The Clinical Implications and Molecular Mechanism of CX3CL1 Expression in Urothelial Bladder Cancer

Guangliang Jiang; Hui Wang; Da Huang; Yishuo Wu; Weihong Ding; Qidong Zhou; Qiang Ding; Ning Zhang; Rong Na; Ke Xu

doi:10.3389/fonc.2021.752860

The Clinical Implications and Molecular Mechanism of CX3CL1 Expression in Urothelial Bladder Cancer

Front Oncol. 2021 Oct 4:11:752860. doi: 10.3389/fonc.2021.752860. eCollection 2021.

Authors

Guangliang Jiang¹, Hui Wang^{2

3

4}, Da Huang¹, Yishuo Wu^{2

3}, Weihong Ding^{2

3}, Qidong Zhou^{2

3}, Qiang Ding^{2

3}, Ning Zhang¹, Rong Na¹, Ke Xu^{2

3}

Affiliations

¹ Department of Urology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
² Department of Urology, Huashan Hospital, Fudan University, Shanghai, China.
³ Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China.
⁴ Department of Nuclear Medicine, West China Hospital, Sichuan University, Chengdu, China.

Abstract

Background: CX3CL1 is a chemokine that may play important roles in cancer immune regulation. Its mechanism in bladder cancer (BCa) is poorly understood. The objective of the current study was to evaluate the association between CX3CL1 and BCa and the related biological mechanisms.

Methods: A total of 277 patients with BCa were enrolled in the present study. The association between CX3CL1 expression and disease outcome was evaluated. In vitro and in vivo experiments were performed using the TCCSUP cell line to investigate the function of CX3CL1 in BCa.

Results: Compared with low expression, high expression of CX3CL1 was significantly associated with poorer progression-free survival (hazard ratio [HR]=2.03, 95% confidence interval [95% CI]: 1.26-3.27, P=0.006), cancer-specific survival (HR=2.16, 95% CI: 1.59-2.93, P<0.001), and overall survival (HR=1.55, 95% CI: 1.08-2.24, P=0.039). Multivariable Cox regression analysis suggested that CX3CL1 was an independent prognostic factor for BCa outcomes. In vitro and in vivo experiments indicated that high expression of CX3CL1 was significantly associated with cell proliferation (P<0.001) and invasion (P<0.001). Gene expression profiling results showed that after CX3CL1 knockdown, CDH1 was significantly upregulated, while ETS1, RAF1, and EIF4E were significantly downregulated. Pathway enrichment analysis suggested that the ERK/MAPK signaling pathway was significantly inhibited (P<0.001).

Conclusions: CX3CL1 is an independent predictor of a poor prognosis in BCa and can promote the proliferation and invasion of BCa cells.

Keywords: CX3CL1; ERK; MAPK; bladder cancer; survival analysis.