Skip to main content
Top
Published in: World Journal of Surgical Oncology 1/2014

Open Access 01-12-2014 | Research

Overexpression of lactate dehydrogenase-A in human intrahepatic cholangiocarcinoma: its implication for treatment

Authors: Yaping Yu, Minqi Liao, Ruiwen Liu, Jian Chen, Hao Feng, Zan Fu

Published in: World Journal of Surgical Oncology | Issue 1/2014

Login to get access

Abstract

Background

Previous studies have shown that lactate dehydrogenase-A (LDH-A) is strongly expressed in several malignancies, that LDH-A expression is associated with poor prognosis, and that LDH-A inhibition severely diminishes tumorigenicity. However, little is known about the implications of LDH-A expression in intrahepatic cholangiocarcinoma. The purpose of this study was to investigate the expression of LDH-A and to clarify its effect on intrahepatic cholangiocarcinoma.

Methods

We studied the expression of LDH-A in tissue samples from patients with intrahepatic cholangiocarcinoma (n = 54) using the ultrasensitive surfactant protein (S-P) immunohistochemical method. We then inhibited LDH-A using small hairpin RNA (shRNA) in the cholangiocarcinoma cell line HuCCT-1 in vitro to study the role it plays in promoting growth and escaping apoptosis.

Results

We report that LDH-A was overexpressed in 52 of 54 (96%) paraffin-embedded cancer tissue samples and 0 of 54 para-carcinoma tissue samples. Reduction of LDH-A by RNA interference (RNAi) inhibited cell growth and induced apoptosis in HuCCT-1 cells. This result correlated with the elevation of cytoplasmic reactive oxygen species (ROS) levels.

