The predictive value of microRNA-126 in relation to first line treatment with capecitabine and oxaliplatin in patients with metastatic colorectal cancer

BMC Cancer

Anders Jakobsen³  Jan Lindebjerg¹  Flemming Brandt Sørensen¹  Torben Frøstrup Hansen² 

[1]Department of Clinical Pathology, Vejle Hospital, Kabbeltoft 25, 7100 Vejle, Denmark

[2]Danish Colorectal Cancer Group South, Vejle Hospital, Kabbeltoft 25, 7100 Vejle, Denmark

[3]Department of Oncology, Vejle Hospital, Kabbeltoft 25, 7100 Vejle, Denmark

关键词: Predictive biomarkers;    microRNAs;    Colorectal neoplasms;    Chemotherapy;    Angiogenesis;   

Others  :  1080524
DOI  :  10.1186/1471-2407-12-83

 received in 2011-08-17, accepted in 2012-03-08,  发布年份 2012

【 摘 要 】

Background

MicroRNA-126 is the only microRNA (miRNA) known to be endothelial cell-specific influencing angiogenesis in several ways. The aim of the present study was to analyse the possible predictive value of miRNA-126 in relation to first line capecitabine and oxaliplatin (XELOX) in patients with metastatic colorectal cancer (mCRC).

Methods

The study included 89 patients with mCRC. In situ hybridization (ISH) was performed to detect miRNA-126 in formalin-fixed paraffin embedded tissue from primary tumours. The expression of miRNA-126, area per image (μm²), was measured using image analysis. Clinical response was evaluated according to RECIST. Progression free survival (PFS) was compared using the Kaplan-Meier method and the log rank test. Tumours were classified as low or high miRNA-126 expressing tumours using the median value from the patients with response as cut-off.

Results

The median miRNA-126 expression level was significantly higher in patients responding to XELOX, 3629 μm² (95% CI, 2566-4846), compared to the patients not responding, 1670 μm² (95% CI, 1436-2041), p < 0.0001. The positive predictive value was 90%, and the negative predictive value was 71%. The median PFS of patients with high expressing tumours was 11.5 months (95% CI, 9.0-12.7 months) compared to 6.0 months (95% CI, 4.8-6.9 months) for patients with low expressing tumours, p < 0.0001.

Conclusions

Angiogenesis quantified by ISH of miRNA-126 was related to response to first line XELOX in patients with mCRC, translating to a significant difference in PFS. The predictive value of miRNA-126 remains to be further elucidated in prospective studies.

