Richards Edward J, Zhang Gu, Li Zhu-Peng, Permuth-Wey Jennifer, Challa Sridevi, Li Yajuan, Kong William, Dan Su, Bui Marilyn M, Coppola Domenico, Mao Wei-Min, Sellers Thomas A, Cheng Jin Q
From the Departments of Molecular Oncology.
the Zhejiang Cancer Hospital & Zhejiang Cancer Research Institute, Zhejiang 310022, China.
J Biol Chem. 2015 Mar 13;290(11):6857-67. doi: 10.1074/jbc.M114.610915. Epub 2015 Jan 20.
Long noncoding RNAs (lncRNAs) are emerging as key regulators in various biological processes. Epithelial-to-mesenchymal transition (EMT) is a developmental process hijacked by tumor cells to depart from the primary tumor site, invade surrounding tissue, and establish distant metastases. Transforming growth factor β (TGFβ) signaling has been shown to be a major inducer of EMT and to facilitate breast cancer metastasis. However, the role of lncRNAs in this process remains largely unknown. Here we report a genome-wide lncRNA profile in mouse mammary epithelial NMuMG cells upon TGFβ induction of EMT. Among 10,802 lncRNAs profiled, over 600 were up-regulated and down-regulated during the EMT, respectively. Furthermore, we identify that lncRNA-HIT (HOXA transcript induced by TGFβ) mediates TGFβ function, i.e. depletion of lncRNA-HIT inhibits TGFβ-induced migration, invasion, and EMT in NMuMG. LncRNA-HIT is also significantly elevated in the highly metastatic 4T1 cells. Knockdown of lncRNA-HIT in 4T1 results in decrease of cell migration, invasion, tumor growth, and metastasis. E-cadherin was identified as a major target of lncRNA-HIT. Moreover, lncRNA-HIT is conserved in humans and elevated expression associates with more invasive human primary breast carcinoma. Collectively, these data suggest that a subset of lncRNAs such as lncRNA-HIT play a significant role in regulation of EMT and breast cancer invasion and metastasis, and could be potential therapeutic targets in breast cancers.
长链非编码RNA(lncRNAs)正逐渐成为各种生物学过程中的关键调节因子。上皮-间质转化(EMT)是一个发育过程,却被肿瘤细胞利用,使其脱离原发肿瘤部位,侵袭周围组织,并形成远处转移。转化生长因子β(TGFβ)信号已被证明是EMT的主要诱导因子,并促进乳腺癌转移。然而,lncRNAs在此过程中的作用仍 largely未知。在此,我们报告了TGFβ诱导EMT时小鼠乳腺上皮NMuMG细胞中的全基因组lncRNA图谱。在分析的10,802个lncRNAs中,超过600个在EMT过程中分别上调和下调。此外,我们鉴定出lncRNA-HIT(TGFβ诱导的HOXA转录本)介导TGFβ功能,即lncRNA-HIT的缺失抑制了TGFβ诱导的NMuMG细胞迁移、侵袭和EMT。lncRNA-HIT在高转移性4T1细胞中也显著升高。在4T1细胞中敲低lncRNA-HIT导致细胞迁移、侵袭、肿瘤生长和转移减少。E-钙黏蛋白被确定为lncRNA-HIT的主要靶点。此外,lncRNA-HIT在人类中保守,其高表达与更具侵袭性的人类原发性乳腺癌相关。总体而言,这些数据表明,lncRNAs的一个子集,如lncRNA-HIT,在EMT以及乳腺癌侵袭和转移的调节中起重要作用,并且可能是乳腺癌潜在的治疗靶点。