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.

Paola Maria Maroni, Rossella Puglisi, Gianfranco Mattia, Alessandra Care, Emanuela Matteucci, Paola Bendinelli, Maria Alfonsina Desiderio

Research output: Contribution to journalArticle

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.
Original languageEnglish
Pages (from-to)492-503
Number of pages11
JournalCarcinogenesis
Volume38
Publication statusPublished - May 2017

Fingerprint

Oncogenes
Breast Neoplasms
Neoplasm Metastasis
Bone and Bones
Hepatocyte Growth Factor
Biomarkers
Carcinoma, Ductal, Breast
Carcinoma
Phenotype
Ductal Carcinoma
Methyltransferases
Epigenomics
Protein-Tyrosine Kinases
Plastics
Cell Membrane
Ligands
Therapeutics
Proteins

Keywords

  • Bone metastasis
  • Breast carcinomas

Cite this

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. / Maroni, Paola Maria; Puglisi, Rossella; Mattia, Gianfranco; Care, Alessandra; Matteucci, Emanuela; Bendinelli, Paola; Desiderio, Maria Alfonsina.

In: Carcinogenesis, Vol. 38, 05.2017, p. 492-503.

Research output: Contribution to journalArticle

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title = "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.",
abstract = "The highlight of the molecular basis and therapeutic targets of thebone-metastatic process requires the identification of biomarkers of metastasiscolonization. Here, we studied miR-34a-5p expression, and Met-receptor expressionand localization in bone metastases from ductal breast carcinomas, and in ductal carcinomas without history of metastasis (20 cases). miR-34a-5p was elevated innon-metastatic breast carcinoma, intermediate in the adjacent tissue andpractically absent in bone metastases, opposite to pair-matched carcinoma.Met-receptor biomarker was highly expressed and inversely correlated withmiR-34a-5p using the same set of bone-metastasis tissues. The miR-34a-5psilencing might depend on aberrant-epigenetic mechanisms of plastic-bonemetastases, since in 1833 cells under methyltransferase blockade miR-34a-5paugmented. 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-5pwith 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 atnuclear levels in bone metastases. Met-protein level was higher in non-metastatic(low grade) than in metastatic (high grade) breast carcinomas, notwithstandingmiR-34a-5p-elevated expression in both the specimens. Thus, mostly innon-metastatic carcinomas the elevated miR-34a-5p unaffected Met, important forinvasive/mesenchymal phenotype, while possibly targeting some stemness biomarkersrelated to metastatic phenotype. In personalized therapies against bonemetastasis, we suggest miR-34a-5p as a suitable target of epigeneticreprogramming leading to the accumulation of miR-34a-5p and the down-regulationof Met-tyrosine kinase, a key player of the bone-metastatic process.",
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T1 - 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.

AU - Maroni, Paola Maria

AU - Puglisi, Rossella

AU - Mattia, Gianfranco

AU - Care, Alessandra

AU - Matteucci, Emanuela

AU - Bendinelli, Paola

AU - Desiderio, Maria Alfonsina

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N2 - The highlight of the molecular basis and therapeutic targets of thebone-metastatic process requires the identification of biomarkers of metastasiscolonization. Here, we studied miR-34a-5p expression, and Met-receptor expressionand localization in bone metastases from ductal breast carcinomas, and in ductal carcinomas without history of metastasis (20 cases). miR-34a-5p was elevated innon-metastatic breast carcinoma, intermediate in the adjacent tissue andpractically absent in bone metastases, opposite to pair-matched carcinoma.Met-receptor biomarker was highly expressed and inversely correlated withmiR-34a-5p using the same set of bone-metastasis tissues. The miR-34a-5psilencing might depend on aberrant-epigenetic mechanisms of plastic-bonemetastases, since in 1833 cells under methyltransferase blockade miR-34a-5paugmented. 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-5pwith 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 atnuclear levels in bone metastases. Met-protein level was higher in non-metastatic(low grade) than in metastatic (high grade) breast carcinomas, notwithstandingmiR-34a-5p-elevated expression in both the specimens. Thus, mostly innon-metastatic carcinomas the elevated miR-34a-5p unaffected Met, important forinvasive/mesenchymal phenotype, while possibly targeting some stemness biomarkersrelated to metastatic phenotype. In personalized therapies against bonemetastasis, we suggest miR-34a-5p as a suitable target of epigeneticreprogramming leading to the accumulation of miR-34a-5p and the down-regulationof Met-tyrosine kinase, a key player of the bone-metastatic process.

AB - The highlight of the molecular basis and therapeutic targets of thebone-metastatic process requires the identification of biomarkers of metastasiscolonization. Here, we studied miR-34a-5p expression, and Met-receptor expressionand localization in bone metastases from ductal breast carcinomas, and in ductal carcinomas without history of metastasis (20 cases). miR-34a-5p was elevated innon-metastatic breast carcinoma, intermediate in the adjacent tissue andpractically absent in bone metastases, opposite to pair-matched carcinoma.Met-receptor biomarker was highly expressed and inversely correlated withmiR-34a-5p using the same set of bone-metastasis tissues. The miR-34a-5psilencing might depend on aberrant-epigenetic mechanisms of plastic-bonemetastases, since in 1833 cells under methyltransferase blockade miR-34a-5paugmented. 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-5pwith 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 atnuclear levels in bone metastases. Met-protein level was higher in non-metastatic(low grade) than in metastatic (high grade) breast carcinomas, notwithstandingmiR-34a-5p-elevated expression in both the specimens. Thus, mostly innon-metastatic carcinomas the elevated miR-34a-5p unaffected Met, important forinvasive/mesenchymal phenotype, while possibly targeting some stemness biomarkersrelated to metastatic phenotype. In personalized therapies against bonemetastasis, we suggest miR-34a-5p as a suitable target of epigeneticreprogramming leading to the accumulation of miR-34a-5p and the down-regulationof Met-tyrosine kinase, a key player of the bone-metastatic process.

KW - Bone metastasis

KW - Breast carcinomas

M3 - Article

VL - 38

SP - 492

EP - 503

JO - Carcinogenesis

JF - Carcinogenesis

SN - 0143-3334

ER -