Conclusions

LDH-A expression is closely correlated with histopathological variables of intrahepatic cholangiocarcinoma, indicating that LDH-A may serve as a new treatment target.
Appendix
Available only for authorised users
Literature
2.
go back to reference Zhu AX, Meyerhardt JA, Blaszkowsky LS, Kambadakone AR, Muzikansky A, Zheng H, Clark JW, Abrams TA, Chan JA, Enzinger PC, Bhargava P, Kwak EL, Allen JN, Jain SR, Stuart K, Horgan K, Sheehan S, Fuchs CS, Ryan DP, Sahani DV: Efficacy and safety of gemcitabine, oxaliplatin, and bevacizumab in advanced biliary-tract cancers and correlation of changes in 18-fluorodeoxyglucose PET with clinical outcome: a phase 2 study. Lancet Oncol. 2010, 11: 48-54. 10.1016/S1470-2045(09)70333-X.CrossRefPubMed Zhu AX, Meyerhardt JA, Blaszkowsky LS, Kambadakone AR, Muzikansky A, Zheng H, Clark JW, Abrams TA, Chan JA, Enzinger PC, Bhargava P, Kwak EL, Allen JN, Jain SR, Stuart K, Horgan K, Sheehan S, Fuchs CS, Ryan DP, Sahani DV: Efficacy and safety of gemcitabine, oxaliplatin, and bevacizumab in advanced biliary-tract cancers and correlation of changes in 18-fluorodeoxyglucose PET with clinical outcome: a phase 2 study. Lancet Oncol. 2010, 11: 48-54. 10.1016/S1470-2045(09)70333-X.CrossRefPubMed
3.
go back to reference Valle J, Wasan H, Palmer DH, Cunningham D, Anthoney A, Maraveyas A, Madhusudan S, Iveson T, Hughes S, Pereira SP, Roughton M, Bridgewater J, ABC-02 Trial Investigators: Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010, 362: 1273-1281. 10.1056/NEJMoa0908721.CrossRefPubMed Valle J, Wasan H, Palmer DH, Cunningham D, Anthoney A, Maraveyas A, Madhusudan S, Iveson T, Hughes S, Pereira SP, Roughton M, Bridgewater J, ABC-02 Trial Investigators: Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010, 362: 1273-1281. 10.1056/NEJMoa0908721.CrossRefPubMed
4.
go back to reference Warburg O: On the origin of cancer cells. Science. 1956, 123: 309-314. 10.1126/science.123.3191.309.CrossRefPubMed Warburg O: On the origin of cancer cells. Science. 1956, 123: 309-314. 10.1126/science.123.3191.309.CrossRefPubMed
5.
go back to reference Granchi C, Bertini S, Macchia M, Minutolo F: Inhibitors of lactate dehydrogenase isoforms and their therapeutic potentials. Curr Med Chem. 2010, 17: 672-697. 10.2174/092986710790416263.CrossRefPubMed Granchi C, Bertini S, Macchia M, Minutolo F: Inhibitors of lactate dehydrogenase isoforms and their therapeutic potentials. Curr Med Chem. 2010, 17: 672-697. 10.2174/092986710790416263.CrossRefPubMed
6.
go back to reference Fantin VR, St-Pierre J, Leder P: Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance. Cancer Cell. 2006, 9: 425-434. 10.1016/j.ccr.2006.04.023.CrossRefPubMed Fantin VR, St-Pierre J, Leder P: Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance. Cancer Cell. 2006, 9: 425-434. 10.1016/j.ccr.2006.04.023.CrossRefPubMed
7.
go back to reference Papaconstantinou J, Colowick SP: The role of glycolysis in the growth of tumor cells. I. Effects of oxamic acid on the metabolism of Ehrlich ascites tumor cells in vitro. J Biol Chem. 1961, 236: 278-284.PubMed Papaconstantinou J, Colowick SP: The role of glycolysis in the growth of tumor cells. I. Effects of oxamic acid on the metabolism of Ehrlich ascites tumor cells in vitro. J Biol Chem. 1961, 236: 278-284.PubMed
8.
go back to reference Kayser G, Kassem A, Sienel W, Schulte-Uentrop L, Mattern D, Aumann K, Stickeler E, Werner M, Passlick B, zur Hausen A: Lactate-dehydrogenase 5 is overexpressed in non-small cell lung cancer and correlates with the expression of the transketolase-like protein 1. Diagn Pathol. 2010, 5: 22-10.1186/1746-1596-5-22.PubMedCentralCrossRefPubMed Kayser G, Kassem A, Sienel W, Schulte-Uentrop L, Mattern D, Aumann K, Stickeler E, Werner M, Passlick B, zur Hausen A: Lactate-dehydrogenase 5 is overexpressed in non-small cell lung cancer and correlates with the expression of the transketolase-like protein 1. Diagn Pathol. 2010, 5: 22-10.1186/1746-1596-5-22.PubMedCentralCrossRefPubMed
