FBLN2表現對於尿路上皮癌病人預後之影響

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 utility of FBLN2 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:

Abnormal extracellular matrix (ECM) remodeling plays an essential role in urothelial carcinoma (UC) invasiveness and metastasis. Focusing on the ECM structural constituent (GO: 0005201), we recognized a significant upregulation of the fibulin 2 gene (FBLN2) during UC progression in a published UC transcriptome (GSE31684). Thus, we aimed to investigate the roles of FBLN2 expression and its prognostic value in upper urinary tract UC (UTUC) and urinary bladder UC (UBUC) in our large, well-characterized cohort.

Materials and Methods:

Clinicopathological data and formalin-fixed paraffin-embedded UC tissues were analyzed retrospectively. We determined FBLN2 expression using immunohistochemical staining assessed by H-scores. FBLN2 expression correlated with clinicopathological features and patient outcomes, including metastasis-free survival (MFS) and disease-specific survival (DSS). 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 Ingenuity Pathway Analysis (IPA) to clarify the functional significance of dysregulated FBLN2 in UC.

Results:

Data from 295 UBUC and 340 UTUC patients were available for the final evaluation. Pearson’s chi-square test showed that high FBLN2immunoexpression significantly correlated with adverse pathologic variables, such as advanced pathologic tumor stage, high histological grade, perineural invasion, vascular invasion, lymph node metastasis, and increased mitotic rate (all p<0.05). Kaplan-Meier analysis demonstrated associations of high FBLN2 expression with worse DSS (p<0.001) and MFS (p<0.001). Furthermore, multivariate analysis identified high FBLN2 expression as an independent predictive risk factor for DSS (hazard ratio [HR] in UBUC, 2.306, p=0.014; in UTUC, 2.561, p=0.012) and MFS (HR in UBUC, 2.493, p=0.001; in UTUC, 2.837, p=0.001). IPA demonstrated that multiple signaling pathways were enriched, including the oxidative phosphorylation, mitochondrial dysfunction, and regulation of the epithelial-mesenchymal transition pathways.

Conclusions:

High FBLN2 expression was associated with adverse pathologic features and worse oncological outcomes and may serve as a prognostic biomarker for UC.