NEDD4L和ULK1在非小细胞肺癌中的表达及预后价值

The expression and prognostic value of NEDD4L and ULK1 in non-small cell lung cancer

摘要:

目的 研究非小细胞肺癌（NSCLC）组织中NEDD4样E3泛素蛋白连接酶（NEDD4L）、UNC-51样激酶1（ULK1）的表达及临床意义。方法 选取2017年1月—2018年1月三二〇一医院收治的88例NSCLC患者作为研究对象。应用R语言分析癌症基因组图谱（TCGA）数据库中NSCLC及癌旁组织中NEDD4L和ULK1 mRNA的表达差异，免疫组织化学法分析癌组织和癌旁组织中NEDD4L和ULK1蛋白的表达，Kaplan-Meier法分析NEDD4L、ULK1表达与患者生存预后的关系，单因素及多因素Cox回归分析影响NSCLC患者生存预后的危险因素。结果 癌组织NEDD4L mRNA相对表达量低于癌旁组织（P <0.05），ULK1 mRNA相对表达量高于癌旁组织（P <0.05）。癌组织NEDD4L的阳性表达率低于癌旁组织（P <0.05），ULK1的阳性表达率高于癌旁组织（P <0.05）。有无淋巴结转移、不同TNM分期患者的癌组织NEDD4L、ULK1阳性表达率比较，差异有统计学意义（P <0.05）。Spearman相关性分析结果显示，NSCLC患者癌组织中NEDD4L与ULK1的表达呈负相关（r_s =-0.587，P <0.05）。NEDD4L阴性表达患者3年总体生存率较阳性表达患者低（P <0.05），NEDD4L阳性表达患者平均生存时间较阴性表达患者长（P <0.05）。ULK1阳性表达患者3年总体生存率较阴性表达患者低（P <0.05），LK1阳性表达患者平均生存时间较阴性表达患者长（P <0.05）。单因素Cox回归分析结果显示，肿瘤TNM分期Ⅲ期［H^R=1.898（95% CI：1.320，2.729）］、NEDD4L阴性表达［H^R=1.654（95% CI：0.921，2.588）］和ULK1阳性表达［H^R=1.692（95% CI：0.860，2.650）］是NSCLC患者预后的影响因素（P <0.05）。多因素Cox回归分析结果显示，NEDD4L阴性表达［H^R=1.878（95% CI：0.961，2.995）］、ULK1阳性表达［H^R=1.679（95% CI：0.785，2.884）］及肿瘤TNM分期Ⅲ期［H^R=1.937（95% CI：1.131，3.317）］是NSCLC患者不良预后的独立危险因素（P <0.05）。结论 NSCLC中NEDD4L表达降低，ULK1表达升高，NEDD4L、ULK1的表达与肿瘤TNM分期、淋巴结转移有关，NEDD4L阴性表达、ULK1阳性表达是NSCLC患者不良预后的独立危险因素。

Abstract:

Objective To decipher the expression and clinical significance of NEDD4-like E3 ubiquitin protein ligase (NEDD4L) and UNC-51-like kinase 1 (ULK1) in tumor tissues from patients with non-small cell lung cancer (NSCLC).Methods The 88 NSCLC patients admitted to 3201 Hospital from January 2017 to January 2018 were enrolled as participants. The differences in the mRNA expressions of NEDD4L and ULK1 in NSCLC and adjacent normal tissues as revealed in The Cancer Genome Atlas (TCGA) were analyzed with R software. Immunohistochemistry was performed to detect the protein expressions of NEDD4L and ULK1 in the cancer and adjacent normal tissues. The relationship between the expressions of NEDD4L and ULK1 in cancer tissues and the prognosis of patients was analyzed by Kaplan-Meier method. Univariable and multivariable COX proportional hazards models were used to analyze the risk factors that affect the prognosis of NSCLC patients.Results The mRNA expression level of NEDD4L in NSCLC tissues was lower than that in adjacent tissues (P < 0.05), while the mRNA expression level of ULK1 was significantly higher than that in adjacent tissues (P < 0.05). Consistently, the positivity rate of NEDD4L in NSCLC tissues was lower than that in adjacent tissues (P < 0.05), while the positivity rate of ULK1 in NSCLC tissues was higher than that in adjacent tissues (P < 0.05). The positivity rates of NEDD4L and ULK1 in NSCLC tissues were different between patients with and without lymph node metastasis and among those with distinct TNM stages (P < 0.05). The expression of NEDD4L and that of ULK1 in NSCLC tissues were negatively correlated (r_s = -0.587, P < 0.05). The 3-year overall survival rate was lower in patients with negative expression of NEDD4L than in those with positive expression of NEDD4L (P < 0.05), and the mean survival time was longer in patients with positive expression of NEDD4L than in those with negative expression of NEDD4L (P <0.05). The 3-year overall survival rate was lower in patients with positive expression of ULK1 than in those with negative expression of ULK1 (P < 0.05), and the mean survival time was longer in patients with positive expression of ULK1 than in those with negative expression of ULK1 (P < 0.05). The univariable Cox regression analysis exhibited that stage Ⅲ NSCLC, negative expression of NEDD4L, and positive expression of ULK1 were factors affecting the prognosis of NSCLC patients (P < 0.05). The multivariable Cox regression analysis revealed that negative expression of NEDD4L [H^R = 0.978 (95% CI: 0.961, 0.995) ], positive expression of ULK1 [H^R = 0.879 (95% CI: 0.785, 0.984) ], and stage Ⅲ NSCLC [H^R = 1.937 (95% CI: 1.131, 3.317) ] were independent risk factors for poor prognosis in NSCLC patients (P < 0.05).Conclusions The expression of NEDD4L decreases, while the expression of ULK1 increases in patients with NSCLC. The expressions of NEDD4L and ULK1 are related to the TNM stage of NSCLC and lymph node metastasis. The negative expression of NEDD4L and positive expression of ULK1 are independent risk factors for the poor prognosis of NSCLC patients.