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目的:分析长链非编码RNA MIR4435-2宿主基因(LncRNA MIR4435-2HG)、微小RNA-125b-5p(miR-125b-5p)在非小细胞肺癌(NSCLC)患者抗程序性死亡受体1(PD-1)疗效和预后评估中的价值。方法:本研究为队列研究。采用目的抽样法纳入2022年2月至2023年2月延安市人民医院确诊的96例NSCLC患者作为NSCLC患者组，以及同期的健康体检人群96名为健康对照组。将96例NSCLC患者根据接受抗PD-1治疗6周后的疗效分为有效组(54例)和无效组(42例)，根据1年预后分为生存组(32例)和死亡组(64例)。采用starbase网站预测LncRNA MIR4435-2HG与miR-125b-5p的靶向关系。比较NSCLC患者组与健康对照组的血清LncRNA MIR4435-2HG、miR-125b-5p水平。比较有效组与无效组患者血清LncRNA MIR4435-2HG、miR-125b-5p水平和PD-L1表达情况。采用Spearman法分析治疗无效NSCLC患者血清LncRNA MIR4435-2HG、miR-125b-5p与PD-L1表达的相关性。分析NSCLC患者血清LncRNA MIR4435-2HG、miR-125b-5p与临床特征(性别、年龄、病理类型、肿瘤长径、TNM分期、分化程度和淋巴结转移)的关系。比较生存组和死亡组患者的血清LncRNA MIR4435-2HG、miR-125b-5p水平。采用单因素和多因素Cox回归分析NSCLC患者预后影响因素。采用受试者操作特征曲线分析血清LncRNA MIR4435-2HG、miR-125b-5p对预后的预测价值。结果:NSCLC患者组中男58例，女38例；年龄(60.42±10.75)岁，年龄范围32～76岁。健康对照组中男54名，女42名；年龄(60.81±10.13)岁，年龄范围30～78岁。starbase网站预测结果显示，LncRNA MIR4435-2HG与miR-125b-5p存在靶向调节关系。NSCLC患者组血清LncRNA MIR4435-2HG水平高于健康对照组[(1.62±0.40)比(1.01±0.22)， t＝13.09]，miR-125b-5p低于健康对照组[(0.65±0.17)比(1.02±0.23)， t＝12.68]，差异均有统计学意义(均 P<0.001)。无效组血清LncRNA MIR4435-2HG水平和PD-L1阳性比例均高于有效组[(1.94±0.51)比(1.37±0.32)， t＝6.70；24例(57.14%)比3例(5.56%)， χ2＝31.10]，miR-125b-5p水平低于有效组[(0.52±0.14)比(0.75±0.18)， t＝6.83]，差异均有统计学意义(均 P<0.001)。治疗无效NSCLC患者血清LncRNA MIR4435-2HG与PD-L1呈正相关，miR-125b-5p与PD-L1呈负相关( r值分别为0.542、－0.519，均 P<0.001)。不同性别、年龄、病理类型、肿瘤长径的NSCLC患者血清LncRNA MIR4435-2HG、miR-125b-5p水平比较，差异均无统计学意义(均 P>0.05)。不同TNM分期、分化程度和淋巴结转移的NSCLC患者血清LncRNA MIR4435-2HG、miR-125b-5p水平比较，差异均有统计学意义(均 P<0.05)，其中TNM分期Ⅳ期、低分化、有淋巴结转移的患者血清LncRNA MIR4435-2HG水平更高，miR-125b-5p水平更低。死亡组血清LncRNA MIR4435-2HG水平高于生存组[(1.88±0.49)比(1.10±0.32)， t＝8.17]，miR-125b-5p水平低于生存组[(0.55±0.15)比(0.85±0.17)， t＝8.83]，差异均有统计学意义(均 P<0.001)。多因素Cox回归分析结果显示，较高的LncRNA MIR4435-2HG水平是NSCLC患者死亡的独立危险因素，较高的miR-125b-5p水平是NSCLC患者死亡的独立保护因素(均 P<0.05)。LncRNA MIR4435-2HG、miR-125b-5p单独及联合预测NSCLC患者死亡的曲线下面积(AUC)分别为0.859(95% CI：0.780～0.938)、0.865(95% CI：0.787～0.942)、0.934(95% CI：0.882～0.986)，其中联合AUC高于LncRNA MIR4435-2HG、miR-125b-5p单独预测AUC( Z值分别为2.21、2.02， P<0.05)。LncRNA MIR4435-2HG的最佳截断值为1.39，miR-125b-5p的最佳截断值为0.74，二者单独及联合预测的敏感度分别为82.85%、81.38%、84.42%，特异度分别为81.24%、75.63%、90.65%。 结论:LncRNA MIR4435-2HG、miR-125b-5p可能是抗PD-1治疗NSCLC患者疗效和预后的潜在生物学标志物。

Objective:To analyze the value of long non-coding RNA MIR4435-2 host gene (LncRNA MIR4435-2HG) and microRNA-125b-5p (miR-125b-5p) in evaluating the efficacy and prognosis of anti-programmed death-1 (PD-1) therapy in non-small cell lung cancer (NSCLC) patients.Methods:This was a cohort study retrospectively involving 96 NSCLC patients diagnosed in Yan′an People′s Hospital between February 2022 and February 2023 in the NSCLC group by objective sampling method.During the same period, 96 healthy individuals undergoing physical examinations were regarded as the healthy control group.A total of 96 NSCLC patients were assigned into the effective group (54 cases) and ineffective group (42 cases) based on their efficacy of anti-PD-1 treatment after 6 weeks.Moreover, they were assigned into the survival group (32 cases) and death group (64 cases) based on their 1-year prognosis.The targeting relationship between LncRNA MIR4435-2HG and miR-125b-5p was predicted on Starbase.Serum LncRNA MIR4435-2HG and miR-125b-5p levels were compared between NSCLCgroup and healthy control group.Serum LncRNA MIR4435-2HG, miR-125b-5p, and PD-L1 levels were compared between the effective and ineffective groups.Spearman′s correlation was used to analyze the correlation among serum LncRNA MIR4435-2HG, miR-125b-5p, and PD-L1 levelsin NSCLC patients of the ineffective group.The correlation of serum LncRNA MIR4435-2HG and miR-125b-5p with clinical features (gender, age, pathological type, tumor