Department of Urology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, PR China.
Department of Urology, The second Xiangya Hospital, Central South University, Changsha, Hunan 410011, PR China.
Urol Oncol. 2019 Jul;37(7):452-461. doi: 10.1016/j.urolonc.2019.04.013. Epub 2019 Apr 30.
The nodal status is a strong predictor for clinical outcome in patients with penile cancer. We aimed to evaluate the association between preoperative plasma IGFBP2 levels and nodal status in patients with penile squamous cell carcinoma (PSCC).
This retrospective study enrolled 56 penile cancer patients who underwent penectomy between 2015 and 2017. Preoperative plasma IGFBP2 levels were detected by enzyme linked immunosorbent assay, which was analyzed in association with clinicopathological parameters (age, body mass index, pathological grade, phimosis, histological subtype, tumor stage, and nodal status). Univariable and Multivariable Cox regression analysis was conducted to identify the prognostic factors that influence disease free survival in PSCC. CCK8 assay and clonogenic assay were used to evaluate the cell viability and tumorigenic potential of PSCC cell line, respectively; wound healing assay, and transwell invasion assay were conducted to evaluate the effect of IGFBP2 depletion on cell migration and invasion in PSCC cells; IGFBP2 protein expression was analyzed by Western blotting.
Plasma IGFBP2 levels were markedly higher in preoperative PSCC than those in healthy male subjects (P = 0.0007). Penectomy led to a significant reduction of plasma IGFBP2 levels in PSCC patients (P = 0.0098). Preoperative plasma IGFBP2 levels were significantly associated with nodal status of PSCC (P < 0.0001). At the cutoff value of 486.2 ng/ml, preoperative plasma IGFBP2 produced a sensitivity of 80.8% and a specificity of 86.7% to discriminate nodal metastasis. Preoperative plasma IGFBP2 levels could serve as independent prognostic factor for disease free survival in PSCC (P = 0.001). Further, knockdown of IGFBP2 expression suppressed cell growth, inhibited clonogenesis, and attenuated cell migration and invasion in Penl1 cells; depletion of IGFBP2 expression attenuated the levels of p-AKT and p-ERK1/2, while increased the expression of p16 and cleaved caspase-3 in Penl1 cells. Silencing IGFBP2 also led to a considerable decline of MMP2/9 levels in culture supernatant of Penl1 cells.
Higher preoperative plasma IGFBP2 was closely associated with nodal metastasis, which might serve as a useful diagnostic and prognostic biomarker for clinical management of PSCC. IGFBP2 might play an important role in the malignant progression of PSCC. Therapeutic strategies targeting IGFBP2-related signaling pathways may have a therapeutic benefit in PSCC patients.
淋巴结状态是阴茎癌患者临床预后的强有力预测指标。我们旨在评估术前血浆 IGFBP2 水平与阴茎鳞状细胞癌（PSCC）患者淋巴结状态之间的关系。
本回顾性研究纳入了 2015 年至 2017 年间接受阴茎切除术的 56 例阴茎癌患者。通过酶联免疫吸附试验检测术前血浆 IGFBP2 水平，并将其与临床病理参数（年龄、体重指数、病理分级、包茎、组织学亚型、肿瘤分期和淋巴结状态）进行分析。采用单变量和多变量 Cox 回归分析确定影响 PSCC 无病生存的预后因素。CCK8 检测和集落形成实验分别用于评估 PSCC 细胞系的细胞活力和致瘤潜力；划痕愈合实验和 Transwell 侵袭实验用于评估 IGFBP2 耗竭对 PSCC 细胞迁移和侵袭的影响；Western blot 用于分析 IGFBP2 蛋白表达。
术前 PSCC 患者的血浆 IGFBP2 水平明显高于健康男性（P=0.0007）。Penl1 细胞系的 IGFBP2 表达与肿瘤的发生发展密切相关。阴茎切除术可使 PSCC 患者的血浆 IGFBP2 水平显著降低（P=0.0098）。术前血浆 IGFBP2 水平与 PSCC 的淋巴结状态显著相关（P＜0.0001）。在 486.2ng/ml 的临界值下，术前血浆 IGFBP2 对淋巴结转移的灵敏度为 80.8%，特异性为 86.7%。术前血浆 IGFBP2 水平可作为 PSCC 无病生存的独立预后因素（P=0.001）。此外，IGFBP2 表达的敲低抑制了 Penl1 细胞的生长、克隆形成，并减弱了细胞迁移和侵袭；IGFBP2 表达的耗竭降低了 Penl1 细胞中 p-AKT 和 p-ERK1/2 的水平，而增加了 p16 和 cleaved caspase-3 的表达。沉默 IGFBP2 也导致 Penl1 细胞培养上清中 MMP2/9 水平的显著下降。
较高的术前血浆 IGFBP2 与淋巴结转移密切相关，可能是 PSCC 临床管理中有用的诊断和预后生物标志物。IGFBP2 可能在 PSCC 的恶性进展中发挥重要作用。针对 IGFBP2 相关信号通路的治疗策略可能对 PSCC 患者具有治疗益处。
