Abstract
BACKGROUND: Chemokine (C-X-C motif) ligands (CXCLs) are important regulators of tumor progression in many cancers and could serve as potential cancer biomarkers. However, the expression patterns as well as functions of CXCLs remain unclear in penile cancer (PC). The aim of this study was to evaluate the usefulness of serum CXCL13 as a potential cancer biomarker for PC. PATIENTS AND METHODS: This retrospective study enrolled 76 patients diagnosed with PC between 2016 and 2018. Serum CXCL13 level was detected by enzyme-linked immunosorbent assay. Univariable and multivariable Cox regression analyses were conducted to identify the prognostic factors that influence disease-free survival. Human penile cancer cell lines Penl1, Penl2, 149RCa and LM156 were used as in vitro models. The expression of CXCL13 protein in PC cell lines was analyzed by Western blotting. RESULTS: Our initial analysis on GSE57955 dataset identified CXCL13 as a top CXCL gene enriched in PC. Higher preoperative serum CXCL13 level was detected in PC cohorts than in healthy male controls (P<0.001). The area under the curve was 0.911 with the sensitivity of 84.2% and specificity of 87.0% to distinguish PC. Preoperative serum CXCL13 level was associated with pathological grade (P=0.048), T stage (P=0.009), nodal status (P<0.001) and pelvic lymph node metastasis (P=0.005) in PC. Serum CXCL13 level could serve as an independent prognostic factor for disease-free survival with a HR of 3.818 (95%CI: 1.126-12.946). Furthermore, autocrine expression of CXCL13 was detected in PC tissues and cell lines. Knockdown of CXCL13 expression suppressed malignant phenotypes (cell proliferation, clonogenesis, apoptosis escape, migration and invasion), attenuated STAT3 and ERK1/2 signaling and reduced MMP2/9 secretion in PC cell lines. CONCLUSION: Serum CXCL13 could serve as a novel diagnostic and prognostic biomarker for PC. CXCL13 signaling might activate oncogenic signaling pathways to promote malignant progression of PC.