Downregulation of RNF128 Predicts Progression and Poor Prognosis in Patients with Urothelial Carcinoma of the Upper Tract and Urinary Bladder

Abstract

Background: The TP53 tumor suppressor gene plays a crucial role in the carcinogenesis of many malignancies, including urothelial carcinoma (UC). Overexpression of p53 is associated with poor prognosis in UC. Recently, RING finger protein 128 (RNF128) was shown to be involved in p53-induced apoptosis, forming a negative feedback loop. However, the significance of RNF128 in patients with UC remains unknown. In this study, our aim was to evaluate the expression of RNF128 in UC and to assess its predictive and prognostic value in a well-established cohort.Methods: Through data mining from a published transcriptome (GSE31684), RNF128 was identified as the most differentially expressed gene in UC among those associated with negative regulation of the cytokine biosynthetic process (GO:0042036). Its immunoexpression was further evaluated using the H-scores of 340 patients with upper urinary tract UC (UTUC) and 295 with urinary bladder UC (UBUC). The scores were correlated with clinicopathological features, disease-specific survival (DSS) and metastasis-free survival (MeFS). We also used Western blot analysis to evaluate RNF128 protein expression in human urothelial cell (HUC) lines.Results: Downregulation of RNF128 expression was significantly associated with advanced pT stage (p<0.001), high histological grade (UTUC, p<0.001; UBUC, p=0.035), nodal metastasis (UTUC, p<0.001; UBUC, p=0.001), vascular invasion (UTUC, p<0.001; UBUC, p=0.008) and high mitotic rate (UTUC, p=0.003; UBUC, p=0.023). Low expression of RNF128 was an adverse prognosticator for DSS (UTUC, p<0.0001; UBUC, p<0.0001) and MeFS (UTUC, p<0.0001; UBUC, p=0.0002). Moreover, low expression was predictive of poor DSS (UTUC, p=0.006; UBUC, p=0.003) and MeFS (UTUC, p=0.009; UBUC, p=0.036) in multivariate comparisons. Western blot analysis showed that the RNF128 protein was downregulated in invasive urothelial cancer cell lines.Conclusion: Our findings showed that downregulation of RNF128 was correlated with cancer invasiveness and metastasis as well as reduced survival in patients with UTUC and UBUC, identifying RNF128 as a prognostic factor in UC.

Downregulation of RNF128 activates Wnt/β-catenin signaling to induce cellular EMT and stemness via CD44 and CTTN ubiquitination in melanoma

“…Chen et al found that RNF128, as a tumor promoter, physically interacts with and degrades p53 under stress conditions [27]. Conversely, Lee et al found that downregulation of RNF128 was associated with the reduced survival in patients with urothelial carcinoma [28]. Here, we found that RNF128 expression is downregulated in melanoma compared with that in adjacent peritumoral tissues.…”

<p>RNF128 Promotes Malignant Behaviors via EGFR/MEK/ERK Pathway in Hepatocellular Carcinoma</p>

“…19 In addition, RNF128 also regulates energy metabolism 20 and cytoskeletal reorganization. 21 RNF128 has recently been documented to be involved in the progression of diverse cancers, including esophageal cancer, 12 melanoma, 13 urothelial carcinoma 14 and lymphoma. 11 Nonetheless, the role of RNF128 in HCC remains unexplored.…”

“…12 In melanoma, however, RNF128 regulates Wnt/β-catenin signaling to suppress EMT and stemness through a mechanism involving CD44 ubiquitination. 13 RNF128 downregulation is associated with poor prognosis in upper urinary tract and bladder cancer, 14 whereas there is a lack of research about the role of RNF128 in HCC.…”

Chromatin reorganization during myoblast differentiation involves the caspase-dependent removal of SATB2

“…The corollary to this is the impact on SATB2 targeted loci during differentiation, where SATB2 is removed from the nucleus, which simultaneously represses growth-related euchromatic genes and relieves repression of differentiation-specific genes that were previously sequestered in the heterochomatic regions of the nucleus. This hypothesis is supported by the ChIP-and RNA-seq data where a number of genes that are potent promoters of cell proliferation were downregulated during early myoblast differentiation, including Hdac9 (Lapierre et al 2016), Celf1 (Xia et al, 2015), Ncoa1 (Wang et al, 2018), Hdgfrp3 (Xiao et al, 2013), and Rnf128 (Lee et al, 2016), all of which were significantly downregulated following SATB2 removal during early stages of the differentiation program ( Figure 3F).…”