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Experimental and Molecular Therapeutics

Abstract 3549: miR-451 links CRC stem-like cells with chemoresistance

Nerea Bitarte, Valentina Boni, Ruth Zarate, Marisol Gonzalez-Huarriz, Ines Lopez, Javier Rodriguez, Eva Bandres and Jesus Garcia-Foncillas
Nerea Bitarte
1Laboratory of Pharmacogenomics, Division of Oncology, Center for Applied Medical Research (CIMA), Pamplona, Spain
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Valentina Boni
1Laboratory of Pharmacogenomics, Division of Oncology, Center for Applied Medical Research (CIMA), Pamplona, Spain
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Ruth Zarate
1Laboratory of Pharmacogenomics, Division of Oncology, Center for Applied Medical Research (CIMA), Pamplona, Spain
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Marisol Gonzalez-Huarriz
1Laboratory of Pharmacogenomics, Division of Oncology, Center for Applied Medical Research (CIMA), Pamplona, Spain
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Ines Lopez
1Laboratory of Pharmacogenomics, Division of Oncology, Center for Applied Medical Research (CIMA), Pamplona, Spain
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Javier Rodriguez
2Department of Oncology, Clínica Universidad de Navarra, University of Navarra, Pamplona, Spain.
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Eva Bandres
1Laboratory of Pharmacogenomics, Division of Oncology, Center for Applied Medical Research (CIMA), Pamplona, Spain
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Jesus Garcia-Foncillas
1Laboratory of Pharmacogenomics, Division of Oncology, Center for Applied Medical Research (CIMA), Pamplona, Spain
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DOI: 10.1158/1538-7445.AM10-3549 Published April 2010
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Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC

Abstract

Introduction: In recent years, an emerging role for microRNAs (miRNAs) in human cancer has been proposed. Our group has previously identified miR-451 as a potential tumor suppressor microRNA involved in cell cycle progression and radiation response. We hypothesized whether miRNAs may be involved in drug resistance mechanisms among cytotoxic agents commonly used in metastatic colorectal cancer (mCRC).

Experimental Design: miR-451 was overexpressed by ectopically synthetic pre-miR-451 transient transfection and by generating stable-miR-451 overexpressed cells through retroviral vectors. The role of miR-451 on chemosensitivity to 5-fluorouracil (5FU), oxaliplatin (LOHP) and SN38, an active metabolite of irinotecan, was characterized by MTS. We sought to determine links between miR-451 and cancer stem cells (CSCs) by colonspheres generation, soft-agar cell invasion and xenograft in vivo experiments. Down-stream targets involved in drug-resistance mechanisms were also identified.

Results: Overexpression of miR-451 significantly increased the sensitivity of CRC cell lines to SN38. The IC50 values were significantly lower in pre-miR-451-transfected cells, including DLD1, LoVo and RKO than in controls (950 nM versus 460 nM for DLD1; 10 nM versus 1.4 nM for LoVo and 20 nM versus 5.9 nM for RKO). No changes were detected for 5-FU and LOHP response. ATP-binding cassette transporter protein 1 (ABCB1) proved to be miR-451-target directly associated with SN38 sensitivity. Moreover, restoring miR-451 levels translated into a reduced tumorigenicity in a xenograft model and a decreased ability of CRC cells to growth under anchorage-independent conditions in soft agar.

These results suggest that miR-451 down-regulation in CRC cells may be involved in CSCs generation. Indeed, overexpression of miR-451 was able to reduce the number and size of CRC cells-derived colonspheres. The phenotype of formed colonspheres was confirmed evaluating overexpression of several putative CSCs markers (CD133, CD44, EpCam and CD166). We also found colonspheres to be more resistant to SN38 treatment and to express higher levels of ABCB1 than parental cells. Finally, miR-451 restoration levels reverted CSCs resistance to SN38 through ABCB1 down-regulation.

Conclusions: Our findings suggest that miR-451 is involved in SN38 resistance through suppression of ABCB1 and regulation of CRC stem-like cell phenotype. Therefore, miR-451 may represent a novel potential candidate target to circumvent drug resistance in CRC.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3549.

  • ©2010 American Association for Cancer Research
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Cancer Research: 70 (8 Supplement)
April 2010
Volume 70, Issue 8 Supplement
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Abstract 3549: miR-451 links CRC stem-like cells with chemoresistance
Nerea Bitarte, Valentina Boni, Ruth Zarate, Marisol Gonzalez-Huarriz, Ines Lopez, Javier Rodriguez, Eva Bandres and Jesus Garcia-Foncillas
Cancer Res April 15 2010 (70) (8 Supplement) 3549; DOI: 10.1158/1538-7445.AM10-3549

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Abstract 3549: miR-451 links CRC stem-like cells with chemoresistance
Nerea Bitarte, Valentina Boni, Ruth Zarate, Marisol Gonzalez-Huarriz, Ines Lopez, Javier Rodriguez, Eva Bandres and Jesus Garcia-Foncillas
Cancer Res April 15 2010 (70) (8 Supplement) 3549; DOI: 10.1158/1538-7445.AM10-3549
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Cancer Research Online ISSN: 1538-7445
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