Abstract
Purpose
Previous studies have demonstrated that monocarboxylate transporters (MCTs) play important roles in the development and progression of many cancers. The purpose of this study was to assess the effects of single-nucleotide polymorphisms (SNPs) of MCT genes on prognosis of colorectal cancer (CRC) patients.
Patients and methods
Nine functional SNPs in three MCT genes (MCT1, MCT2 and MCT4) were selected and genotyped using Sequenom iPLEX genotyping system in 697 Chinese CRC patients receiving surgery. Multivariate Cox proportional hazards model and Kaplan–Meier curve were used for the prognostic analysis.
Results
One SNP (MCT1: rs1049434/exon) was significantly associated with overall survival of CRC patients (HR 0.74; P = 0.046). Two other SNPs (MCT1: rs60844753/5′ near gene and MCT2: rs995343/intron) exhibited associations with recurrence-free survival of CRC patients (HR 0.67; P = 0.078 and HR 0.74; P = 0.036, respectively). Our study also showed that MCT1 rs1049434, rs60844753 and MCT2 rs995343 SNPs had a cumulative effect on CRC recurrence-free survival (P for trend 0.011). Those who carrying three unfavorable genotypes (WW for all SNPs) had a 2.06-fold increased risk of recurrence compared with patients carrying no unfavorable genotypes (P = 0.016). Moreover, we found that patients carrying no <2 risk genotypes showed significant OS and RFS benefits from adjuvant chemotherapy.
Conclusions
Our findings suggest that SNPs in MCT1 and MCT2 genes may affect clinical outcomes and can be used to predict the response to adjuvant chemotherapy in CRC patients who received surgical treatment once validated in future study.
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References
Boidot R et al (2012) Regulation of monocarboxylate transporter MCT1 expression by p53 mediates inward and outward lactate fluxes in tumors. Cancer Res 72:939–948. doi:10.1158/0008-5472.CAN-11-2474
Broer S, Broer A, Schneider HP, Stegen C, Halestrap AP, Deitmer JW (1999) Characterization of the high-affinity monocarboxylate transporter MCT2 in Xenopus laevis oocytes. Biochem J 341(Pt 3):529–535
Cupeiro R, Benito PJ, Maffulli N, Calderon FJ, Gonzalez-Lamuno D (2010) MCT1 genetic polymorphism influence in high intensity circuit training: a pilot study. J Sci Med Sport 13:526–530. doi:10.1016/j.jsams.2009.07.004
Cupeiro R, Gonzalez-Lamuno D, Amigo T, Peinado AB, Ruiz JR, Ortega FB, Benito PJ (2012) Influence of the MCT1-T1470A polymorphism (rs1049434) on blood lactate accumulation during different circuit weight trainings in men and women. J Sci Med Sport 15:541–547. doi:10.1016/j.jsams.2012.03.009
Diers AR, Broniowska KA, Chang CF, Hogg N (2012) Pyruvate fuels mitochondrial respiration and proliferation of breast cancer cells: effect of monocarboxylate transporter inhibition. Biochem J 444:561–571. doi:10.1042/BJ20120294
Dimmer KS, Friedrich B, Lang F, Deitmer JW, Broer S (2000) The low-affinity monocarboxylate transporter MCT4 is adapted to the export of lactate in highly glycolytic cells. Biochem J 350(Pt 1):219–227
Dufau I et al (2012) Multicellular tumor spheroid model to evaluate spatio-temporal dynamics effect of chemotherapeutics: application to the gemcitabine/CHK1 inhibitor combination in pancreatic cancer. BMC Cancer 12:15. doi:10.1186/1471-2407-12-15
Elf SE, Chen J (2014) Targeting glucose metabolism in patients with cancer. Cancer 120:774–780. doi:10.1002/cncr.28501
Gerlinger M et al (2012) Genome-wide RNA interference analysis of renal carcinoma survival regulators identifies MCT4 as a Warburg effect metabolic target. J Pathol 227:146–156. doi:10.1002/path.4006
Gullino PM, Clark SH, Grantham FH (1964) The interstitial fluid of solid tumors. Cancer Res 24:780–797
Halestrap AP (2013) The SLC16 gene family–structure, role and regulation in health and disease. Mol Aspects Med 34:337–349. doi:10.1016/j.mam.2012.05.003
Halestrap AP, Meredith D (2004) The SLC16 gene family-from monocarboxylate transporters (MCTs) to aromatic amino acid transporters and beyond. Pflugers Arch 447:619–628. doi:10.1007/s00424-003-1067-2
Halestrap AP, Price NT (1999) The proton-linked monocarboxylate transporter (MCT) family: structure, function and regulation. Biochem J 343(Pt 2):281–299
Izumi H et al (2003) Cellular pH regulators: potentially promising molecular targets for cancer chemotherapy. Cancer Treat Rev 29:541–549
Izumi H et al (2011) Monocarboxylate transporters 1 and 4 are involved in the invasion activity of human lung cancer cells. Cancer Sci 102:1007–1013. doi:10.1111/j.1349-7006.2011.01908.x
Lean CB, Lee EJ (2009) Genetic variations in the MCT1 (SLC16A1) gene in the Chinese population of Singapore. Drug Metab Pharmacokinet 24:469–474
