Abstract
We investigated the association of receptor tyrosine kinase-like orphan receptor 2 (ROR2) expression with clinicopathological features and oncologic outcomes in large urothelial carcinoma (UC) of the upper tract (UTUC) and urinary bladder (UBUC) cohorts. Through transcriptomic profiling of a published dataset (GSE31684), ROR2 was discovered to be the most upregulated gene during UC progression, focusing on the JNK cascade (GO:0007254). Initially, the evaluation of ROR2 mRNA expression in 50 frozen UBUCs showed significantly upregulated levels in high-stage UC. Moreover, high ROR2 immunoexpression significantly correlated with high tumor stage, high tumor grade, lymph node metastasis, and vascular invasion (all p < 0.05). In multivariate analysis, after adjusting for standard clinicopathological features, ROR2 expression status was an independent prognosticator of cancer-specific survival and metastasis-free survival in UTUC and UBUC (all p < 0.01). In the subgroup analysis, it also significantly predicted bladder tumor recurrence in non-muscle invasive UBUC. Furthermore, the GO enrichment analysis showed that fatty acid, monocarboxylic acid, carboxylic acid metabolic processes, negative regulation of neutrophil migration, and negative regulation of granulocyte and neutrophil chemotaxis were significantly enriched by ROR2 dysregulation. In conclusion, high ROR2 immunoexpression was associated with aggressive pathological characteristics in UC and independently predicted worse prognosis, suggesting it could play roles in clinical risk stratification and therapy decisions.
Highlights
Urothelial carcinoma (UC) of the upper tract (UT) and urinary bladder (UB) is one of the most frequently occurring malignancies worldwide
Some of them, such as MLK3, TAK1, ASK1, MKK4, MKK7, JNK1, and JNK2, have been demonstrated to regulate cell proliferation, cell survival, cell differentiation, and cell renewal [8,9].We found that receptor tyrosine kinase-like orphan receptor 2 (ROR2) was the most upregulated gene during bladder cancer progression, from non-muscle-invasive bladder cancer (NMIBC) to muscle-invasive bladder cancer (MIBC)
After adjusting for primary tumor stage, tumor grade, perineural invasion, vascular invasion, lymph node status, and mitotic rate for metastasis-free survival (MFS) and CSS, we found that ROR2 expression status remained an independent predictor of CSS (HR:2.166; 95% CI = 1.178–3.983; p = 0.013) and MFS (HR: 2.786; 95% CI = 1.646–4.714; p < 0.001)
Summary
Urothelial carcinoma (UC) of the upper tract (ureter and renal pelvis) (UT) and urinary bladder (UB) is one of the most frequently occurring malignancies worldwide. Tobacco smoking and Biomedicines 2021, 9, 1054. Biomedicines 2021, 9, 1054 occupational exposure to aromatic amines or polycyclic are the main environmental risk factors for UC [2,3,4]. Recent meta-analyses have demonstrated that current and former smokers are at an increased risk of UC. Dose-response analyses indicate that even after long-term smoking cessation, an elevated risk of UC remains [5]. Family history and heritable gene variants seem to have little impact, genetic studies have demonstrated a potential role of genetic predisposition to urothelial carcinogenesis [6,7]
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