miR-31 and its host gene lncRNA LOC554202 are regulated by promoter hypermethylation in triple-negative breast cancer.
miR-31 and its host gene lncRNA LOC554202 are regulated by promoter hypermethylation in triple-negative breast cancer.
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DOI：
10.1186/1476-4598-11-5
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发表时间：
2012-01-30
期刊：
影响因子：
37.3
通讯作者：
Sossey-Alaoui K
中科院分区：
文献类型：
--
作者：
Augoff K;McCue B;Plow EF;Sossey-Alaoui K
microRNA已被确立为正常生理以及病理条件（包括癌症进展和转移）中基因表达的有力调节剂。最近的研究表明，miR-31在乳腺癌的进展和转移中起着关键作用。miR-31的下调增强了乳腺癌中侵袭-转移级联的几个步骤，即，局部侵袭、外渗和在循环系统中的存活，以及远处部位的转移性定殖。miR-31通过靶向一组促转移基因（包括RhoA和WAVE 3）发挥其转移抑制活性。然而，在侵袭-转移级联反应的这些特定步骤中导致miR-31丢失及其促转移靶基因活化的分子机制尚不清楚。在本报告中，我们确定启动子超甲基化是乳腺癌中沉默miR-31的主要机制之一，特别是在基底亚型的三阴性乳腺癌（TNBC）细胞系中。miR-31定位于一种新的长非编码（lnc）RNA的内含子序列，LOC 554202，其转录活性的调控受LOC 554202的控制。miR-31和宿主基因L0 C554202在基底亚型的TNBC细胞系中下调，而在管腔对应物中过表达。用单独的去甲基化剂或与去乙酰化剂组合的去甲基化剂处理TNBC细胞系导致miR-31及其宿主基因的显著增加，表明通过启动子超甲基化沉默这两个基因的表观遗传机制。最后，甲基化特异性PCR和亚硫酸氢盐转化的DNA的测序表明，L0 C554202启动子相关的CpG岛在TNBC细胞系中高度甲基化，并且在管腔亚型中低甲基化。TNBC细胞系中miR-31表达的缺失归因于其启动子相关CpG岛的高甲基化。总之，我们的研究结果提供了miR-31（侵袭转移级联反应的重要决定因素）在乳腺癌中受到调控的机制的初步证据。
microRNAs have been established as powerful regulators of gene expression in normal physiological as well as in pathological conditions, including cancer progression and metastasis. Recent studies have demonstrated a key role of miR-31 in the progression and metastasis of breast cancer. Downregulation of miR-31 enhances several steps of the invasion-metastasis cascade in breast cancer, i.e., local invasion, extravasation and survival in the circulation system, and metastatic colonization of distant sites. miR-31 exerts its metastasis-suppressor activity by targeting a cohort of pro-metastatic genes, including RhoA and WAVE3. The molecular mechanisms that lead to the loss of miR-31 and the activation of its pro-metastatic target genes during these specific steps of the invasion-metastasis cascade are however unknown. In the present report, we identify promoter hypermethylation as one of the major mechanisms for silencing miR-31 in breast cancer, and in the triple-negative breast cancer (TNBC) cell lines of basal subtype, in particular. miR-31 maps to the intronic sequence of a novel long non-coding (lnc)RNA, LOC554202 and the regulation of its transcriptional activity is under control of LOC554202. Both miR-31 and the host gene LOC554202 are down-regulated in the TNBC cell lines of basal subtype and over-expressed in the luminal counterparts. Treatment of the TNBC cell lines with either a de-methylating agent alone or in combination with a de-acetylating agent resulted in a significant increase of both miR-31 and its host gene, suggesting an epigenetic mechanism for the silencing of these two genes by promoter hypermethylation. Finally, both methylation-specific PCR and sequencing of bisulfite-converted DNA demonstrated that the LOC554202 promoter-associated CpG island is heavily methylated in the TNBC cell lines and hypomethylated in the luminal subtypes. Loss of miR-31 expression in TNBC cell lines is attributed to hypermethylation of its promoter-associated CpG island. Together, our results provide the initial evidence for a mechanism by which miR-31, an important determinant of the invasion metastasis cascade, is regulated in breast cancer.
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影响因子：
3.7
作者：
Corcoran DL;Pandit KV;Gordon B;Bhattacharjee A;Kaminski N;Benos PV
通讯作者：
Benos PV
DOI：
10.1158/1541-7786.mcr-11-0311
发表时间：
2011-11
期刊：
Molecular cancer research : MCR
影响因子：
--
作者：
Augoff K;Das M;Bialkowska K;McCue B;Plow EF;Sossey-Alaoui K
通讯作者：
Sossey-Alaoui K
影响因子：
3.5
作者：
Fernando, H. S.;Davies, S. R.;Jiang, W. G.
通讯作者：
Jiang, W. G.
影响因子：
2
作者：
Akao, Yukihiro;Nakagawa, Yoshihito;Naoe, Tomoki
通讯作者：
Naoe, Tomoki
影响因子：
4.3
作者：
Jiang, Zhe;Jones, Robert;Zacksenhaus, Eldad
通讯作者：
Zacksenhaus, Eldad