【 授权许可】

   
2012 Hansen et al; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

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【 参考文献 】

• [1]Folkman J: What is the evidence that tumors are angiogenesis dependent? J Natl Cancer Inst 1990, 82:4-6.
• [2]Carmeliet P: Angiogenesis in health and disease. Nat Med 2003, 9:653-660.
• [3]Folkman J: Tumor angiogenesis: therapeutic implications. N Engl J Med 1971, 285:1182-1186.
• [4]Filipowicz W, Bhattacharyya SN, Sonenberg N: Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? Nat Rev Genet 2008, 9:102-114.
• [5]Esquela-Kerscher A, Slack FJ: Oncomirs - microRNAs with a role in cancer. Nat Rev Cancer 2006, 6:259-269.
• [6]Slaby O, Svoboda M, Michalek J, Vyzula R: MicroRNAs in colorectal cancer: translation of molecular biology into clinical application. Mol Cancer 2009, 8:102. BioMed Central Full Text
• [7]Rossi L, Bonmassar E, Faraoni I: Modification of miR gene expression pattern in human colon cancer cells following exposure to 5-fluorouracil in vitro. Pharmacol Res 2007, 56:248-253.
• [8]Svoboda M, Izakovicova HL, Sefr R, Vrtkova I, Kocakova I, Tichy B, Dvorak J: Micro-RNAs miR125b and miR137 are frequently upregulated in response to capecitabine chemoradiotherapy of rectal cancer. Int J Oncol 2008, 33:541-547.
• [9]Zhou J, Zhou Y, Yin B, Hao W, Zhao L, Ju W, Bai C: 5-Fluorouracil and oxaliplatin modify the expression profiles of microRNAs in human colon cancer cells in vitro. Oncol Rep 2010, 23:121-128.
• [10]Nakajima G, Hayashi K, Xi Y, Kudo K, Uchida K, Takasaki K, Yamamoto M, Ju J: Non-coding MicroRNAs hsa-let-7 g and hsa-miR-181b are Associated with Chemoresponse to S-1 in Colon Cancer. Cancer Genomics Proteomics 2006, 3:317-324.
• [11]Wienholds E, Kloosterman WP, Miska E, varez-Saavedra E, Berezikov E, de BE, Horvitz HR, Kauppinen S, Plasterk RH: MicroRNA expression in zebrafish embryonic development. Science 2005, 309:310-311.
• [12]Fish JE, Santoro MM, Morton SU, Yu S, Yeh RF, Wythe JD, Ivey KN, Bruneau BG, Stainier DY, Srivastava D: miR-126 regulates angiogenic signaling and vascular integrity. Dev Cell 2008, 15:272-284.
• [13]Kuehbacher A, Urbich C, Zeiher AM, Dimmeler S: Role of Dicer and Drosha for endothelial microRNA expression and angiogenesis. Circ Res 2007, 101:59-68.
• [14]Wang S, Aurora AB, Johnson BA, Qi X, McAnally J, Hill JA, Richardson JA, Bassel-Duby R, Olson EN: The endothelial-specific microRNA miR-126 governs vascular integrity and angiogenesis. Dev Cell 2008, 15:261-271.
• [15]Nicoli S, Standley C, Walker P, Hurlstone A, Fogarty KE, Lawson ND: MicroRNA-mediated integration of haemodynamics and Vegf signalling during angiogenesis. Nature 2010, 464:1196-1200.
• [16]Guo C, Sah JF, Beard L, Willson JK, Markowitz SD, Guda K: The noncoding RNA, miR-126, suppresses the growth of neoplastic cells by targeting phosphatidylinositol 3-kinase signaling and is frequently lost in colon cancers. Genes Chromosomes Cancer 2008, 47:939-946.
• [17]Tavazoie SF, Alarcon C, Oskarsson T, Padua D, Wang Q, Bos PD, Gerald WL, Massague J: Endogenous human microRNAs that suppress breast cancer metastasis. Nature 2008, 451:147-152.
• [18]Crawford M, Brawner E, Batte K, Yu L, Hunter MG, Otterson GA, Nuovo G, Marsh CB, Nana-Sinkam SP: MicroRNA-126 inhibits invasion in non-small cell lung carcinoma cell lines. Biochem Biophys Res Commun 2008, 373:607-612.
• [19]Zhong M, Ma X, Sun C, Chen L: MicroRNAs reduce tumor growth and contribute to enhance cytotoxicity induced by gefitinib in non-small cell lung cancer. Chem Biol Interact 2010, 184:431-438.
• [20]Musiyenko A, Bitko V, Barik S: Ectopic expression of miR-126*, an intronic product of the vascular endothelial EGF-like 7 gene, regulates prostein translation and invasiveness of prostate cancer LNCaP cells. J Mol Med 2008, 86:313-322.
• [21]Liu B, Peng XC, Zheng XL, Wang J, Qin YW: MiR-126 restoration down-regulate VEGF and inhibit the growth of lung cancer cell lines in vitro and in vivo. Lung Cancer 2009, 66:169-175.
• [22]Tong RT, Boucher Y, Kozin SV, Winkler F, Hicklin DJ, Jain RK: Vascular normalization by vascular endothelial growth factor receptor 2 blockade induces a pressure gradient across the vasculature and improves drug penetration in tumors. Cancer Res 2004, 64:3731-3736.
• [23]Jain RK: Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 2005, 307:58-62.
• [24]Jain RK: Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat Med 2001, 7:987-989.
• [25]Wildiers H, Guetens G, De BG, Verbeken E, Landuyt B, Landuyt W, de Bruijn EA, van Oosterom AT: Effect of antivascular endothelial growth factor treatment on the intratumoral uptake of CPT-11. Br J Cancer 2003, 88:1979-1986.
• [26]Nielsen BS, Jorgensen S, Fog JU, Sokilde R, Christensen IJ, Hansen U, Brunner N, Baker A, Moller S, Nielsen HJ: High levels of microRNA-21 in the stroma of colorectal cancers predict short disease-free survival in stage II colon cancer patients. Clin Exp Metastasis 2011, 28:27-38.
• [27]Jorgensen S, Baker A, Moller S, Nielsen BS: Robust one-day in situ hybridization protocol for detection of microRNAs in paraffin samples using LNA probes. Methods 2010, 52:375-381.
• [28]Vincenzi B, Santini D, Russo A, Gavasci M, Battistoni F, Dicuonzo G, Rocci L, Rosaria VM, Gebbia N, Tonini G: Circulating VEGF reduction, response and outcome in advanced colorectal cancer patients treated with cetuximab plus irinotecan. Pharmacogenomics 2007, 8:319-327.
• [29]Hansen TF, Garm Spindler KL, Andersen RF, Lindebjerg J, Brandslund I, Jakobsen A: The predictive value of genetic variations in the vascular endothelial growth factor A gene in metastatic colorectal cancer. Pharmacogenomics J 2010, 11:53-60.
• [30]Diaz R, Silva J, Garcia JM, Lorenzo Y, Garcia V, Pena C, Rodriguez R, Munoz C, Garcia F, Bonilla F, Dominguez G: Deregulated expression of miR-106a predicts survival in human colon cancer patients. Genes Chromosomes Cancer 2008, 47:794-802.
• [31]Schepeler T, Reinert JT, Ostenfeld MS, Christensen LL, Silahtaroglu AN, Dyrskjot L, Wiuf C, Sorensen FJ, Kruhoffer M, Laurberg S, Kauppinen S, Orntoft TF, Andersen CL: Diagnostic and prognostic microRNAs in stage II colon cancer. Cancer Res 2008, 68:6416-6424.