Abstract
The expression and function of caldesmon (CAD) in urothelial bladder carcinoma (BC) have not been reported. Here, we investigated the expression, prognostic value, and potential functional mechanism of CAD in primary non-muscle-invasive bladder cancer (NMIBC). Protein profiling of tissue samples using antibody microarrays showed significantly higher CAD expression in muscle-invasive BC tissues compared with NMIBC tissues. We then validated the CAD expression in BC cells by immunohistochemistry analysis using paraffin-embedded tissue blocks and western blots using BC cell lines. In addition, we examined the expression of CAD variants by reverse transcription-polymerase chain reaction, and confirmed the expression of low-molecular-weight isoforms (L-CAD), specifically encoded by WI-38 L-CAD II (transcript variant 2), in BC cells. Survival analysis in an independent primary NMIBC cohort comprising 132 patients showed that positive CAD expression was significantly associated with poorer prognosis than no CAD expression with regard to recurrence- and progression-free survival (p = 0.001 and 0.014, respectively). Multivariate analyses further indicated that positive CAD expression was an independent predictor of progression-free survival (p = 0.032; HR = 5.983). Data obtained from in vitro silencing and overexpression studies indicated that L-CAD promotes migration and invasiveness of BC cells. Immunofluorescence assays showed dramatic structural changes in the actin cytoskeleton of BC cells after L-CAD overexpression. Our findings collectively suggest that L-CAD overexpression in primary NMIBC is significantly associated with tumor progression and that a possible mechanism for L-CAD's activity is implicated in increased cell motility and invasive characteristics through morphological changes in BC cells.
Highlights
Bladder cancer (BC) is the second most common cancer of the genitourinary tract worldwide [1]
Among the high-throughput technology platforms, we previously demonstrated the potential applicability of antibody microarray (AbM) profiling in identifying novel biomarkers in primary non-muscle-invasive BC (NMIBC) [9]
While CAD was expressed primarily in the cell membrane and cytoplasm of BC cells, its expression was significantly higher in muscle-invasive high-grade BC cells compared with NMIBC cells, consistent with the results of AbM profiling
Summary
Bladder cancer (BC) is the second most common cancer of the genitourinary tract worldwide [1]. NMIBC [2], which is treated with transurethral resection of bladder tumor (TURBT) with/without intravesical therapy. Despite complete removal of NMIBC by TURBT, the recurrence rate is 15%–90% within 5 years, and the progression rate is 7%–50% [3,4,5]. Variable recurrence and progression rates reflect the heterogeneity of NMIBC, while identification of prognostic factors is crucial for optimal management of patients with NMIBC. High-throughput technology allows us to analyze multiple concurrent molecular alterations; it is widely used to identify BC-related biomarkers [6,7,8]. Among the high-throughput technology platforms, we previously demonstrated the potential applicability of antibody microarray (AbM) profiling in identifying novel biomarkers in primary NMIBC [9]. In our previous AbM profiling using tissue specimens, caldesmon (CAD) was identified as one of the proteins with significant differential expression between BC tissue and normal urothelial tissue [9]
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