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Long non-coding RNA (lncRNA) transcriptional landscape in breast cancer identifies LINC01614 as non-favorable prognostic biomarker regulated by TGFβ and focal adhesion kinase (FAK) signaling
Cell Death Discovery ( IF 6.1 ) Pub Date : 2019-06-24 , DOI: 10.1038/s41420-019-0190-6
Radhakrishnan Vishnubalaji , Hibah Shaath , Eyad Elkord , Nehad M. Alajez

Long non-coding RNAs (lncRNAs) represent a class of epigenetic regulators implicated in a number of physiological and pathological conditions. Herein, we characterized the lncRNA expression portrait from 837 patients with invasive breast cancer and 105 normals from the cancer genome atlas (TCGA), which revealed eighteen upregulated and forty-six downregulated lncRNAs. Clustering analysis revealed distinct lncRNA profile for the triple negative breast cancer (TNBC) and normal breast tissue, while less separation was observed among the HER2+HR+, HER2+HR, HER2HR+ molecular subtypes. LINC01614, and LINC01235 correlated with worse disease-free survival (DFS), while the expression of lnc-LRR1–1, lnc-ODF3B-2, AC015712.5, lnc-LAMB3–1, lnc-SPP2–3, and lnc-MAP9–2 correlated with better DFS. The expression of LINC01235 correlated with worse overall survival (OS), while the expression of MIR205HG, lnc-MAP2K6–5, FGF14-AS2, lnc-SPP2–3 correlated with better OS. Highest expression of LINC01614 was observed in progesterone receptor (PR)+, Estrogen receptor (PR)+, and HER2+ tumors, while lowest expression was in TNBC. Concordantly, LINC01614 was highly expressed in the luminalB/HER2+ subtype from the SRP062132 dataset. Elevated expression of LINC01614 was subsequently validated in primary breast cancer tissue and breast cancer cell lines. Bioinformatics and pathway analyses on LINC01614high vs. LINC01614low BC tissue revealed TGFβ1 and ECM as the most activated networks in LINC01614high tumors. Concordantly, strong correlation between the expression of LINC01614 and COL10A1 (R2 = 0.6929), SPOCK1 (R2 = 0.5156), ZEB1 (R2 = 0.3372), TGFBI (R2 = 0.2978), TGFB1 (R2 = 0.1985), ACTA2 (R2 = 0.1833), and TAGLN (R2 = 0.1909) was observed. Mechanistically, exogenous TGFB1 induced LINC01614 expression in the BT474 triple positive BC model, while small-molecule inhibition of transforming growth factor β (TGFβ, SB-431542) or focal adhesion kinase (FAK, PF-573228) abrogated LINC01614 expression. Our data revealed the lncRNA transcription landscape in breast cancer and its molecular subtypes. Our data provide novel insight implicating LINC01614 as unfavorable prognostic marker in BC, its association with the HR+/HER2+ BC molecular subtype and its regulation by TGFβ and FAK signaling.



中文翻译:

乳腺癌中的长非编码RNA(lncRNA)转录态势将LINC01614鉴定为受TGFβ和黏着斑激酶(FAK)信号调节的不良预后生物标志物

长的非编码RNA(lncRNA)代表一类表观遗传调控因子,涉及许多生理和病理状况。在这里,我们表征了837例浸润性乳腺癌患者的lncRNA表达肖像和癌症基因组图谱(TCGA)的105个正常个体的特征,其中揭示了十八种上调和四十六种下调的lncRNA。聚类分析显示为三阴性乳腺癌(TNBC)和正常乳腺组织不同lncRNA轮廓,而HER2中观察到较少的分离+ HR +,HER2 + HR -,HER2 - HR +分子亚型。LINC01614和LINC01235与较差的无病生存期(DFS)相关,而lnc-LRR1-1,lnc-ODF3B-2,AC015712.5,lnc-LAMB3-1,lnc-SPP2-3和lnc- MAP9–2与更好的DFS相关。LINC01235的表达与较差的总生存期(OS)相关,而MIR205HG,lnc-MAP2K6-5,FGF14-AS2,lnc-SPP2-3的表达与较好的OS相关。LINC01614在孕激素受体(PR)+,雌激素受体(PR)+和HER2 +肿瘤中表达最高,而在TNBC中则最低。一致地,LINC01614在luminalB / HER2 +中高表达SRP062132数据集的子类型。随后在原发性乳腺癌组织和乳腺癌细胞系中验证了LINC01614的表达升高。在LINC01614BC与LINC01614BC组织上的生物信息学和通路分析显示,TGFβ1和ECM是LINC01614肿瘤中最活跃的网络。一致地,LINC01614和COL10A1(R 2  = 0.6929),SPOCK1(R 2  = 0.5156),ZEB1(R 2  = 0.3372),TGFBI(R 2  = 0.2978),TGFB1(R 2  = 0.1985)的表达之间有很强的相关性, ACTA2(R 2  = 0.1833)和TAGLN( 观察到R 2= 0.1909。从机理上讲,外源TGFB1诱导了BT474三重阳性BC模型中LINC01614的表达,而对转化生长因子β(TGFβ,SB-431542)或粘着斑激酶(FAK,PF-573228)的小分子抑制消除了LINC01614的表达。我们的数据揭示了乳腺癌及其分子亚型中lncRNA转录的态势。我们的数据提供了新的见解,暗示LINC01614在BC中是不利的预后标志物,与HR + / HER2 + BC分子亚型相关,并且受TGFβ和FAK信号调节。

更新日期:2019-11-18
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