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

Abstract

BackgroundThe 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.MethodsThe 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.ResultsWe 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.ConclusionsPKM2 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-015-0462-6) contains supplementary material, which is available to authorized users.

Emerging roles of syndecan 2 in epithelial and mesenchymal cancer progression

“…On the other hand, Hrabar et al report a positive correlation of epithelial SDC2 expression with patient survival in pancreatic cancer . The upregulation of SDC2 expression via glycolytic enzyme M2 splice isoform of PK (PKM2) is associated with enhanced neural invasion and poor prognosis in the case of hilar cholangiocarcinoma . SDC2 stromal expression is likewise important in head and neck squamous cell carcinoma.…”

Metabolism in cancer metastasis: bioenergetics, biosynthesis, and beyond

“…The embryonic isoform of pyruvate kinase, pyruvate kinase isozyme M2 (PKM2), has also been associated with tumor development and metastasis. Upregulation of PKM2 in patients with colorectal and pancreatic tumors is associated with late tumor stage and metastasis, and elevated PKM2 levels predict poor prognosis in gallbladder cancer, hepatocellular carcinoma, and human hilar cholangiocarcinoma . PKM2 is also present in the plasma of gastric and colorectal cancer patients, with increased levels in late stage and in metastatic patients .…”

LIM and SH3 Protein 1 Stands for a Bio-Marker for Cholangiocarcinoma Detection

“…Nowadays, more and more speci c biological markers were studied which play important roles in the detection and treatment of patients with different cancer types, including CCA [22][23][24][25][26][27][28]. Kawin Leelawat et al measured the level of CEA, CA19-9, MMP-7 and MMP-9 in the serum of cholangiocarcinoma and benign biliary tract diseases patients and found only the serum MMP-7 appears to be a valuable diagnostic marker in the discrimination of CCA from benign biliary tract disease [25].…”

“…Zhang et al pointed that the biology of calretinin and CK5/6 expression in CCA is unclear but calretinin and CK5/6 immunohistochemical stains may be useful for diagnosing a CCA [26]. Yu et al determined the expression of PKM2 in and its impact on biology and clinical outcome of human hilar cholangiocarcinoma (HC), and pointed that PKM2 is an independent prognostic factor and potential therapeutic target for human HC [27]. In recent years, serum tumor markers have been the objects of extensive investigation to assist CCA diagnosis because of the easy obtaining samples and relatively low cost.…”