Abstract
Basal and luminal subtypes of muscle-invasive bladder cancer (MIBC) have distinct molecular profiles and heterogeneous clinical behaviors. The interactions between mRNAs and lncRNAs, which might be regulated by miRNAs, have crucial roles in many cancers. However, the miRNA-dependent crosstalk between lncRNA and mRNA in specific MIBC subtypes still remains unclear. In this study, we first classified MIBC into two conservative subtypes using miRNA, mRNA and lncRNA expression data derived from The Cancer Genome Atlas. Then we investigated subtype-related biological pathways and evaluated the subtype classification performance using Decision Trees, Random Forest and eXtreme Gradient Boosting (XGBoost). At last, we explored potential miRNA-mediated lncRNA-mRNA crosstalks based on co-expression analysis. Our results show that: (1) the luminal subtype is primarily characterized by upregulation of metabolism-related pathways while the basal subtype is predominantly characterized by upregulation of epithelial-mesenchymal transition, metastasis, and immune system process-related pathways; (2) the XGBoost prediction model is consistently robust for classification of the molecular subtypes of MIBC across four datasets (The area under the ROC curve > 0.9); (3) the expression levels of the molecules in the miR-200c and miR141-mediated lncRNA-mRNA crosstalks differ considerably between the two subtypes and have close relationships with the prognosis of MIBC. The miR-200c and miR-141-dependent mRNA-lncRNA crosstalks might be of great significance in tumorigenesis and tumor progression and may serve as the novel prognostic predictors and classification markers of MIBC subtypes.
Highlights
Urothelial bladder cancer (UBC) is one of the most common malignant tumors of urinary system
The muscle-invasive bladder cancer (MIBC) RNA-Seq (FPKM) and clinical data were obtained from The Cancer Genome Atlas (TCGA) public data portal1, and miRNA-Seq (RPM) data was downloaded from the Broad GDAC Firehose2
The consensus clustering (CC) was once again performed on the cluster of cluster (CoC) dataset to generate the different Ks, and the Average of Silhouette Width (ASW), cophenetic correlation coefficient (CPCC), K, and proportion of ambiguous clustering (PAC) were used to evaluate the optimal K (Supplementary Figure S1)
Summary
Urothelial bladder cancer (UBC) is one of the most common malignant tumors of urinary system. A great number of studies have reported that according to shared RNA expression patterns or specific genomic alterations MIBC can be further classified into two major subtypes, namely basal and luminal (Sjodahl et al, 2012; Iyer et al, 2013; Choi et al, 2014a,b; Damrauer et al, 2014; Network, 2014; Robertson et al, 2017), which are strikingly similar to the molecular subtypes first described in breast cancer (Perou et al, 2000; Prat et al, 2010). Pathways that are involved in EMT and immune-associated pathways are upregulated in the basal subtype (Choi et al, 2014a). The molecular biomarkers and pathways involved in MIBC subtypes are the key to understanding its subtype heterogeneity and identifying subtype-specific biomarkers that can be used to better manage MIBC patients
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