吉非替尼敏感与耐药NSCLC患者miR-200c、miR-19a、miR-155表达差异及其对患者预后的影响

摘要/Abstract

摘要：

目的探讨吉非替尼敏感与耐药非小细胞肺癌(NSCLC)患者miR-200c、miR-19a、miR-155表达差异,并分析miR-200c、miR-19a、miR-155表达差异对患者预后的影响。方法选取2015年8月1日至2019年8月1日南京医科大学第四附属医院采用吉非替尼治疗的80例Ⅲ~Ⅳ期NSCLC患者作为研究对象,其中吉非替尼敏感患者36例,作为敏感组,吉非替尼耐药患者44例,作为耐药组。比较两组患者一般资料、血清miR-200c、miR-19a、miR-155水平,探究NSCLC患者吉非替尼敏感影响因素及血清miR-200c、miR-19a、miR-155与NSCLC患者临床病理特征的相关性。分析患者生存情况。结果与耐药组比较,敏感组患者吸烟例数较少(χ²=5.541,P=0.019 )、临床分期Ⅲ期例数较多(χ²=8.984,P=0.003 )、分化程度高分化例数较多(χ²=8.673,P=0.003 )、淋巴结转移例数较少(χ²=6.082,P=0.014 )、血清miR-200c、miR-19a、miR-155水平均较高(t=7.249,P<0.001;t=8.222,P<0.001;t=10.467,P<0.001 )。多因素logistic回归分析显示,吸烟(OR=0.355,95%CI为0.149~0.845,P<0.001 )、临床分期(OR=0.494,95%CI为0.274~0.892,P=0.021 )、分化程度(OR=6.062,95%CI为3.258~11.279,P=0.013 )、淋巴结转移(OR=0.422,95%CI为0.245~0.726,P=0.019 )、血清miR-200c(OR=5.521,95%CI为3.126~9.752,P<0.001 )、miR-19a(OR=5.384,95%CI为2.947~9.836,P<0.001 )、miR-155(OR=5.325,95%CI为3.058~9.274,P<0.001 )水平均为NSCLC患者吉非替尼敏感的影响因素。血清miR-200c、miR-19a、miR-155水平与NSCLC患者临床分期(t=3.230,P=0.002,r=-0.578;t=3.188,P=0.002,r=-0.612;t=3.123,P=0.003,r=-0.594 )、分化程度(t=2.586,P=0.012,r=0.610;t=4.009,P<0.001,r=0.632;t=4.773,P<0.001,r=0.594 )、淋巴结转移(t=2.902,P=0.005,r=-0.587;t=3.721,P<0.001,r=-0.629;t=3.391,P=0.001,r=-0.614 )均显著相关。与miR-200c、miR-19a、miR-155低水平患者比较,miR-200c( 63.19%vs.4.37%,χ²=32.562,P<0.001 )、miR-19a( 61.01%vs.4.75%,χ²=37.807,P<0.001 )以及miR-155( 57.82%vs.0,χ²=44.454,P<0.001 )高水平患者1年生存率均较高,差异均有统计学意义。结论血清miR-200c、miR-19a、miR-155水平在吉非替尼敏感NSCLC患者中明显升高,是吉非替尼敏感的重要影响因素,且与NSCLC患者临床分期、分化程度、淋巴结转移密切相关,血清高水平患者预后较好。

关键词:癌,非小细胞肺,微RNAs,吉非替尼,敏感,耐药

Abstract:

