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Long non-coding RNAs XIST and MALAT1 hijack the PD-L1 regulatory signaling pathway in breast cancer subtypes.

ABSTRACT: Long non-coding RNAs (lncRNAs) have attracted widespread attention as potential biological and pathological regulators. lncRNAs are involved in several biological processes in cancer. Triple negative breast cancer (TNBC) is characterized by strong heterogeneity and aggressiveness. At present, the implication of microRNAs (miRs) and lncRNAs in immunotherapy has been poorly studied. Nevertheless, the blockade of immune checkpoints, particularly that of the programmed cell-death protein-1/programmed cell-death ligand-1 (PD-L1) axis, is considered as a principle approach in breast cancer (BC) therapy. The present study aimed to investigate the interaction between immune-modulatory upstream signaling pathways of the PD-L1 transcript that could enhance personalized targeted therapy. MDA-MB-231 cells were transfected with miR-182-5p mimics followed by RNA extraction and cDNA synthesis using a reverse transcription kit, and the expression levels of the target genes were assessed by reverse transcription-quantitative PCR. Furthermore, the expression levels of target genes were measured in tissues derived from 41 patients with BC, including patients with luminal BC and TNBC, as well as their adjacent lymph nodes. The results revealed that the expression levels of miR-182-5p, PD-L1 and metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) were upregulated in MDA-MB-231 cells and BC tissues. However, X-inactive specific transcript (XIST) expression was downregulated in cancer tissues and TNBC cells. Following co-transfection of cells with small interfering RNAs specific for each target gene and miR-182-5p antagomirs, the effect of miR-182-5p was abolished in the presence of lncRNAs. Therefore, the results of the present study indicated that although miR-182-5p exhibited an oncogenic effect, XIST exerted a dominant effect on the regulation of the PD-L1 signaling pathway via the inhibition of the oncogenic function of MALAT1.

SUBMITTER: Samir A

PROVIDER: S-EPMC8200942 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundLong non-coding RNAs (lncRNAs) have emerged as a novel class of RNA due to its diverse mechanism in cancer development and progression. However, the role and expression pattern of lncRNAs in molecular subtypes of B cell acute lymphoblastic leukemia (BCP-ALL) have not yet been investigated. Here, we assess to what extent lncRNA expression and DNA methylation is driving the progression of relapsed BCP-ALL subtypes and we determine if the expression and DNA methylation profile of lncRNAs correlates with established BCP-ALL subtypes.MethodsWe performed RNA sequencing and DNA methylation (Illumina Infinium microarray) of 40 diagnosis and 42 relapse samples from 45 BCP-ALL patients in a German cohort and quantified lncRNA expression. Unsupervised clustering was applied to ascertain and confirm that the lncRNA-based classification of the BCP-ALL molecular subtypes is present in both our cohort and an independent validation cohort of 47 patients. A differential expression and differential methylation analysis was applied to determine the subtype-specific, relapse-specific, and differentially methylated lncRNAs. Potential functions of subtype-specific lncRNAs were determined by using co-expression-based analysis on nearby (cis) and distally (trans) located protein-coding genes.ResultsUsing an integrative Bioinformatics analysis, we developed a comprehensive catalog of 1235 aberrantly dysregulated BCP-ALL subtype-specific and 942 relapse-specific lncRNAs and the methylation profile of three subtypes of BCP-ALL. The 1235 subtype-specific lncRNA signature represented a similar classification of the molecular subtypes of BCP-ALL in the independent validation cohort. We identified a strong correlation between the DUX4-specific lncRNAs and genes involved in the activation of TGF-β and Hippo signaling pathways. Similarly, Ph-like-specific lncRNAs were correlated with genes involved in the activation of PI3K-AKT, mTOR, and JAK-STAT signaling pathways. Interestingly, the relapse-specific lncRNAs correlated with the activation of metabolic and signaling pathways. Finally, we found 23 promoter methylated lncRNAs epigenetically facilitating their expression levels.ConclusionHere, we describe a set of subtype-specific and relapse-specific lncRNAs from three major BCP-ALL subtypes and define their potential functions and epigenetic regulation. The subtype-specific lncRNAs are reproducible and can effectively stratify BCP-ALL subtypes. Our data uncover the diverse mechanism of action of lncRNAs in BCP-ALL subtypes defining which lncRNAs are involved in the pathogenesis of disease and are relevant for the stratification of BCP-ALL subtypes.

Project description:PD-L1 expression in the tumor immune microenvironment is recognized as both a prognostic and predictive biomarker in patients with cutaneous melanoma, a finding closely related to its adaptive (IFN-?-mediated) mechanism of expression. Approximately 35% of cutaneous melanomas express PD-L1, however, the expression patterns, levels, and prevalence in rarer melanoma subtypes are not well described. We performed immunohistochemistry for PD-L1 and CD8 on 200 formalin-fixed paraffin-embedded specimens from patients with acral (n=16), mucosal (n=36), uveal (n=103), and chronic sun-damaged (CSD) (n=45) melanomas (24 lentigo maligna, 13 'mixed' desmoplastic, and 8 'pure' desmoplastic melanomas). CD8+ tumor-infiltrating lymphocyte (TIL) densities were characterized as mild, moderate, or severe, and their geographic association with PD-L1 expression was evaluated. Discrete lymphoid aggregates, the presence of a spindle cell morphology, and the relationship of these features with PD-L1 expression were assessed. PD-L1 expression was observed in 31% of acral melanomas, 44% of mucosal melanomas, 10% of uveal melanomas, and 62% of CSD melanomas (P<0.0001). Compared to our previously characterized cohort of cutaneous melanomas, the proportion of PD-L1(+) tumors was lower in uveal (P=0.0002) and higher in CSD (P=0.0073) melanomas, while PD-L1 expression in the acral and mucosal subtypes was on par. PD-L1 expression in all subtypes correlated with a moderate-severe grade of CD8+ TIL (all, P<0.003), supporting an adaptive mechanism of expression induced during the host antitumor response. The tumor microenvironments observed in CSD melanomas segregated by whether they were the pure desmoplastic subtype, which showed lower levels of PD-L1 expression when compared to other CSD melanomas (P=0.047). The presence of lymphoid aggregates was not associated with the level of PD-L1 expression, while PD-L1(+) cases with spindle cell morphology demonstrated higher levels of PD-L1 than those with a nested phenotype (P<0.0001). Our findings may underpin the reported clinical response rates for anti-PD-1 monotherapy, which vary by subtype.

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Long non-coding RNAs XIST and MALAT1 hijack the PD-L1 regulatory signaling pathway in breast cancer subtypes.

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