Abstract
Urothelial carcinoma of the bladder (UCB) is one of the commonly diagnosed cancers in the world. The UCB has the highest rate of recurrence of any malignancy. A genome-wide screening of transcriptome dysregulation between cancer and normal tissue would provide insight into the molecular basis of UCB recurrence and is a key step to discovering biomarkers for diagnosis and therapeutic targets. Compared with microarray technology, which is commonly used to identify expression level changes, the recently developed RNA-seq technique has the ability to detect other abnormal regulations in the cancer transcriptome, such as alternative splicing. In this study, we performed high-throughput transcriptome sequencing at ∼50× coverage on a recurrent muscle-invasive cisplatin-resistance UCB tissue and the adjacent non-tumor tissue. The results revealed cancer-specific differentially expressed genes between the tumor and non-tumor tissue enriched in the cell adhesion molecules, focal adhesion and ECM-receptor interaction pathway. Five dysregulated genes, including CDH1, VEGFA, PTPRF, CLDN7, and MMP2 were confirmed by Real time qPCR in the sequencing samples and the additional eleven samples. Our data revealed that more than three hundred genes showed differential splicing patterns between tumor tissue and non-tumor tissue. Among these genes, we filtered 24 cancer-associated alternative splicing genes with differential exon usage. The findings from RNA-Seq were validated by Real time qPCR for CD44, PDGFA, NUMB, and LPHN2. This study provides a comprehensive survey of the UCB transcriptome, which provides better insight into the complexity of regulatory changes during recurrence and metastasis.
Highlights
The bladder cancer is the seventh most prevalent type of cancer worldwide
Our study provides the first comprehensive insight into the transcriptome of a recurrent, drug-resistant and muscle-invasive urothelial carcinoma of the bladder with RNA-Seq
We identified the levels of differentially expressed genes and alternative splicing patterns associated with cancer
Summary
The bladder cancer is the seventh most prevalent type of cancer worldwide. Global estimates suggest that in 2008, approximately 386,300 new bladder cancer cases were diagnosed and that 150,200 patients succumbed to the disease [1]. As the major subtype of bladder cancer, urothelial carcinoma of the bladder (UCB) is the fifth most expensive cancer to treat, accounting for $3.7 billion in direct costs in 2001 [2]. The costs are high because most patients survive long term, recurrence is frequent and lifelong surveillance is required. This disease occurs predominantly in men, yet it is increasing in incidence among women in a manner that cannot be entirely explained by increased tobacco use [3]. 80% of bladder cancers present as non-muscle invasive urothelial carcinoma, 70% of them will recur, and 10– 20% of them will progress and invade the bladder muscle [4]. High-grade muscleinvasive disease represents a life-threatening condition and requires timely treatment [7,8]
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