Abstract
There is increasing evidence that the Let-7 microRNA (miRNA) exerts an effect as a tumor suppressor by targeting the KRAS mRNA. The Let-7 complementary site (LCS6) T>G variant in the KRAS 3′-untranslated region weakens Let-7 binding. We analyzed whether the LCS6 variant may be clinically relevant to patients with metastatic colorectal cancer (MCRC) treated with anti-epidermal growth factor receptor (EGFR) therapy. LCS6 genotypes and KRAS/BRAF mutations were determined in the tumor DNA of 134 patients with MCRC who underwent salvage cetuximab–irinotecan therapy. There were 34 G-allele (T/G+G/G) carriers (25%) and 100 T/T genotype carriers (75%). G-allele carriers were significantly more frequent in the KRAS mutation group than in patients with KRAS wild type (P=0.004). In the 121 patients without BRAF V600E mutation, overall survival (OS) and progression-free survival (PFS) times were compared between carriers of the LCS6 G-allele genotypes and carriers of the wild-type T/T genotype. LCS6 G-allele carriers showed worse OS (P=0.001) and PFS (P=0.004) than T/T genotype carriers (confirmed in the multivariate model including the KRAS status). In the exploratory analysis of the 55 unresponsive patients with KRAS mutation, LCS6 G-allele carriers showed adverse OS and PFS times. These findings deserve additional investigations as they may open novel perspectives for the treatment of patients with MCRC.
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References
Ambros V . The evolution of our thinking about microRNAs. Nat Med 2008; 14: 1036–1040.
Visone R, Croce CM . MiRNAs and cancer. Am J Pathol 2009; 174: 1131–1138.
Schickel R, Boyerinas B, Park SM, Peter ME . MicroRNAs: key players in the immune system, differentiation, tumorigenesis and cell death. Oncogene 2008; 27: 5959–5974.
Lee YH, Dutta A . MicroRNAs: small but potent oncogenes or tumor suppressors. Curr Opin Investig Drugs 2006; 7: 560–564.
Roush S, Slack FJ . The let-7 family of microRNAs. Trends Cell Biol 2008; 18: 505–516.
Johnson SM, Grosshans H, Shingara J, Byrom M, Jarvis R, Cheng A et al. RAS is regulated by the let-7 microRNA family. Cell 2005; 120: 635–647.
Jérôme T, Laurie P, Louis B, Pierre C . Enjoy the silence: the story of let-7 microRNA and cancer. Curr Genomics 2007; 8: 229–233.
Johnson CD, Esquela-Kerscher A, Stefani G, Byrom M, Kelnar K, Ovcharenko D et al. The let-7 microRNA represses cell proliferation pathways in human cells. Cancer Res 2007; 67: 7713–7722.
Kumar MS, Erkeland SJ, Pester RE, Chen CY, Ebert MS, Sharp PA et al. Suppression of non-small cell lung tumor development by the let-7 microRNA family. Proc Natl Acad Sci USA 2008; 105: 3903–3908.
Akao Y, Nakagawa Y, Naoe T . let-7 microRNA functions as a potential growth suppressor in human colon cancer cells. Biol Pharm Bull 2006; 29: 903–906.
Mishra PJ, Bertino JR . MicroRNA polymorphisms: the future of pharmacogenomics, molecular epidemiology and individualized medicine. Pharmacogenomics 2009; 10: 399–416.
Chin LJ, Ratner E, Leng S, Zhai R, Nallur S, Babar I et al. A SNP in a let-7 microRNA complementary site in the KRAS 3′ untranslated region increases non-small cell lung cancer risk. Cancer Res 2008; 68: 8535–8540.
Christensen BC, Moyer BJ, Avissar M, Ouellet LG, Plaza S, McClean MD et al. A let-7 microRNA binding site polymorphism in the KRAS 3′ UTR is associated with reduced survival in oral cancers. Carcinogenesis 2009; 30: 1003–1007.
Di Nicolantonio F, Martini M, Molinari F, Sartore-Bianchi A, Arena S, Saletti P et al. Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol 2008; 26: 5705–5712.
