4.2 Biomarkers of bladder cancer
Cancer biomarkers are biological molecules available in tissues, body fluids, or blood that helps in cancer prognosis, diagnosis, prediction of response to treatment, and monitoring disease progression.86,87 To date, there have been several studies conducted to determine a potential bladder cancer biomarkers in order to enhance the diagnostic accuracy,87,88however, due to the false-positive and false-negative results, the use of these biomarkers have sparked clinical controversy.89 Nevertheless, utilizing the potential biomarkers to enhance the therapeutic surveillance and outcome has been investigated. A study on 105 NMIBC patients showed the alteration of certain genes that includes; TP53 , PIK3CA, FGFR, TERTpromoter, STAG2, ARIDIA, and KDM6A . Among these genes, theTERT promoter accounted for 73% of alteration in NMBIC.90 While in MIBC, RNA-Seq analysis on high-grade bladder cancer (urine sample) revealed high expression of 15 genes such as PLEKHS1, CP, WNT5A, RARRES1, MYBPC1, AR, ROBO1, SLC14A1, AKR1C2, FBLN1, IGFBP5, STEAP2, ENTPD5, GPD1L, andSYBU. 91 Recently, Sucularli92determined genes differentially expressed among bladder cancer (n=404) compared to the normal bladder (n=28) and found 559 genes were downregulated and 171 were upregulated . Six genes were associated with the patient’s survival that includes CDC20, PTTG1, PLK1, SFN, CCNB1, and BUB1B. 92
Furthermore, Shen et al93 conducted a study on cancer stem cells to determine the potential of Sox4 as a biomarker for bladder cancer. Findings from the study showed a reduction in sphere formation and an elevation in the levels of aldehyde dehydrogenase in cells and the tumour forming ability upon the knockdown of Sox4 . Moreover, the elevated expression of Sox4 was found to be correlated with stages of cancer and a reduction in the rate of survival, making it a potential biomarker in the aggressive bladder cancer phenotype.93
Recent research has incorporated circular RNA to develop functional biomarkers for bladder cancer. The involvement of circRNA in gene transcription as well as translation suggests the potential participation of circRNA in the process of disease progression including cancer.94 In a study by Li et al95RNA-Seq results demonstrated down regulation of circular RNA (circHIPK3) in cell lines and tissues of bladder cancer. CircHIPK3 can sponge miR-558 which in turn suppresses heparanase (HPSE ) expression as demonstrated mechanistically. The circHIPK3 overexpression was found to halt the bladder cell angiogenesis, migration, and invasion in vitro and inhibit the metastasis and growth of bladder cancer in vivo, suggesting a potential biomarker for bladder cancer therapy.95Similarly, a study by Dong et al,94 utilized a novel circRNA and circACVR2A of which their overexpression is linked with migration, proliferation and invasion of bladder cancer cells.94 It was demonstrated that circACVR2A is able to interact directly with miR-626, thus acting as a miRNA sponge which in turn regulates the expression of EYA4. 94Despite the above findings and the potential of several genes as bladder cancer biomarkers, to date, there have been no available prognostic and diagnostic biomarkers that have successfully been translated clinically, implying the need for further future studies to improvise the available biomarkers.