Lee I, Lee SJ, Kang WK, Park C (2012) Inhibition of monocarboxylate transporter 2 induces senescence-associated mitochondrial dysfunction and suppresses progression of colorectal malignancies in vivo. Mol Cancer Ther 11:2342–2351. doi:10.1158/1535-7163.MCT-12-0488
Li Q, Du J, Guan P, Du J, Qu CF, Dai M (2012) Estimation and prediction of incidence, mortality and prevalence on liver cancer, in 2008, China. Zhonghua Liu Xing Bing Xue Za Zhi 33:554–557
Manning Fox JE, Meredith D, Halestrap AP (2000) Characterisation of human monocarboxylate transporter 4 substantiates its role in lactic acid efflux from skeletal muscle. J Physiol 529(Pt 2):285–293
Markowitz SD, Bertagnolli MM (2009) Molecular origins of cancer: molecular basis of colorectal cancer. N Engl J Med 361:2449–2460. doi:10.1056/NEJMra0804588
Michaelidou K, Tzovaras A, Missitzis I, Ardavanis A, Scorilas A (2013) The expression of the CEACAM19 gene, a novel member of the CEA family, is associated with breast cancer progression. Int J Oncol 42:1770–1777. doi:10.3892/ijo.2013.1860
Miranda-Goncalves V et al (2013) Monocarboxylate transporters (MCTs) in gliomas: expression and exploitation as therapeutic targets. Neuro-oncology 15:172–188. doi:10.1093/neuonc/nos298
Nakayama Y, Torigoe T, Inoue Y, Minagawa N, Izumi H, Kohno K, Yamaguchi K (2012) Prognostic significance of monocarboxylate transporter 4 expression in patients with colorectal cancer. Exp Ther Med 3:25–30. doi:10.3892/etm.2011.361
Pertega-Gomes N, Baltazar F (2014) Lactate transporters in the context of prostate cancer metabolism: What do we know? Int J Mol Sci 15:18333–18348. doi:10.3390/ijms151018333
Pertega-Gomes N et al (2011) Monocarboxylate transporter 4 (MCT4) and CD147 overexpression is associated with poor prognosis in prostate cancer. BMC Cancer 11:312. doi:10.1186/1471-2407-11-312
Pertega-Gomes N, Vizcaino JR, Attig J, Jurmeister S, Lopes C, Baltazar F (2014) A lactate shuttle system between tumour and stromal cells is associated with poor prognosis in prostate cancer. BMC Cancer 14:352. doi:10.1186/1471-2407-14-352
Pinheiro C et al (2008) Increased expression of monocarboxylate transporters 1, 2, and 4 in colorectal carcinomas. Virchows Arch Int J Pathol 452:139–146. doi:10.1007/s00428-007-0558-5
Pinheiro C et al (2010) Monocarboxylate transporter 1 is up-regulated in basal-like breast carcinoma. Histopathology 56:860–867. doi:10.1111/j.1365-2559.2010.03560.x
Pinheiro C et al (2011) GLUT1 and CAIX expression profiles in breast cancer correlate with adverse prognostic factors and MCT1 overexpression. Histol Histopathol 26:1279–1286
Ritzhaupt A, Ellis A, Hosie KB, Shirazi-Beechey SP (1998) The characterization of butyrate transport across pig and human colonic luminal membrane. J Physiol 507(Pt 3):819–830
Sanita P et al (2014) Tumor–stroma metabolic relationship based on lactate shuttle can sustain prostate cancer progression. BMC Cancer 14:154. doi:10.1186/1471-2407-14-154
Shastry BS (2009) SNPs: impact on gene function and phenotype. Methods Mol Biol 578:3–22. doi:10.1007/978-1-60327-411-1_1
Su J, Chen X, Kanekura T (2009) A CD147-targeting siRNA inhibits the proliferation, invasiveness, and VEGF production of human malignant melanoma cells by down-regulating glycolysis. Cancer Lett 273:140–147. doi:10.1016/j.canlet.2008.07.034
Ulrich CM, Robien K, McLeod HL (2003) Cancer pharmacogenetics: polymorphisms, pathways and beyond. Nat Rev Cancer 3:912–920. doi:10.1038/nrc1233
Vegran F, Boidot R, Michiels C, Sonveaux P, Feron O (2011) Lactate influx through the endothelial cell monocarboxylate transporter MCT1 supports an NF-kappaB/IL-8 pathway that drives tumor angiogenesis. Cancer Res 71:2550–2560. doi:10.1158/0008-5472.CAN-10-2828
Zhu J et al (2014) Monocarboxylate transporter 4 facilitates cell proliferation and migration and is associated with poor prognosis in oral squamous cell carcinoma patients. PLoS One 9:e87904. doi:10.1371/journal.pone.0087904
Acknowledgments
This work was supported by Program for National Natural Science Foundation of China (81272275); Projects of International Cooperation and Exchanges NSFC (2013DFA32110).
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Fei Fei and Xu Guo have contributed equally to this work.
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Fei, F., Guo, X., Chen, Y. et al. Polymorphisms of monocarboxylate transporter genes are associated with clinical outcomes in patients with colorectal cancer. J Cancer Res Clin Oncol 141, 1095–1102 (2015). https://doi.org/10.1007/s00432-014-1877-y
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DOI: https://doi.org/10.1007/s00432-014-1877-y