Linardou H, Dahabreh IJ, Kanaloupiti D, Siannis F, Bafaloukos D, Kosmidis P et al. Assessment of somatic k-RAS mutations as a mechanism associated with resistance to EGFR-targeted agents: a systematic review and meta-analysis of studies in advanced non-small-cell lung cancer and metastatic colorectal cancer. Lancet Oncol 2008; 9: 962–972.
Allegra CJ, Jessup JM, Somerfield MR, Hamilton SR, Hammond EH, Hayes DF et al. American society of clinical oncology provisional clinical opinion: testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy. J Clin Oncol 2009; 27: 2091–2096.
Osier MV, Cheung KH, Kidd JR, Pakstis AJ, Miller PL, Kidd KK . ALFRED: an allele frequency database for diverse populations and DNA polymorphisms—an update. Nucleic Acids Res 2001; 29: 317–319.
Shell S, Park SM, Radjabi AR, Schickel R, Kistner EO, Jewell DA et al. Let-7 expression defines two differentiation stages of cancer. Proc Natl Acad Sci USA 2007; 104: 11400–11405.
Ding XC, Slack FJ, Grosshans H . The let-7 microRNA interfaces extensively with the translation machinery to regulate cell differentiation. Cell Cycle 2008; 7: 3083–3090.
Torrisani J, Bournet B, Chalret du Rieu M, Bouisson M, Souque A, Escourrou J et al. Let-7 microRNA transfer in pancreatic cancer-derived cells inhibits in vitro cell proliferation but fails to alter tumor progression. Hum Gene Ther 2009; 20: 831–844.
Esquela-Kerscher A, Trang P, Wiggins JF, Patrawala L, Cheng A, Ford L et al. The let-7 microRNA reduces tumor growth in mouse models of lung cancer. Cell Cycle 2008; 7: 759–764.
Yu F, Yao H, Zhu P, Zhang X, Pan Q, Gong C et al. let-7 regulates self renewal and tumorigenicity of breast cancer cells. Cell 2007; 131: 1109–1123.
Takamizawa J, Konishi H, Yanagisawa K, Tomida S, Osada H, Endoh H et al. Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival. Cancer Res 2004; 64: 3753–3756.
Nicoloso MS, Spizzo R, Shimizu M, Rossi S, Calin GA . MicroRNAs—the micro steering wheel of tumour metastases. Nat Rev Cancer 2009; 9: 293–302.
Brown BD, Naldini L . Exploiting and antagonizing microRNA regulation for therapeutic and experimental applications. Nat Rev Genet 2009; 10: 578–585.
Tsang WP, Kwok TT . The miR-18a* microRNA functions as a potential tumor suppressor by targeting on K-Ras. Carcinogenesis 2009; 30: 953–959.
Chen X, Guo X, Zhang H, Xiang Y, Chen J, Yin Y et al. Role of miR-143 targeting KRAS in colorectal tumorigenesis. Oncogene 2009; 28: 1385–1392.
Weidhaas JB, Babar I, Nallur SM, Trang P, Roush S, Boehm M et al. MicroRNAs as potential agents to alter resistance to cytotoxic anticancer therapy. Cancer Res 2007; 67: 11111–11116.
Li Y, VandenBoom II TG, Kong D, Wang Z, Ali S, Philip PA et al. Up-regulation of miR-200 and let-7 by natural agents leads to the reversal of epithelial-to-mesenchymal transition in gemcitabine-resistant pancreatic cancer cells. Cancer Res 2009; 69: 6704–6712.
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This study was performed with a grant from Consorzio Interuniversitario per le Biotecnologie and Fanoateneo.
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Graziano, F., Canestrari, E., Loupakis, F. et al. Genetic modulation of the Let-7 microRNA binding to KRAS 3′-untranslated region and survival of metastatic colorectal cancer patients treated with salvage cetuximab–irinotecan. Pharmacogenomics J 10, 458–464 (2010). https://doi.org/10.1038/tpj.2010.9
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DOI: https://doi.org/10.1038/tpj.2010.9
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