length, tumor-node-metastasis (TNM) staging, differentiation degree, and lymph node metastasis) in NSCLC patients was analyzed.Serum LncRNA MIR4435-2HG and miR-125b-5p levels between survival and death groups were compared.Univariate and multivariate Cox regression analyses were conducted to analyze the prognostic factors of NSCLC.Receiver operating characteristic (ROC) curve analysis was used to analyze the predictive value of serum LncRNA MIR4435-2HG and miR-125b-5p in the prognosis of NSCLC.Results:There were 58 males and 38 females in the NSCLC group, with a mean age of 60.42±10.75 (32-76) years.There were 54 males and 42 females in the healthy control group, with a mean age of 60.81±10.13 (30-78) years.The prediction results from Starbase showeda targeted regulatory relationship between LncRNA MIR4435-2HG and miR-125b-5p.Serum LncRNA MIR4435-2HG level in the NSCLC patients group was significantly higher than that of the healthy control group ([1.62±0.40] vs [1.01±0.22], t=13.09), while serum miR-125b-5p level was significantly lower ([0.65±0.17] vs [1.02±0.23], t=12.68)(both P<0.001).Serum LncRNA MIR4435-2HG levels ([1.94±0.51] vs [1.37±0.32], t=6.70) and PD-L1 positivity ratio (57.14% [ n=24] vs 5.56% [ n=3], χ2=31.10) in the ineffective group were significantly higher than those of the effective group, miR-125b-5p levels ([0.52±0.14] vs [0.75±0.18], t=6.83) were significantly lower than those of the effective group(both P<0.001).Serum LncRNA MIR4435-2HG level in NSCLC patients with ineffective treatment was positively correlated with PD-L1, while miR-125b-5p was negatively correlated with PD-L1 ( r values were 0.542 and -0.519, respectively, both P<0.001).Comparison of serum LncRNA MIR4435-2HG and miR-125b-5p levels in NSCLC patients with different genders, ages, pathological types, and tumor lengths showed no significant differences (all P>0.05).Comparison of serum LncRNA MIR4435-2HG and miR-125b-5p levels in NSCLC patients with different TNM staging, differentiation levels, and lymph node metastasis showed significant differences (all P<0.05).Among them, NSCLC patients with stage Ⅳ, low differentiation, and lymph node metastasis had significantly higher serum LncRNA MIR4435-2HG levels and lower miR-125b-5p levels.Serum LncRNA MIR4435-2HG levels in the death group were higher than those of the survival group ([1.88±0.49] vs [1.10±0.32], t=8.17), while miR-125b-5p levels were significantly lower ([0.55±0.15] vs [0.85±0.17], t=8.83)(both P<0.001).The results of multivariate Cox regression analysis showed that higher levels of LncRNA MIR4435-2HG were independent risk factors for death in NSCLC patients, and higher levels of miR-125b-5p were independent protective factors for NSCLC patients (both P<0.05).The area under the curve (AUC) of LncRNA MIR4435-2HG and miR-125b-5p and their combination in predicting death in NSCLC patients was 0.859 (95% CI: 0.780-0.938), 0.865 (95% CI: 0.787-0.942), and 0.934 (95% CI: 0.882-0.986), respectively.The AUC of the combination detection of LncRNA MIR4435-2HG and miR-125b-5p was significantlyhigher than that of a single detection in predicting the prognosis of NSCLC ( Z values were 2.21 and 2.02, respectively, P<0.05).The optimal cutoff value for LncRNA MIR4435-2HG, and miR-125b-5pwas 1.39, and 0.74, respectively.The sensitivity of ncRNA MIR4435-2HG and miR-125b-5p and their combinationin predicting death in NSCLC patients was 82.85%, 81.38%, and 84.42%, respectively; and the specificity was 81.24%, 75.63%, and 90.65%, respectively. Conclusions:LncRNA MIR4435-2HG and miR-125b-5p may be potential biological markers for the therapeutic efficacy and prognosis of anti-PD-1 therapy in NSCLC patients.