Chemokine (C-X-C motif) ligand 5 is an important regulator of tumor progression in many cancers, and could serve as potential serum cancer biomarker. Our initial analysis identified CXCL5 as a cancer-related gene highly expressed in PC. Patients with PC exhibited markedly higher preoperative serum CXCL5 levels compared with that in healthy individuals (P<0.001). The area under the curve (AUC) was 0.880 with the sensitivity of 84.0%, and specificity of 80.4% to distinguish PC. Serum CXCL5 levels were also significantly decreased following tumor resection in patients with PC (P=0.001). Preoperative serum CXCL5 level was significantly associated with clinicopathological characteristics including T stage (P=0.001), nodal status (P<0.001), and pelvic lymph node metastasis (P=0.018). Cox regression analysis showed that serum CXCL5 level could serve as an independent prognostic factor for disease-free survival with a HR of 6.363 (95% CI 2.185-18.531, P=0.001). CXCL5 and its receptor CXCR2 exhibited correlated expression pattern in PC tissues. Differential CXCL5 expression was observed in normal penile tissues, PC cell lines and their culture supernatants. Furthermore, knockdown of CXCL5 or CXCR2 expression markedly suppressed malignant phenotypes (cell proliferation, clonogenesis, apoptosis escape, migration and invasion), attenuated STAT3 and AKT signaling and reduced MMP2/9 secretion in PC cell lines. In conclusion, our findings revealed that serum CXCL5 level might serve as a potential diagnostic and prognostic cancer biomarker for penile cancer. Autocrine CXCL5/CXCR2 signaling might activate multiple downstream oncogenic signaling pathways (STAT3, AKT, MMP2/9) to promote malignant progression of PC, which may warrant further investigation in the future.

中文翻译：

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血清 CXCL5 水平与阴茎癌的肿瘤进展相关。

趋化因子（CXC 基序）配体 5 是许多癌症中肿瘤进展的重要调节剂，可作为潜在的血清癌症生物标志物。我们的初步分析确定 CXCL5 是一种在 PC 中高度表达的癌症相关基因。与健康人相比，PC 患者术前血清 CXCL5 水平显着升高（P<0.001）。曲线下面积（AUC）为0.880，区分PC的敏感性为84.0%，特异性为80.4%。PC 患者肿瘤切除后血清 CXCL5 水平也显着降低（P=0.001）。术前血清CXCL5水平与T分期（P=0.001）、淋巴结状态（P<0.001）和盆腔淋巴结转移（P=0.018）等临床病理特征显着相关。Cox回归分析显示血清CXCL5水平可以作为无病生存的独立预后因素，HR为6.363（95% CI 2.185-18.531，P=0.001）。CXCL5 及其受体 CXCR2 在 PC 组织中表现出相关的表达模式。在正常阴茎组织、PC 细胞系及其培养上清液中观察到差异的 CXCL5 表达。此外，敲低 CXCL5 或 CXCR2 表达可显着抑制恶性表型（细胞增殖、克隆发生、细胞凋亡逃逸、迁移和侵袭），减弱 STAT3 和 AKT 信号传导并减少 PC 细胞系中的 MMP2/9 分泌。总之，我们的研究结果表明，血清 CXCL5 水平可能作为阴茎癌的潜在诊断和预后癌症生物标志物。