Abstract
The highlight of the molecular basis and therapeutic targets of the
bone-metastatic process requires the identification of biomarkers of metastasis
colonization. Here, we studied miR-34a-5p expression, and Met-receptor expression
and localization in bone metastases from ductal breast carcinomas, and in ductal
carcinomas without history of metastasis (20 cases). miR-34a-5p was elevated in
non-metastatic breast carcinoma, intermediate in the adjacent tissue and
practically absent in bone metastases, opposite to pair-matched carcinoma.
Met-receptor biomarker was highly expressed and inversely correlated with
miR-34a-5p using the same set of bone-metastasis tissues. The miR-34a-5p
silencing might depend on aberrant-epigenetic mechanisms of plastic-bone
metastases, since in 1833 cells under methyltransferase blockade miR-34a-5p
augmented. In fact, 1833 cells showed very low endogenous miR-34a-5p, in respect
to parental MDA-MB231 breast carcinoma cells, and the restoration of miR-34a-5p
with the mimic reduced Met and invasiveness. Notably, hepatocyte growth factor
(HGF)-dependent Met stabilization was observed in bone-metastatic 1833 cells,
consistent with Met co-distribution with the ligand HGF at plasma membrane and at
nuclear levels in bone metastases. Met-protein level was higher in non-metastatic
(low grade) than in metastatic (high grade) breast carcinomas, notwithstanding
miR-34a-5p-elevated expression in both the specimens. Thus, mostly in
non-metastatic carcinomas the elevated miR-34a-5p unaffected Met, important for
invasive/mesenchymal phenotype, while possibly targeting some stemness biomarkers
related to metastatic phenotype. In personalized therapies against bone
metastasis, we suggest miR-34a-5p as a suitable target of epigenetic
reprogramming leading to the accumulation of miR-34a-5p and the down-regulation
of Met-tyrosine kinase, a key player of the bone-metastatic process.
bone-metastatic process requires the identification of biomarkers of metastasis
colonization. Here, we studied miR-34a-5p expression, and Met-receptor expression
and localization in bone metastases from ductal breast carcinomas, and in ductal
carcinomas without history of metastasis (20 cases). miR-34a-5p was elevated in
non-metastatic breast carcinoma, intermediate in the adjacent tissue and
practically absent in bone metastases, opposite to pair-matched carcinoma.
Met-receptor biomarker was highly expressed and inversely correlated with
miR-34a-5p using the same set of bone-metastasis tissues. The miR-34a-5p
silencing might depend on aberrant-epigenetic mechanisms of plastic-bone
metastases, since in 1833 cells under methyltransferase blockade miR-34a-5p
augmented. In fact, 1833 cells showed very low endogenous miR-34a-5p, in respect
to parental MDA-MB231 breast carcinoma cells, and the restoration of miR-34a-5p
with the mimic reduced Met and invasiveness. Notably, hepatocyte growth factor
(HGF)-dependent Met stabilization was observed in bone-metastatic 1833 cells,
consistent with Met co-distribution with the ligand HGF at plasma membrane and at
nuclear levels in bone metastases. Met-protein level was higher in non-metastatic
(low grade) than in metastatic (high grade) breast carcinomas, notwithstanding
miR-34a-5p-elevated expression in both the specimens. Thus, mostly in
non-metastatic carcinomas the elevated miR-34a-5p unaffected Met, important for
invasive/mesenchymal phenotype, while possibly targeting some stemness biomarkers
related to metastatic phenotype. In personalized therapies against bone
metastasis, we suggest miR-34a-5p as a suitable target of epigenetic
reprogramming leading to the accumulation of miR-34a-5p and the down-regulation
of Met-tyrosine kinase, a key player of the bone-metastatic process.
| Original language | English |
|---|---|
| Pages (from-to) | 492-503 |
| Number of pages | 11 |
| Journal | Carcinogenesis |
| Volume | 38 |
| Publication status | Published - May 2017 |
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Keywords
- Bone metastasis
- Breast carcinomas
Cite this
Maroni, P. M., Puglisi, R., Mattia, G., Care, A., Matteucci, E., Bendinelli, P., & Desiderio, M. A. (2017). In bone metastasis miR-34a-5p absence inversely correlates with Met expression, while Met oncogene is unaffected by miR-34a-5p in non-metastatic and metastatic breast carcinomas. Carcinogenesis, 38, 492-503.