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Loss of miR-200 family in 5-fluorouracil resistant colon cancer drives lymphendothelial invasiveness in vitro
- Source :
- Human Molecular Genetics.
- Publication Year :
- 2015
- Publisher :
- Oxford University Press (OUP), 2015.
-
Abstract
- Invasive colorectal cancer is associated with poor prognosis requiring treatment with systemic chemotherapies usually including 5-fluorouracil. A consequence of prolonged treatment is the acquisition of resistance eventually resulting in the recurrence of highly metastatic cancer cells. To address the relationship between drug resistance and increased lymphatic metastatic potential, we used a 3D co-culture model of colon tumour cell spheroids of parent CCL227 cells and subclones with gradually increasing resistance against 5-fluorouracil. From each investigated cell line, homogeneous tumour spheroids were generated in the presence of methylcellulose yielding emboli of ∼700 µm diameter. When invasive, tumour spheroids disrupt the continuous lymphendothelial cell (LEC) layer and generate a 'circular chemorepellent-induced defect' (CCID), reminiscent of the entry gates through which tumour emboli intravasate lymphatic vasculature. Here we provide evidence that increasingly chemoresistant colon cancer spheroids were strongly associated with enhanced intravasative properties. In naive CCL227 spheroids, miR-200 family members were released into exosomes thereby repressing the epithelial to mesenchymal transition-regulating transcription factors ZEB1 and SLUG in LEC. As a consequence of attenuated plasticity and migration of LEC, CCID formation was impaired. Loss of exosomal transferred miR-200c in resistant colon cells rendered LEC more susceptible to pro-migratory signals that were generated and directly transmitted by colon cancer spheroids. This observation indicates a common molecular axis in colon cancer and LEC where miR-200 family members act as regulators of ZEB proteins. The data support the notion that horizontal miR-200 signalling prevents the permeation of cells into adjacent epithelia and contributes to organ integrity.
- Subjects :
- Colorectal cancer
Cell
Biology
Cell Line, Tumor
Spheroids, Cellular
microRNA
Tumor Cells, Cultured
Genetics
medicine
Humans
Neoplasm Invasiveness
Molecular Biology
Genetics (clinical)
Homeodomain Proteins
Mesenchymal stem cell
Endothelial Cells
Zinc Finger E-box-Binding Homeobox 1
General Medicine
medicine.disease
Microvesicles
MicroRNAs
Lymphatic system
medicine.anatomical_structure
Drug Resistance, Neoplasm
Cell culture
Lymphatic Metastasis
Multigene Family
Colonic Neoplasms
Cancer cell
Immunology
Cancer research
Fluorouracil
Snail Family Transcription Factors
Transcription Factors
Subjects
Details
- ISSN :
- 14602083 and 09646906
- Database :
- OpenAIRE
- Journal :
- Human Molecular Genetics
- Accession number :
- edsair.doi.dedup.....62f1fb1e52848378cf3d5ddfc7414788