Prognostic Utility of FBLN2 Expression in Patients With Urothelial Carcinoma

Wei-Ming Li; Ti-Chun Chan; Steven Kuan-Hua Huang; Wen-Jeng Wu; Hung-Lung Ke; Peir-In Liang; Yu-Ching Wei; Yow-Ling Shiue; Chien-Feng Li

doi:10.3389/fonc.2020.570340

Prognostic Utility of FBLN2 Expression in Patients With Urothelial Carcinoma

Front Oncol. 2020 Oct 29:10:570340. doi: 10.3389/fonc.2020.570340. eCollection 2020.

Authors

Wei-Ming Li^{1

2

3

4}, Ti-Chun Chan⁵, Steven Kuan-Hua Huang⁶, Wen-Jeng Wu^{1

2

3

7

8}, Hung-Lung Ke^{1

2}, Peir-In Liang^{9

2}, Yu-Ching Wei^{2

10}, Yow-Ling Shiue^{8

11}, Chien-Feng Li^{8

12

13}

Affiliations

¹ Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
² Department of Urology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
³ Cohort Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan.
⁴ Department of Urology, Ministry of Health and Welfare Pingtung Hospital, Pingtung, Taiwan.
⁵ Department of Medical Research, Chi-Mei Medical Center, Tainan, Taiwan.
⁶ Division of Urology, Department of Surgery, Chi Mei Medical Center, Tainan, Taiwan.
⁷ Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan.
⁸ Institute of Medical Science and Technology, National Sun Yat-sen University, Kaohsiung, Taiwan.
⁹ Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
¹⁰ Department of Pathology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan.
¹¹ Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan.
¹² Department of Pathology, Chi-Mei Medical Center, Tainan, Taiwan.
¹³ National Cancer Research Institute, National Health Research Institutes, Tainan, Taiwan.

Abstract

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

Keywords: FBLN2; bladder cancer; prognosis; upper urinary tract cancer; urothelial carcinoma.