14q32-encoded microRNAs mediate an oligometastatic phenotype

• DOI: 10.18632/oncotarget.2920
• Publication Date: 2015-09-15T07:56:59Z
• Authors: Abhineet Uppal; Sean C. Wightman; Stephen Mallon; Go Oshima; Sean P. Pitroda; Qingbei Zhang; Xiaona Huang; Thomas E. Darga; Lei Huang; Jorge Andrade; Huiping Liu; Mark K. Ferguson; Geoffrey L. Greene; Mitchell C. Posner; Samuel Hellman; Nikolai N. Khodarev; Ralph R. Weichsel...
• Keywords: Chromosomes, Human, Pair 14; Gene Expression; Breast Neoplasms; Mice, SCID; 3. Good health; Mice; MicroRNAs; 03 medical and health sciences; Phenotype; 0302 clinical medicine; Mice, Inbred NOD; Cell Line, Tumor; Neoplasms; Animals; Heterografts; Humans; Neoplasm Metastasis

Oligometastasis is a clinically distinct subset of metastasis characterized by a limited number of metastases potentially curable with localized therapies. We analyzed pathways targeted by microRNAs over-expressed in clinical oligometastasis samples and identified suppression of cellular adhesion, invasion, and motility pathways in association with the oligometastatic phenotype. We identified miR-127-5p, miR-544a, and miR-655-3p encoded in the 14q32 microRNA cluster as co-regulators of multiple metastatic pathways through repression of shared target genes. These microRNAs suppressed cellular adhesion and invasion and inhibited metastasis development in an animal model of breast cancer lung colonization. Target genes, including TGFBR2 and ROCK2, were key mediators of these effects. Understanding the role of microRNAs expressed in oligometastases may lead to improved identification of and interventions for patients with curable metastatic disease, as well as an improved understanding of the molecular basis of this unique clinical entity.