期刊
CANCER RESEARCH
卷 78, 期 7, 页码 1751-1765出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-17-2101
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资金
- National Natural Science Foundation [81320108024, 81421001, 81530072, 81522008, 81790632, 31371420, 31371273, 81372267, 81402347]
- Shanghai Natural Science Foundation [13ZR14244000]
- Program for Professor of Special Appointment at Shanghai Institutions of Higher Learning [201268, QD2015003]
- Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support [20152512, 20161309]
- Chenxing Project of Shanghai Jiao-Tong University
Colorectal cancer includes an invasive stem-like/mesenchymal subtype, but its genetic drivers, functional, and clinical relevance are uncharacterized. Here we report the definition of an altered miRNA signature defining this subtype that includes a major genomic loss of miR-508. Mechanistic investigations showed that this miRNA affected the expression of cadherin CDH1 and the transcription factors ZEB1, SALL4, and BMI1. Loss of miR-508 in colorectal cancer was associated with upregulation of the novel hypoxia-induced long noncoding RNA AK000053. Ectopic expression of miR-508 in colorectal cancer cells blunted epithelial- to-mesenchymal transition (EMT), stemness, migration, and invasive capacity in vitro and in vivo. In clinical colorectal cancer specimens, expression of miR-508 negatively correlated with stemness and EMT-associated gene expression and positively correlated with patient survival. Overall, our results showed that miR-508 is a key functional determinant of the stem-like/mesenchymal colorectal cancer subtype and a candidate therapeutic target for its treatment. Significance: These results define a key functional determinant of a stem-like/mesenchymal subtype of colorectal cancers and a candidate therapeutic target for its treatment. (C) 2018 AACR.
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