ECTS2013 Poster Presentations Cancer and bone: basic, translational and clinical (31 abstracts)
miR-192 impairs invasion and tumor-induced osteolysis by repressing CCL2 in bone metastatic colonization
Karmele Valencia 1 , Diego Luis-Ravelo 1 , Nicolas Bovy 2 , Susana Martínez-Canarias 1 , Cristina Ormazábal 1 , Carolina Zandueta 1 , Iker Antón 1 , Ingrid Struman 2 , Sébastien Tabruyn 2 , Victor Segura 1 , Javier De Las Rivas 3 & Eva Bandrés 1
1Center for Applied Medical Research, Pamplona, Spain; 2University of Liège, Liège, Belgium; 3University of Salamanca, Salamanca, Spain.
Emerging evidence suggests that miRNAs (miR) can modulate a complex gene network in a cell-intrinsic and non-cell autonomous manner. We previously identified by transcriptomic analysis miR-192 to be heavily downregulated in different highly metastatic subpopulations (HMS) isolated from bone metastases in a lung cancer mice model, but its mechanistic contribution to the prometastatic activity remains unknown.
To delineate the pleiotropic functions elicited by miR-192 in metastatic activity we retrovirally overexpress miR-192 in HMS. Forced expression of miR-192 led to stunted decrease invasiveness in Boyden chamber assay and a diminished metalloproteolytic activity using a fluorogenic assay as compared to mock transduced cells. Next, we inoculated miR-192 overexpressing cells by i.c. injection in nude mice. Animals inoculated with miR-192 cells showed a dramatic decrease in bone tumor burden assessed by bioluminescence imaging (BLI) and a marked reduction in osteolytic lesions assessed by X-rays and μCT scans as compared to mock cells. In contrast miR-192 was ineffective decreasing cell proliferation and subcutaneous tumor growth. To explore its role in bone colonization, we intratibially injected miR-192 overexpressing cells. In agreement with previous findings, miR-192 tumors showed a significant decrease in BLI indicating a marked decreased in tumor burden as compared to mice injected with mock cells. Interestingly, immunohistochemical analysis showed no in vivo effect of miR-192 on growth kinetics and apoptosis. Moreover, the number TRAP+ cells at tumor-bone interphase were impaired in mice i.c. injected with miR-192 cells. Transcriptomic analysis identified the pro-osteoclastogenic cytokine CCL-2 as a factor severely repressed in miR-192 derived tumors. This finding was validated by real time PCR. Consistently, incubation with conditioned medium derived from miR192 tumor cells showed a decrease TRAP+ cells in vitro. Thus, miR-192 appeases bone metastatic colonization by a novel mechanism involving tumor cell-dependent functions and non-cell autonomously regulating tumor–induced osteolysis.
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Bone Abstracts
ISSN 2052-1219 (online)
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