9.
go back to reference Koukourakis MI, Kontomanolis E, Giatromanolaki A, Sivridis E, Liberis V: Serum and tissue LDH levels in patients with breast/gynaecological cancer and benign diseases. Gynecol Obstet Invest. 2009, 67: 162-168. 10.1159/000183250.CrossRefPubMed Koukourakis MI, Kontomanolis E, Giatromanolaki A, Sivridis E, Liberis V: Serum and tissue LDH levels in patients with breast/gynaecological cancer and benign diseases. Gynecol Obstet Invest. 2009, 67: 162-168. 10.1159/000183250.CrossRefPubMed
10.
go back to reference Kolev Y, Uetake H, Takagi Y, Sugihara K: Lactate dehydrogenase-5 (LDH-5) expression in human gastric cancer: association with hypoxia-inducible factor (HIF-1alpha) pathway, angiogenic factors production and poor prognosis. Ann Surg Oncol. 2008, 15: 2336-2344. 10.1245/s10434-008-9955-5.CrossRefPubMed Kolev Y, Uetake H, Takagi Y, Sugihara K: Lactate dehydrogenase-5 (LDH-5) expression in human gastric cancer: association with hypoxia-inducible factor (HIF-1alpha) pathway, angiogenic factors production and poor prognosis. Ann Surg Oncol. 2008, 15: 2336-2344. 10.1245/s10434-008-9955-5.CrossRefPubMed
11.
go back to reference Orrenius S, Gogvadze V, Zhivotovsky B: Mitochondrial oxidative stress: implications for cell death. Annu Rev Pharmacol Toxicol. 2007, 47: 143-183. 10.1146/annurev.pharmtox.47.120505.105122.CrossRefPubMed Orrenius S, Gogvadze V, Zhivotovsky B: Mitochondrial oxidative stress: implications for cell death. Annu Rev Pharmacol Toxicol. 2007, 47: 143-183. 10.1146/annurev.pharmtox.47.120505.105122.CrossRefPubMed
12.
go back to reference Benhar M, Engelberg D, Levitzki A: ROS, stress-activated kinases and stress signaling in cancer. EMBO Rep. 2002, 3: 420-425. 10.1093/embo-reports/kvf094.PubMedCentralCrossRefPubMed Benhar M, Engelberg D, Levitzki A: ROS, stress-activated kinases and stress signaling in cancer. EMBO Rep. 2002, 3: 420-425. 10.1093/embo-reports/kvf094.PubMedCentralCrossRefPubMed
13.
go back to reference Fruehauf JP, Meyskens FL: Reactive oxygen species: A breath of life or death?. Clin Cancer Res. 2007, 13: 789-794. 10.1158/1078-0432.CCR-06-2082.CrossRefPubMed Fruehauf JP, Meyskens FL: Reactive oxygen species: A breath of life or death?. Clin Cancer Res. 2007, 13: 789-794. 10.1158/1078-0432.CCR-06-2082.CrossRefPubMed
14.
go back to reference Ruckenstuhl C, Buttner S, Carmona-Gutierrez D, Eisenberg T, Kroemer G, Sigrist SJ, Frohlich KU, Madeo F: The Warburg effect suppresses oxidative stress induced apoptosis in a yeast model for cancer. PLoS One. 2009, 4: e4592-10.1371/journal.pone.0004592.PubMedCentralCrossRefPubMed Ruckenstuhl C, Buttner S, Carmona-Gutierrez D, Eisenberg T, Kroemer G, Sigrist SJ, Frohlich KU, Madeo F: The Warburg effect suppresses oxidative stress induced apoptosis in a yeast model for cancer. PLoS One. 2009, 4: e4592-10.1371/journal.pone.0004592.PubMedCentralCrossRefPubMed
15.
go back to reference Koukourakis MI, Giatromanolaki A, Sivridis E, Gatter KC, Harris AL: Lactate dehydrogenase 5 expression in operable colorectal cancer: strong association with survival and activated vascular endothelial growth factor pathway–a report of the Tumour Angiogenesis Research Group. J Clin Oncol. 2006, 24: 4301-4308. 10.1200/JCO.2006.05.9501.CrossRefPubMed Koukourakis MI, Giatromanolaki A, Sivridis E, Gatter KC, Harris AL: Lactate dehydrogenase 5 expression in operable colorectal cancer: strong association with survival and activated vascular endothelial growth factor pathway–a report of the Tumour Angiogenesis Research Group. J Clin Oncol. 2006, 24: 4301-4308. 10.1200/JCO.2006.05.9501.CrossRefPubMed
16.
