Monocarboxylate Transporter 1 (MCT1) is an independent prognostic biomarker in endometrial cancer
Tóm tắt
Endometrial cancer (EC) is a major health concern due to its rising incidence. Whilst early stage disease is generally cured by surgery, advanced EC has a poor prognosis with limited treatment options. Altered energy metabolism is a hallmark of malignancy. Cancer cells drive tumour growth through aerobic glycolysis and must export lactate to maintain intracellular pH. The aim of this study was to evaluate the expression of the lactate/proton monocarboxylate transporters MCT1 and MCT4 and their chaperone CD147 in EC, with the ultimate aim of directing future drug development. MCT1, MCT4 and CD147 expression was examined using immunohistochemical analysis in 90 endometrial tumours and correlated with clinico-pathological characteristics and survival outcomes. MCT1 and MCT4 expression was observed in the cytoplasm, the plasma membrane or both locations. CD147 was detected in the plasma membrane and associated with MCT1 (p = 0.003) but not with MCT4 (p = 0.207) expression. High MCT1 expression was associated with reduced overall survival (p = 0.029) and remained statistically significant after adjustment for survival covariates (p = 0.017). Our data suggest that MCT1 expression is an important marker of poor prognosis in EC. MCT1 inhibition may have potential as a treatment for advanced or recurrent EC.
Tài liệu tham khảo
Cancer Research UK Statistics. http://www.cancerresearchuk.org/health-professional/cancer-statistics.
Thigpen JT, Brady MF, Alvarez MD, Adelson RD, Homesley HD, Manetta A, et al. Oral medroxyprogesterone acetate in the treatment of advanced or recurrent endometrial carcinoma: a dose-response study by the gynecologic oncology group. J Clin Oncol. 1999;17:1736–44.
Ma BB, Oza A, Eisenhauer E, Stanimir G, Carey M, Chapman W, et al. The activity of letrozole in patients with advanced or recurrent endometrial cancer and correlation with biological markers--a study of the National Cancer Institute of Canada clinical trials group. Int J Gynecol Cancer. 2004;14:650–8.
Bellone S, Shah HR, McKenney JK, Stone PJ, Santin AD. Recurrent endometrial carcinoma regression with the use of the aromatase inhibitor anastrozole. Am J Obstet Gynecol. 2008;199:e7–e10.
Friberg E, Orsini N, Mantzoros CS, Wolk A. Diabetes mellitus and risk of endometrial cancer: a meta-analysis. Diabetologia. 2007;50:1365–74.
Crosbie EJ, Zwahlen M, Kitchener HC, Egger M, Renehan AG. Body mass index, hormone replacement therapy, and endometrial cancer risk: a meta-analysis. Cancer Epidemiol Biomark Prev. 2010;19:3119–30.
Renehan AG, Tyson M, Egger M, Heller RF, Zwahlen M. Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet. 2008;371:569–78.
Algire C, Amrein L, Zakikhani M, Panasci L, Pollak M. Metformin blocks the stimulative effect of a high-energy diet on colon carcinoma growth in vivo and is associated with reduced expression of fatty acid synthase. Endocr Relat Cancer. 2010;17:351–60.
Warburg O, Wind F, Negelein E. The metabolism of tumors in the body. J Gen Physiol. 1927;8:519–30.
Halestrap AP. The SLC16 gene family - structure, role and regulation in health and disease. Mol Asp Med. 2013;34:337–49.
Halestrap AP, Price NT. The proton-linked monocarboxylate transporter (MCT) family: structure, function and regulation. Biochem J. 1999;343:281–99.
Nakayama Y, Torigoe T, Inoue Y, Minagawa N, Izumi H, Kohno K, et al. Prognostic significance of monocarboxylate transporter 4 expression in patients with colorectal cancer. Exp Ther Med. 2012;3:25–30.
Pinheiro C, Longatto-Filho A, Scapulatempo C, Ferreira L, Martins S, Pellerin L, et al. Increased expression of monocarboxylate transporters 1, 2, and 4 in colorectal carcinomas. Virchows Arch. 2008;452:139–46.
Pinheiro C, Longatto-Filho A, Pereira SM, Etlinger D, Moreira MA, Jube LF, et al. Monocarboxylate transporters 1 and 4 are associated with CD147 in cervical carcinoma. Dis Markers. 2009;26:97–103.
