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
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
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DOI：
10.1093/carcin/bgx027
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发表时间：
2017-05-01
期刊：
影响因子：
4.7
通讯作者：
Desiderio, Maria Alfonsina
中科院分区：
文献类型：
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作者：
Maroni, Paola;Puglisi, Rossella;Desiderio, Maria Alfonsina
骨转移过程的分子基础和治疗靶点的突出需要转移定植的生物标志物的鉴定。在这里，我们研究了miR-34 a-5 p的表达，Met-受体的表达和定位在乳腺导管癌骨转移，并在导管癌无转移史（20例）。miR-34 a-5 p在非转移性乳腺癌中升高，在邻近组织中居中，在骨转移中几乎不存在，与配对匹配的癌相反。使用同一组骨转移组织，Met受体生物标志物高度表达，并且与miR-34 a-5 p呈负相关。miR-34 a-5 p沉默可能依赖于塑料骨转移的异常表观遗传机制，因为在甲基转移酶阻断的1833细胞中，miR-34 a-5 p增加。事实上，相对于亲本MDA-MB 231乳腺癌细胞，1833细胞显示出非常低的内源性miR-34 a-5 p，并且用模拟物恢复miR-34 a-5 p降低了Met和侵袭性。值得注意的是，在骨转移1833细胞中观察到肝细胞生长因子（HGF）依赖性Met稳定，这与骨转移中Met与配体HGF在质膜和核水平上的共分布一致。Met蛋白水平在非转移性（低级别）乳腺癌中高于转移性（高级别）乳腺癌，尽管在两个标本中miR-34 a-5 p表达升高。因此，大多数在非转移性癌中，升高的miR-34 a-5 p不影响Met，这对于侵袭性/间充质表型很重要，同时可能靶向与转移性表型相关的一些干性生物标志物。在针对骨转移的个性化治疗中，我们建议miR-34 a-5 p作为表观遗传重编程的合适靶点，导致miR-34 a-5 p的积累和Met-酪氨酸激酶的下调，这是骨转移过程的关键参与者。
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.