Identification of microRNA-214 as a negative regulator of colorectal cancer liver metastasis by way of regulation of fibroblast growth factor receptor 1 expression.

Abstract

UNLABELLED:

The purpose of this study was to identify microRNAs (miRNAs) involved in the pathology of colorectal cancer (CRC) liver metastasis and investigate their underlying mechanisms. A total of 39 miRNAs were identified to be differentially expressed between 16 primary CRC tissues with liver metastases and 16 CRC tissues without liver metastases from 32 patients by Affymetric miRNA microarrays. A panel of eight miRNAs were confirmed to be significantly and differentially expressed between CRC tissues with and without liver metastases through quantitative reverse-transcription polymerase chain reaction (RT-PCR) analysis in the 32 patients. In a validated cohort of 99 CRC patients (44 with and 55 without liver metastases), only miR-214 was validated to be significantly down-regulated in CRC with liver metastases, which was associated with an unfavorable prognosis. Ectopic expression of miR-214 suppressed proliferation, migration, and invasion in vitro, tumor growth and liver metastasis in an in vivo xenograft mouse model, whereas miR-214 knockdown promoted proliferation, migration, and invasion in CRC cell lines. Further studies indicated that fibroblast growth factor receptor 1 (FGFR1) was a potential target of miR-214. Restoring miR-214 expression in CRC cells decreased endogenous FGFR1 messenger RNA (mRNA) and protein levels. FGFR1 knockdown mimicked the tumor suppressive effect of miR-214 on CRC cells, while reintroduction of FGFR1 abolished the tumor suppressive effect of miR-214 on CRC cells. Moreover, miR-214 expression levels were inversely correlated with FGFR1 in CRC patients.

CONCLUSION:

Down-regulation of miR-214 expression was correlated with increased FGFR1 expression levels, which may contribute to increased CRC liver metastasis. miR-214 may serve as a potential marker to predict survival, and the miR-214-FGFR1 axis may be a therapeutic target in CRC patients.

• Authors: Dong-Liang Chen, Zhi-Qiang Wang, Zhao-Lei Zeng, Wen-Jing Wu, Dong-Sheng Zhang, Hui-Yan Luo, Feng Wang, Miao-Zhen Qiu, De-Shen Wang, Chao Ren, Feng-Hua Wang, Lucia J Chiao, Helene Pelicano, Peng Huang, Yu-Hong Li, Rui-Hua Xu
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 60 Issue 2 Pg. 598-609 (Aug 2014) ISSN: 1527-3350 [Electronic] United States
• PMID: 24616020 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 by the American Association for the Study of Liver Diseases.

Chemical References

• MIRN214 microRNA, human
• MicroRNAs
• FGFR1 protein, human
• Receptor, Fibroblast Growth Factor, Type 1

Topics

• Animals
• Carcinogenesis (genetics, metabolism)
• Cell Movement (physiology)
• Cell Proliferation
• Colorectal Neoplasms (genetics, metabolism, pathology)
• Down-Regulation (physiology)
• Female
• Gene Expression Regulation, Neoplastic
• HCT116 Cells
• Humans
• Liver Neoplasms (genetics, metabolism, secondary)
• Lymphatic Metastasis
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• MicroRNAs (genetics, metabolism)
• Middle Aged
• Neoplasm Invasiveness
• Neoplasm Transplantation
• Receptor, Fibroblast Growth Factor, Type 1 (genetics, metabolism)