Role of Non-Coding RNAs in the Etiology of Bladder Cancer

Abstract

According to data of the International Agency for Research on Cancer and the World Health Organization (Cancer Incidence in Five Continents, GLOBOCAN, and the World Health Organization Mortality), bladder is among the top ten body locations of cancer globally, with the highest incidence rates reported in Southern and Western Europe, North America, Northern Africa and Western Asia. Males (M) are more vulnerable to this disease than females (F), despite ample frequency variations in different countries, with a M:F ratio of 4.1:1 for incidence and 3.6:1 for mortality, worldwide. For a long time, bladder cancer was genetically classified through mutations of two genes, fibroblast growth factor receptor 3 (FGFR3, for low-grade, non-invasive papillary tumors) and tumor protein P53 (TP53, for high-grade, muscle-invasive tumors). However, more recently scientists have shown that this disease is far more complex, since genes directly involved are more than 150; so far, it has been described that altered gene expression (up- or down-regulation) may be present for up to 500 coding sequences in low-grade and up to 2300 in high-grade tumors. Non-coding RNAs are essential to explain, at least partially, this ample dysregulation. In this review, we summarize the present knowledge about long and short non-coding RNAs that have been linked to bladder cancer etiology.

Keywords: FGFR3; TP53; epigenetics; long non-coding RNA (lncRNA); microRNA (miR); small non-coding RNA (sncRNA).

Figure 1

Classification of long non-coding RNA (lncRNA) and micro-RNA (miR) involved in bladder cancer (BC) etiology based on their regulation. (A) lncRNA classes according to their levels of expression in BC vs. normal urothelium. lncRNA are divided into two classes: (i) lncRNA that are up-regulated (in red; 24/32); and (ii) lncRNA that are down-regulated (in green; 8/32). To date, BC-related lncRNA have been univocally described as up- or downregulated. (B) miR classes according to their levels of expression in BC vs. normal urothelium. miR are split into three classes: (i) miR that are upregulated (in red; 16/65); (ii) miR that are downregulated (in green; 44/65); and (iii) miR that have been described both as up- and downregulated and, as such, cannot be univocally classified using the available data (in grey; 5/65). Notably, while 75% of the BC-related lncRNA are upregulated (i.e., they act as oncogenes), more than 70% of these miR are potentially downregulated (considering all downregulated and half of the non-univocally classified miR), i.e., act as tumor suppressors.