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Long non-coding RNA (lncRNA) transcriptional landscape in breast cancer identifies LINC01614 as non-favorable prognostic biomarker regulated by TGF? and focal adhesion kinase (FAK) signaling.

ABSTRACT: 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-, HER2-HR+ 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 TGF?1 and ECM as the most activated networks in LINC01614high tumors. Concordantly, strong correlation between the expression of LINC01614 and 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), ACTA2 (R 2?=?0.1833), and TAGLN (R 2?=?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 ? (TGF?, 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 TGF? and FAK signaling.

SUBMITTER: Vishnubalaji R

PROVIDER: S-EPMC6591245 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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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.

Vishnubalaji Radhakrishnan R Shaath Hibah H Elkord Eyad E Alajez Nehad M NM

Cell death discovery 20190624

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 ...[more]

PMID: 31263577

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Project description:PurposeRegulation of lens development involves an intricate interplay between growth factor (e.g. FGF and TGFbeta) and extracellular matrix (ECM) signaling pathways. Focal adhesion kinase (FAK) is a cytoplasmic tyrosine kinase that plays key roles in transmitting ECM signals by integrins. In this study, we delineated patterns of FAK expression and tyrosine phosphorylation (Y397) in the developing lens and investigated its regulation by FGF2. We also examined FAK expression and activation during disrupted fiber differentiation in mice expressing a dominant-negative TGFbeta receptor.MethodsFAK expression and activation (phosphorylation on Y397) was studied in embryonic and postnatal rodent lenses by in situ hybridization, immunofluorescence, and western blotting. Rat lens explants were used to investigate the effects of FGF2 on FAK expression and activation. Immunofluorescence and western blotting were used to examine FAK expression and phosphorylation in transgenic mice that express a dominant-negative TGFbeta receptor.ResultsFAK is widely expressed and phosphorylated during embryonic stages of lens morphogenesis and differentiation. However, in postnatal lenses its expression and activation becomes restricted to the posterior germinative zone and the transitional zone at the lens equator. While both NH2- and COOH-terminal antibodies revealed cytoplasmic and membrane-associated staining in lens cells, the NH2-terminal antibody also showed FAK was present in fiber cell nuclei. In vitro, FAK expression and phosphorylation on Y397 were increased by concentrations of FGF2 that initiate lens epithelial cell migration (10 ng/ml) and differentiation (50 ng/ml) but not proliferation (5 ng/ml). Moreover, reactivity for Y397 phosphorylated FAK is prominent in the nuclei of differentiating fibers both in vivo and in vitro. Disruption of TGFbeta-like signals by ectopic expression of a dominant-negative TGFbeta receptor (TbetaRII(D/N)) results in abnormal lens fiber differentiation in transgenic mice. While FAK expression is initiated normally in the posterior germinative zone of TbetaRII(D/N) transgenic lenses, as fiber differentiation proceeds, FAK becomes localized to a perinuclear compartment, decreases its association with the cytoskeleton and is poorly phosphorylated on Y(397).ConclusionsFAK is widely expressed and activated during early lens morphogenesis. During secondary lens fiber differentiation, FAK is expressed and phosphorylated on Y397 as epithelial cells exit the cell cycle, initiate migration at the equator, and undergo differentiation in the transitional zone. During terminal fiber differentiation an NH2-terminal fragment of FAK, including Y397, is translocated to the nucleus. The expression, activation, and nuclear localization of FAK are regulated, at least partly, by FGF2. FAK activity and subcellular localization are also modulated by TGFbeta-like signals. In fiber cells of TbetaRII(D/N) transgenic lenses, FAK is abnormally retained in a perinuclear compartment, loses its association with the cytoskeleton, and is poorly phosphorylated. These data suggest that integrin signaling via FAK plays important roles during lens differentiation, mediated by FGFs and TGFbeta-superfamily signals.

Dataset Information

Long non-coding RNA (lncRNA) transcriptional landscape in breast cancer identifies LINC01614 as non-favorable prognostic biomarker regulated by TGF? and focal adhesion kinase (FAK) signaling.

Publications

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.

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