go back to reference Brand KA, Hermfisse U: Aerobic glycolysis by proliferating cells: a protective strategy against reactive oxygen species. FASEB J. 1997, 11: 388-395.PubMed Brand KA, Hermfisse U: Aerobic glycolysis by proliferating cells: a protective strategy against reactive oxygen species. FASEB J. 1997, 11: 388-395.PubMed
17.
go back to reference Wang AG, Yoon SY, Oh JH, Jeon YJ, Kim M, Kim JM, Byun SS, Yang JO, Kim JH, Kim DG, Yeom YI, Yoo HS, Kim YS, Kim NS: Identification of intrahepatic cholangiocarcinoma related genes by comparison with normal liver tissues using expressed sequence tags. Biochem Biophys Res Commun. 2006, 345: 1022-1032. 10.1016/j.bbrc.2006.04.175.CrossRefPubMed Wang AG, Yoon SY, Oh JH, Jeon YJ, Kim M, Kim JM, Byun SS, Yang JO, Kim JH, Kim DG, Yeom YI, Yoo HS, Kim YS, Kim NS: Identification of intrahepatic cholangiocarcinoma related genes by comparison with normal liver tissues using expressed sequence tags. Biochem Biophys Res Commun. 2006, 345: 1022-1032. 10.1016/j.bbrc.2006.04.175.CrossRefPubMed
18.
go back to reference Xie H, Valera VA, Merino MJ, Amato AM, Signoretti S, Linehan WM, Sukhatme VP, Seth P: LDH-A inhibition, a therapeutic strategy for treatment of hereditary leiomyomatosis and renal cell cancer. Mol Cancer Ther. 2009, 8: 626-635. 10.1158/1535-7163.MCT-08-1049.PubMedCentralCrossRefPubMed Xie H, Valera VA, Merino MJ, Amato AM, Signoretti S, Linehan WM, Sukhatme VP, Seth P: LDH-A inhibition, a therapeutic strategy for treatment of hereditary leiomyomatosis and renal cell cancer. Mol Cancer Ther. 2009, 8: 626-635. 10.1158/1535-7163.MCT-08-1049.PubMedCentralCrossRefPubMed
19.
go back to reference Vander HMG, Cantley LC, Thompson CB: Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009, 324: 1029-1033. 10.1126/science.1160809.CrossRef Vander HMG, Cantley LC, Thompson CB: Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009, 324: 1029-1033. 10.1126/science.1160809.CrossRef
20.
go back to reference Tennant DA, Duran RV, Gottlieb E, Madhok BM, Yeluri S, Perry SL, Hughes TA, Jayne DG: Targeting metabolic transformation for cancer therapy. Nat Rev Cancer. 2010, 10: 267-277. 10.1038/nrc2817.CrossRefPubMed Tennant DA, Duran RV, Gottlieb E, Madhok BM, Yeluri S, Perry SL, Hughes TA, Jayne DG: Targeting metabolic transformation for cancer therapy. Nat Rev Cancer. 2010, 10: 267-277. 10.1038/nrc2817.CrossRefPubMed
21.
go back to reference Madhok BM, Yeluri S, Perry SL, Hughes TA, Jayne DG: Targeting glucose metabolism: an emerging concept for anticancer therapy. Am J Clin Oncol. 2011, 34: 628-635. 10.1097/COC.0b013e3181e84dec.CrossRefPubMed Madhok BM, Yeluri S, Perry SL, Hughes TA, Jayne DG: Targeting glucose metabolism: an emerging concept for anticancer therapy. Am J Clin Oncol. 2011, 34: 628-635. 10.1097/COC.0b013e3181e84dec.CrossRefPubMed
22.
go back to reference Le A, Cooper CR, Gouw AM, Dinavahi R, Maitra A, Deck LM, Royer RE, Vander Jagt DL, Semenza GL, Dang CV: Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression. Proc Natl Acad Sci U S A. 2010, 107: 2037-2042. 10.1073/pnas.0914433107.PubMedCentralCrossRefPubMed Le A, Cooper CR, Gouw AM, Dinavahi R, Maitra A, Deck LM, Royer RE, Vander Jagt DL, Semenza GL, Dang CV: Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression. Proc Natl Acad Sci U S A. 2010, 107: 2037-2042. 10.1073/pnas.0914433107.PubMedCentralCrossRefPubMed
Metadata
Title
Overexpression of lactate dehydrogenase-A in human intrahepatic cholangiocarcinoma: its implication for treatment
Authors
Yaping Yu
Minqi Liao
Ruiwen Liu
Jian Chen
Hao Feng
Zan Fu
Publication date
01-12-2014
Publisher
BioMed Central
Published in
World Journal of Surgical Oncology / Issue 1/2014
Electronic ISSN: 1477-7819
DOI
https://doi.org/10.1186/1477-7819-12-78

Other articles of this Issue 1/2014

World Journal of Surgical Oncology 1/2014 Go to the issue