Pinheiro C, Albergaria A, Paredes J, Sousa B, Dufloth R, Vieira D, et al. Monocarboxylate transporter 1 is up-regulated in basal-like breast carcinoma. Histopathology. 2010;56:860–7.
Doyen J, Trastour C, Ettore F, Peyrottes I, Toussant N, Gal J, et al. Expression of the hypoxia-inducible monocarboxylate transporter MCT4 is increased in triple negative breast cancer and correlates independently with clinical outcome. Biochem Biophys Res Commun. 2014;451:54–61.
Pertega-Gomes N, Vizcaino JR, Miranda-Goncalves V, Pinheiro C, Silva J, Pereira H, et al. Monocarboxylate transporter 4 (MCT4) and CD147 overexpression is associated with poor prognosis in prostate cancer. BMC Cancer. 2011;11:312.
Froberg MK, Gerhart DZ, Enerson BE, Manivel C, Guzman-Paz M, Seacotte N, et al. Expression of monocarboxylate transporter MCT1 in normal and neoplastic human CNS tissues. Neuroreport. 2001;12:761–5.
Miranda-Goncalves V, Honavar M, Pinheiro C, Martinho O, Pires MM, Pinheiro C, et al. Monocarboxylate transporters (MCTs) in gliomas: expression and exploitation as therapeutic targets. Neuro-Oncology. 2013;15:172–88.
Pinheiro C, Penna V, Morais-Santos F, Abrahao-Machado LF, Ribeiro G, Curcelli EC, et al. Characterization of monocarboxylate transporters (MCTs) expression in soft tissue sarcomas: distinct prognostic impact of MCT1 sub-cellular localization. J Transl Med. 2014;12:118.
Pinheiro C, Longatto-Filho A, Simoes K, Jacob CE, Bresciani CJ, Zilberstein B, et al. The prognostic value of CD147/EMMPRIN is associated with monocarboxylate transporter 1 co-expression in gastric cancer. Eur J Cancer. 2009;45:2418–24.
de Oliveira AT, Pinheiro C, Longatto-Filho A, Brito MJ, Martinho O, Matos D, et al. Co-expression of monocarboxylate transporter 1 (MCT1) and its chaperone (CD147) is associated with low survival in patients with gastrointestinal stromal tumors (GISTs). J Bioenerg Biomembr. 2012;44:171–8.
Simoes-Sousa S, Granja S, Pinheiro C, Fernandes D, Longatto-Filho A, Laus AC, et al. Prognostic significance of monocarboxylate transporter expression in oral cavity tumors. Cell Cycle. 2016;15:1865–73.
Choi JW, Kim Y, Lee JH, Kim YS. Prognostic significance of lactate/proton symporters MCT1, MCT4, and their chaperone CD147 expressions in urothelial carcinoma of the bladder. Urology. 2014;84:245.e249–15.
Eilertsen M, Andersen S, Al-Saad S, Kiselev Y, Donnem T, Stenvold H, et al. Monocarboxylate transporters 1-4 in NSCLC: MCT1 is an independent prognostic marker for survival. PLoS One. 2014;9:e105038.
Kirk P, Wilson MC, Heddle C, Brown MH, Barclay AN, Halestrap AP. CD147 is tightly associated with lactate transporters MCT1 and MCT4 and facilitates their cell surface expression. EMBO. 2000;19:3896–904.
Wilson MC, Meredith D, Fox JE, Manoharan C, Davies AJ, Halestrap AP. Basigin (CD147) is the target for organomercurial inhibition of monocarboxylate transporter isoforms 1 and 4: the ancillary protein for the insensitive MCT2 is EMBIGIN (gp70). J Biol Chem. 2005;280:27213–21.
Deora AA, Philp N, Hu J, Bok D, Rodriguez-Boulan E. Mechanisms regulating tissue-specific polarity of monocarboxylate transporters and their chaperone CD147 in kidney and retinal epithelia. Proc Natl Acad Sci U S A. 2005;102:16245–50.
Gabison EE, Hoang-Xuan T, Mauviel A, Menashi S. EMMPRIN/CD147, an MMP modulator in cancer, development and tissue repair. Biochimie. 2005;87:361–8.
