):138–47.CrossRefPubMed
22.
De Oliveira T, Abiatari I, Raulefs S, Sauliunaite D, Erkan M, Kong B, et al. Syndecan-2 promotes perineural invasion and cooperates with K-ras to induce an invasive pancreatic cancer cell phenotype. Mol Cancer. 2012;11:19.PubMedCentralCrossRefPubMed
23.
Wang K, Cao F, Fang W, Hu Y, Chen Y, Ding H, et al. Activation of SNAT1/SLC38A1 in human breast cancer: correlation with p-Akt overexpression. BMC Cancer. 2013;13:343.PubMedCentralCrossRefPubMed
24.
Wang F, Liu Y, Zhang H. Loss of MTSS1 expression is an independent prognostic factor for Hilar cholangiocarcinoma. Pathol Oncol Res. 2013;19(4):815–20.CrossRefPubMed
25.
Wang C, Yu G, Liu J, Wang J, Zhang Y, Zhang X, et al. Downregulation of PCDH9 predicts prognosis for patients with glioma. J Clin Neurosci. 2012;19(4):541–5.CrossRefPubMed
26.
Kim Y, Park H, Lim Y, Han I, Kwon HJ, Woods A, et al. Decreased syndecan-2 expression correlates with trichostatin-A induced-morphological changes and reduced tumorigenic activity in colon carcinoma cells. Oncogene. 2003;22(6):826–30.CrossRefPubMed
27.
Park H, Kim Y, Lim Y, Han I, Oh ES. Syndecan-2 mediates adhesion and proliferation of colon carcinoma cells. J Biol Chem. 2002;277(33):29730–6.CrossRefPubMed
28.
Huang X, Xiao DW, Xu LY, Zhong HJ, Liao LD, Xie ZF, et al. Prognostic significance of altered expression of SDC2 and CYR61 in esophageal squamous cell carcinoma. Oncol Rep. 2009;21(4):1123–9.PubMed
29.
Lee H, Kim Y, Choi Y, Choi S, Hong E, Oh ES. Syndecan-2 cytoplasmic domain regulates colon cancer cell migration via interaction with syntenin-1. Biochem Biophys Res Commun. 2011;409(1):148–53.CrossRefPubMed
30.
Choi S, Kim Y, Park H, Han IO, Chung E, Lee SY, et al. Syndecan-2 overexpression regulates adhesion and migration through cooperation with integrin alpha2. Biochem Biophys Res Commun. 2009;384(2):231–5.CrossRefPubMed
31.
Huang JW, Chen CL, Chuang NN. Trap RACK1 with Ras to mobilize Src signaling at syndecan-2/p120-GAP upon transformation with oncogenic ras. Biochem Biophys Res Commun. 2005;330(4):1087–94.CrossRefPubMed
32.
Mytilinaiou M, Bano A, Nikitovic D, Berdiaki A, Voudouri K, Kalogeraki A, et al. Syndecan-2 is a key regulator of transforming growth factor beta 2/Smad2-mediated adhesion in fibrosarcoma cells. IUBMB Life. 2013;65(2):134–43.CrossRefPubMed
33.
Chung H, Lee JH, Jeong D, Han IO, Oh ES. Melanocortin 1 receptor regulates melanoma cell migration by controlling syndecan-2 expression. J Biol Chem. 2012;287(23):19326–35.PubMedCentralCrossRefPubMed
34.
35.
Yu G, Fang W, Xia T, Chen Y, Gao Y, Jiao X, et al. Metformin potentiates rapamycin and cisplatin in gastric cancer in mice. Oncotarget. 2015;6(14):12748–62.PubMedCentralCrossRefPubMed
36.
Pierotti MA, Berrino F, Gariboldi M, Melani C, Mogavero A, Negri T, et al. Targeting metabolism for cancer treatment and prevention: metformin, an old drug with multi-faceted effects. Oncogene. 2013;32(12):1475–87.CrossRefPubMed
37.
Xue J, Lin X, Chiu WT, Chen YH, Yu G, Liu M, et al. Sustained activation of SMAD3/SMAD4 by FOXM1 promotes TGF-beta-dependent cancer metastasis. J Clin Invest. 2014;124(2):564–79.PubMedCentralCrossRefPubMed
38.
Fang W, Cui H, Yu D, Chen Y, Wang J, Yu G. Increased expression of phospho-acetyl-CoA carboxylase protein is an independent prognostic factor for human gastric cancer without lymph node metastasis. Med Oncol. 2014;31(7):15.CrossRefPubMed
39.
Jin GZ, Li Y, Cong WM, Yu H, Dong H, Shu H, et al. iTRAQ-2DLC-ESI-MS/MS based identification of a new set of immunohistochemical biomarkers for classification of dysplastic nodules and small hepatocellular carcinoma. J Proteome Res. 2011;10(8):3418–28.CrossRefPubMed
40.
Li L, Li Z, Kong X, Xie D, Jia Z, Jiang W, et al. Downregulation of MicroRNA 494 via Loss of SMAD4 Increases FOXM1 and betacatenin Signaling in Pancreatic Ductal Adenocarcinoma Cells. Gastroenterology. 2014;147(2):485–97.CrossRefPubMed
41.
Cui J, Shi M, Xie D, Wei D, Jia Z, Zheng S, et al. FOXM1 Promotes the Warburg Effect and Pancreatic Cancer Progression via Transactivation of LDHA Expression. Clin Cancer Res. 2014;20(10):2595–606.PubMedCentralCrossRefPubMed
42.
Zhang N, Wei P, Gong A, Chiu WT, Lee HT, Colman H, et al. FoxM1 promotes beta-catenin nuclear localization and controls Wnt target-gene expression and glioma tumorigenesis. Cancer Cell. 2011;20(4):427–42.PubMedCentralCrossRefPubMed
43.
Huang C, Qiu Z, Wang L, Peng Z, Jia Z, Logsdon CD, et al. A novel FoxM1-caveolin signaling pathway promotes pancreatic cancer invasion and metastasis. Cancer Res. 2012;72(3):655–65.PubMedCentralCrossRefPubMed
44.
Quan M, Cui J, Xia T, Jia Z, Xie D, Wei D, et al. Merlin/NF2 Suppresses Pancreatic Tumor Growth and Metastasis by Attenuating the FOXM1-Mediated Wnt/β-Catenin Signaling. Cancer Res. 2015 Oct 19. [Epub ahead of print] PubMed PMID: 26483206.
45.
Xie D, Cui J, Xia T, Jia Z, Wang L, Wei W, et al. Hippo transducer TAZ promotes epithelial mesenchymal transition and supports pancreatic cancer progression. Oncotarget. 2015 Sep 21. [Epub ahead of print] PubMed PMID: 26416426.
Metadata
Title
PKM2 regulates neural invasion of and predicts poor prognosis for human hilar cholangiocarcinoma
Authors
Guanzhen Yu
Wenlong Yu
Guangzhi Jin
Dongyun Xu
Ying Chen
Tian Xia
Allan Yu
Wenzheng Fang
Xiaoli Zhang
Zhaosheng Li
Keping Xie
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2015
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/s12943-015-0462-6

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