ROR2表現在尿路上皮癌病人的預後意義

李威明^1,2,3、吳文正^1,3,4、李經家^1,3、柯宏龍^1,3、韋又菁⁵、葉信志^1,3,4、李香瑩^3,4

李健逢⁶、黃俊農^3,4、黃俊雄^1,3

高雄醫學大學附設中和紀念醫院泌尿部¹; 衛生福利部屏東醫院泌尿科²; 高雄醫學大學醫學系泌尿學科³; 高雄市立大同醫院泌尿科⁴; 高雄市立大同醫院病理科⁵; 奇美醫學中心病理部⁶

The Prognostic Significance of ROR2 Expression in Patients with Urothelial Carcinoma

Wei-Ming Li ^1,2,3, Wen-Jeng Wu ^1,3,4, Ching-Chia Li ^1,3, Hung-Lung Ke ^1,3, Yu-Ching Wei⁵, Hsin-Chin Yen^1,3,4, Hsiang-Ying Lee^3,4, Chien-Feng Li⁶, Chun-Nung Huang ^3,4, Chun-Hsiung Huang ^1,3

¹Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan

² Department of Urology, Pingtung Hospital, Ministry of Health and Welfare, Executive Yuan, Pingtung, Taiwan

³ Department of Urology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

⁴ Department of Urology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan

⁵ Department of Pathology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan

⁶Department of Pathology, Chi Mei Medical Center, Tainan, Taiwan

Purpose: Emerging evidence shows that c-Jun N-terminal kinase (JNK) promotes tumor progression

and is involved in various cancers. JNK-associated signaling pathways also modulate metabolic reprogramming, cancer stem cells, tumor proliferation, and migration. Focusing on the genes belonging to the JNK cascade (GO:0007254) and associated cancer progression, data mining was performed on a public dataset of bladder cancer (GSE31684). We found that receptor tyrosine kinase-like orphan receptor 2 (ROR2) was the most upregulated gene during bladder cancer progression. Thus, we aimed to investigate the roles of ROR2 expression and its prognostic value in upper tract UC (UTUC) and urinary bladder UC (UBUC) in our large, well-characterized cohort.

Materials and Methods: Clinicopathological data, fresh and formalin-fixed paraffin-embedded UC tissues were analyzed retrospectively. We determined ROR2 expression using qRT-PCR and immunohistochemical staining assessed by H-scores. ROR2expression correlated with clinicopathological features and patient outcomes, including metastasis-free survival (MFS) and cancer-specific survival (CSS). Statistical analyses were performed using Pearson’s chi-square test, Kaplan-Meier estimates of DSS and MFS, and the Cox proportional hazards model. We used GO enrichment analysis to clarify the functional significance of dysregulated ROR2 in UC.

Results: Initially, the evaluation of ROR2 mRNA expression in 50 frozen UBUCs showed significantly upregulated levels in high stage UC. Data from 295 UBUC and 340 UTUC patients were available for the final immunohistochemical evaluation. 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 CSS and MFS 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.

Conclusions: 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.