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.