title: Pyruvate Kinase M2 and Lactate Dehydrogenase A Are Overexpressed in Pancreatic Cancer and Correlate with Poor Outcome.
abstract: Pancreatic cancer has a 5-year survival rate of less than 4%. Despite advances in diagnostic technology, pancreatic cancer continues to be diagnosed at a late and incurable stage. Accurate biomarkers for early diagnosis and to predict treatment response are urgently needed. Since alteration of glucose metabolism is one of the hallmarks of cancer cells, we proposed that pyruvate kinase type M2 (M2PK) and lactate dehydrogenase A (LDHA) enzymes could represent novel diagnostic markers and potential therapeutic targets in pancreatic cancer. In 266 tissue sections from normal pancreas, pancreatic cystic neoplasms, pancreatic intraepithelial neoplasia (PanIN) and cancer, we evaluated the expression of PKM2, LDHA, Ki-67 and CD8+ by immunohistochemistry and correlated these markers with clinicopathological characteristics and patient survival. PKM2 and LDHA expression was also assessed by Western blot in 10 human pancreatic cancer cell lines. PKM2 expression increased progressively from cyst through PanIN to cancer, whereas LDHA was overexpressed throughout the carcinogenic process. All but one cell line showed high expression of both proteins. Patients with strong PKM2 and LDHA expression had significantly worse survival than those with weak PKM2 and/or LDHA expression (7.0 months vs. 27.9 months, respectively, p = 0.003, log rank test). The expression of both PKM2 and LDHA correlated directly with Ki-67 expression, and inversely with intratumoral CD8+ cell count. PKM2 was significantly overexpressed in poorly differentiated tumours and both PKM2 and LDHA were overexpressed in larger tumours. Multivariable analysis showed that combined expression of PKM2 and LDHA was an independent poor prognostic marker for survival. In conclusion, our results demonstrate a high expression pattern of two major glycolytic enzymes during pancreatic carcinogenesis, with increased expression in aggressive tumours and a significant adverse effect on survival.
authors.affiliation: UCL Institute for Liver and Digestive Health, Royal Free Hospital Campus, University College London, London, United Kingdom.|Chemistry Department, School of Science, University of Sulaimani, Sulaimanyah, Kurdistan Region, Iraq.
authors.forename: Goran Hamid
authors.initials: GH
authors.lastname: Mohammad
authors.affiliation: UCL Institute for Liver and Digestive Health, Royal Free Hospital Campus, University College London, London, United Kingdom.|Department of Surgery, Maastricht University Medical Centre, Maastricht, the Netherlands.
authors.forename: S W M
authors.initials: SW
authors.lastname: Olde Damink
authors.affiliation: UCL Institute for Liver and Digestive Health, Royal Free Hospital Campus, University College London, London, United Kingdom.
authors.forename: Massimo
authors.initials: M
authors.lastname: Malago
authors.affiliation: UCL Institute for Liver and Digestive Health, Royal Free Hospital Campus, University College London, London, United Kingdom.|King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors.forename: Dipok Kumar
authors.initials: DK
authors.lastname: Dhar
authors.affiliation: UCL Institute for Liver and Digestive Health, Royal Free Hospital Campus, University College London, London, United Kingdom.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Pereira
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor; D018414:CD8-Positive T-Lymphocytes; D021441:Carcinoma, Pancreatic Ductal / Q000175:diagnosis / Q000401:mortality / Q000473:pathology*; D045744:Cell Line, Tumor; D055088:Early Detection of Cancer / Q000379:methods*; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006019:Glycolysis / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000096:biosynthesis; D019394:Ki-67 Antigen / Q000096:biosynthesis; D007770:L-Lactate Dehydrogenase / Q000096:biosynthesis*; D000080864:Lactate Dehydrogenase 5; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D010179:Pancreas / Q000201:enzymology / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000175:diagnosis / Q000401:mortality / Q000473:pathology*; D011379:Prognosis; D011770:Pyruvate Kinase / Q000096:biosynthesis*; D015996:Survival Rate
chemical_list: D014408:Biomarkers, Tumor; D007527:Isoenzymes; D019394:Ki-67 Antigen; D007770:L-Lactate Dehydrogenase; D000080864:Lactate Dehydrogenase 5; D011770:Pyruvate Kinase