Vishnubalaji Radhakrishnan, Elango Ramesh, Alajez Nehad M
Translational Cancer and Immunity Center (TCIC), Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha P.O. Box 34110, Qatar.
College of Health & Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha P.O. Box 34110, Qatar.
Noncoding RNA. 2022 Jun 21;8(4):44. doi: 10.3390/ncrna8040044.
Triple negative breast cancer (TNBC) represents a diverse group of cancers based on their gene expression profiles. While the current mRNA-based classification of TNBC has contributed to our understanding of the heterogeneity of this disease, whether such heterogeneity can be resolved employing a long noncoding RNA (lncRNA) transcriptome has not been established thus far. Herein, we used iterative clustering and guide-gene selection (ICGS) and uniform manifold approximation and projection (UMAP) dimensionality reduction analysis on a large cohort of TNBC transcriptomic data (TNBC = 360, normal = 88) and classified TNBC into four main clusters: LINC00511-enriched, LINC00393-enriched, FIRRE-enriched, and normal tissue-like. Delving into associated gene expression profiles revealed remarkable differences in canonical, casual, upstream, and functional categories among different lncRNA-derived TNBC clusters, suggesting functional consequences for altered lncRNA expression. Correlation and survival analysis comparing mRNA- and lncRNA-based clustering revealed similarities and differences between the two classification approaches. To provide insight into the potential role of the identified lncRNAs in TNBC biology, CRISPR-Cas9 mediated LINC00511 promoter deletion reduced colony formation and enhanced the sensitivity of TNBC cells to paclitaxel, suggesting a role for LINC00511 in conferring tumorigenicity and resistance to therapy. Our data revealed a novel lncRNA-based classification of TNBC and suggested their potential utilization as disease biomarkers and therapeutic targets.
三阴性乳腺癌（TNBC）根据其基因表达谱代表了一组多样化的癌症。虽然目前基于mRNA的TNBC分类有助于我们理解这种疾病的异质性，但迄今为止，尚未确定使用长链非编码RNA（lncRNA）转录组是否能够解决这种异质性。在此，我们对一大组TNBC转录组数据（TNBC = 360，正常 = 88）进行了迭代聚类和引导基因选择（ICGS）以及均匀流形近似和投影（UMAP）降维分析，并将TNBC分为四个主要簇：富含LINC00511的、富含LINC00393的、富含FIRRE的和正常组织样的。深入研究相关基因表达谱发现，不同lncRNA衍生的TNBC簇在典型、偶然、上游和功能类别上存在显著差异，这表明lncRNA表达改变具有功能后果。比较基于mRNA和lncRNA聚类的相关性和生存分析揭示了两种分类方法之间的异同。为了深入了解所鉴定的lncRNAs在TNBC生物学中的潜在作用，CRISPR - Cas9介导的LINC00511启动子缺失减少了集落形成，并增强了TNBC细胞对紫杉醇的敏感性，这表明LINC00511在赋予肿瘤发生能力和抗治疗性方面发挥作用。我们的数据揭示了一种基于lncRNA的TNBC新分类，并表明它们作为疾病生物标志物和治疗靶点的潜在用途。