Nabeshima K, Iwasaki H, Koga K, Hojo H, Suzumiya J, Kikuchi M. Emmprin (basigin/CD147): matrix metalloproteinase modulator and multifunctional cell recognition molecule that plays a critical role in cancer progression. Pathol Int. 2006;56:359–67.
Riethdorf S, Reimers N, Assmann V, Kornfield JW, Terracciano L, Sauter G. High incidence of EMMPRIN expression in human tumors. Int J Cancer. 2006;119:1800–10.
Gallagher SM, Castorino JJ, Wang D, Philp NJ. Monocarboxylate transporter 4 regulates maturation and trafficking of CD147 to the plasma membrane in the metastatic breast cancer cell line MDA-MB-231. Cancer Res. 2007;67:4182–9.
Nakamura K, Kodama J, Hongo A, Hiramatsu Y. Role of emmprin in endometrial cancer. BMC Cancer. 2012;12:191.
Kim Y, Choi JW, Lee JH, Kim YS. Expression of lactate/H(+) symporters MCT1 and MCT4 and their chaperone CD147 predicts tumor progression in clear cell renal cell carcinoma: immunohistochemical and the cancer genome atlas data analyses. Hum Pathol. 2015;46:104–12.
Gatenby RA, Gillies RJ. Why do cancers have high aerobic glycolysis? Nat Rev Cancer. 2004;4:891–9.
Bovenzi CD, Hamilton J, Tassone P, Johnson J, Cognetti DM, Luginbuhi A, et al. Prognostic indications of elevated MCT4 and CD147 across cancer types: a meta-analysis. Biomed Res Int. 2015;2015:242437.
Hashimoto T, Hussien R, Brooks GA. Colocalization of MCT1, CD147, and LDH in mitochondrial inner membrane of L6 muscle cells: evidence of a mitochondrial lactate oxidation complex. American J Physiol Endocrinol Metab. 2006;290:E1237–44.
Hussien R, Brooks GA. Mitochondrial and plasma membrane lactate transporter and lactate dehydrogenase isoform expression in breast cancer cell lines. Physiol Genomics. 2011;43:255–64.
Koukourakis MI, Giatromanolaki A, Bougioukas G, Sivridis E. Lung cancer: a comparative study of metabolism related protein expression in cancer cells and tumor associated stroma. Cancer Biol Ther. 2007;6:1476–9.
Pinheiro C, Reis RM, Ricardo S, Longatto-Filho A, Schmitt F, Baltazar F. Expression of monocarboxylate transporters 1, 2, and 4 in human tumours and their association with CD147 and CD44. J Biomed Biotechnol. 2010;2010:427694.
Pinheiro C, Longatto-Filho A, Azevedo-Silva J, Casal M, Schmitt FC, Baltazar F. Role of monocarboxylate transporters in human cancers: state of the art. J Bioenerg Biomembr. 2012;44:127–39.
Sonveaux P, Vegran F, Schroeder T, Wergin MC, Verrax J, Rabbani ZN, et al. Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. J Clin Invest. 2008;118:3930–42.
Afonso J, Santos LL, Morais A, Amaro T, Longatto-Filho A, Baltazar F. Metabolic coupling in urothelial bladder cancer compartments and its correlation to tumor aggressiveness. Cell Cycle. 2016;15:368–80.
Curry JM, Tuluc M, Whitaker-Menezes D, Ames JA, Anantharaman A, Butera A, et al. Cancer metabolism, stemness and tumor recurrence: MCT1 and MCT4 are functional biomarkers of metabolic symbiosis in head and neck cancer. Cell Cycle. 2013;12:1371–84.
Marchiq I, Le Floch R, Roux D, Simon MP, Pouyssegur J. Genetic disruption of lactate/H+ symporters (MCTs) and their subunit CD147/BASIGIN sensitizes glycolytic tumor cells to phenformin. Cancer Res. 2015;75:171–80.
Slomiany MG, Grass GD, Robertson AD, Yang XY, Maria BL, Beeson C, et al. Hyaluronan, CD44, and emmprin regulate lactate efflux and membrane localization of monocarboxylate transporters in human breast carcinoma cells. Cancer Res. 2009;69:1293–301.