Abstract
Piwi-like proteins are essential for stem-cell maintenance and self-renewal in multicellular organisms. We analyzed the expression of Piwi-like 1 and Piwi-like 2 by immunohistochemistry (IHC) in 95 muscle invasive bladder cancer (MIBC) samples using tissue microarray. Application of an immunoreactive score (IRS) revealed 37 and 45 patients who were Piwi-like 1 and -2 positive (IRS > 2). IHC results were correlated with clinico-pathological and survival data. The expression of both proteins was positively correlated with each other, lymph node metastasis and expression of CK20 and GATA 3. A negative correlation for both proteins was detected for disease-specific survival (DSS), recurrence, Ki67/MIB1 proliferation index, and CK5 expression. Detection of Piwi-like 1 protein positivity was associated with poor DSS (P = 0.019; log rank test, Kaplan-Meier analysis), and in multivariate Cox’s analysis (adjusted to tumor stage and tumor grade), it was an independent prognostic factor for DSS (RR = 2.16; P = 0.011). Piwi-like 2 positivity was associated with DSS (P = 0.008) and recurrence-free survival (RFS; P = 0.040), and in multivariate Cox’s analysis, Piwi-like 2 positivity was an independent prognostic factor for DSS (RR = 2.46; P = 0.004) and RFS (RR = 3.0; P = 0.003). Most interestingly, in the basal type patient subgroup (CK5+/GATA3−), Piwi-like 2 positivity was associated with poorer DSS, OS and RFS (P < 0.001, P = 0.004 and P = 0.05; log rank test). In multivariate analysis, Piwi-like 2 positivity was an independent prognostic factor for DSS (RR = 12.70; P = 0.001), OS (RR = 6.62; = 0.008) and RFS (RR=13.0; P = 0.040). In summary, Piwi-like 1 and -2 positivity are associated with clinico-pathological factors and survival. Both Piwi-like proteins are suggested as biomarkers for MIBC patients.
Highlights
Bladder cancer (BCa) is the ninth most commonly diagnosed cancer and the 13th leading cause of cancer-related death worldwide[1]
We studied a cohort of 95 muscle invasive bladder cancer (MIBC) for their Piwi-like 1 and Piwi-like 2 protein expression by immunohistochemistry (IHC)
Expression of both proteins was positively correlated with lymph node metastasis, CK20 staining, and GATA 3 staining; the expression levels of both Piwi-like proteins were correlated with each other
Summary
Bladder cancer (BCa) is the ninth most commonly diagnosed cancer and the 13th leading cause of cancer-related death worldwide[1]. Piwi-like proteins catalyze an amplification loop (ping-pong cycle) of small RNAs (piRNAs) Both piRNAs and Piwi-like proteins function as a Piwi-ribonucleoprotein complex for transposon repression through target degradation and epigenetic silencing[14,15]. Et al showed that Piwi-like 1 affects the cell cycle by decreasing the expression of transforming growth factor-β receptors (TGFRI/II), and increasing the expression of cyclin-dependent kinases (CDK) 4, CDK6 and CDK8 on the RNA and the protein level in breast cancer cells[21]. An association of Piwi-like 1 (Hiwi) with global DNA methylation and silencing of cyclin-dependent kinase inhibitor (CDKI) has been reported in Hiwi expressing MSCs22 In line with these findings, Piwi-like 1 overexpression promoted cell proliferation and induced global DNA methylation in colon cancer cell lines[23]. Levels of Piwi-like 2 expression could be used to separate a subgroup of MIBC, i.e., the basal type (CK5+/CK20−), into a group possessing better OS, DSS and RFS with Piwi-like 2-negative staining and a group having worse OS, DSS and RFS with Piwi-like 2-positive staining
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