ObjectiveTo investigate the expression differences of miR-200c, miR-19a and miR-155 in gefitinib sensitive and resistant non-small cell lung cancer (NSCLC) patients, and to analyze the effects of miR-200c, miR-19a and miR-155 expression differences on the prognosis of patients.MethodsFrom August 1, 2015 to August 1, 2019, 80 patients with stage Ⅲ-Ⅳ NSCLC who were treated with gefitinib in the Fourth Affiliated Hospital of Nanjing Medical University were selected as the research objects. Among them, 36 cases were sensitive to gefitinib as the sensitive group, and 44 cases were resistant to gefitinib as the drug-resistant group. The general data, serum levels of miR-200c, miR-19a and miR-155 were compared between the two groups, and the sensitive factors of gefitinib in NSCLC patients and the correlations between serum miR-200c, miR-19a, miR-155 and clinicopathological characteristics of NSCLC patients were explored. The survival of the patients was analyzed.ResultsCompared with the drug-resistant group, the number of smoking cases in the sensitive group was less (χ²=5.541,P=0.019), the number of clinical stage Ⅲ cases was more (χ²=8.984,P=0.003), the number of well-differentiated cases was more (χ²=8.673,P=0.003), the number of patients with lymph node metastasis was less (χ²=6.082,P=0.014), and the levels of serum miR-200c, miR-19a and miR-155 were higher (t=7.249,P<0.001;t=8.222,P<0.001;t=10.467,P<0.001). Multivariate logistic regression analysis showed that smoking (OR=0.355, 95%CI: 0.149-0.845,P<0.001), clinical stage (OR=0.494, 95%CI: 0.274-0.892,P=0.021), degree of differentiation (OR=6.062, 95%CI: 3.258-11.279,P=0.013), lymph node metastasis (OR=0.422, 95%CI: 0.245-0.726,P=0.019), the levels of serum miR-200c (OR=5.521, 95%CI: 3.126-9.752,P<0.001), miR-19a (OR=5.384, 95%CI: 2.947-9.836, P<0.001) and miR-155 (OR=5.325, 95%CI: 3.058-9.274,P<0.001) were all influencing factors of gefitinib sensitivity in NSCLC patients. The levels of serum miR-200c, miR-19a and miR-155 were significantly correlated with clinical stage (t=3.230,P=0.002,r=-0.578;t=3.188,P=0.002,r=-0.612;t=3.123,P=0.003,r=-0.594), degree of differentiation (t=2.586,P=0.012,r=0.610;t=4.009,P<0.001,r=0.632;t=4.773,P<0.001,r=0.594) and lymph node metastasis (t=2.902,P=0.005,r=-0.587;t=3.721,P<0.001,r=-0.629;t=3.391,P=0.001,r=-0.614) of NSCLC patients. Compared with the patients with low levels of serum miR-200c, miR-19a and miR-155, the 1-year survival rates of the patients with high levels of serum miR-200c (63.19%vs.4.37%,χ²=32.562,P<0.001), miR-19a (61.01%vs. 4.75%,χ²=37.807,P<0.001) and miR-155 (57.82%vs.0,χ²=44.454,P<0.001) were higher, with statistically significant differences.ConclusionThe levels of serum miR-200c, miR-19a and miR-155 are significantly increased in gefitinib-sensitive NSCLC patients, which are important influencing factors of gefitinib sensitivity, and are closely related to clinicopathological characteristics such as clinical stage, differentiation degree and lymph node metastasis of NSCLC patients, and the prognosis is better in patients with high serum levels.

Key words:Carcinoma,non-small-cell lung,MicroRNAs,Gefitinib,Sensitive,Drug resistance

刘佩, 蒲嘉泽, 黄雯, 汪斐. 吉非替尼敏感与耐药NSCLC患者miR-200c、miR-19a、miR-155表达差异及其对患者预后的影响[J]. 国际肿瘤学杂志, 2021, 48(7): 409-414.

Liu Pei, Pu Jiaze, Huang Wen, Wang Fei. Expression differences of miR-200c, miR-19a and miR-155 in gefitinib sensitive and drug resistant NSCLC patients and their effects on prognosis[J]. Journal of International Oncology, 2021, 48(7): 409-414.

图/表5

表1

两组吉非替尼治疗NSCLC患者的一般资料比较[例(%)/($\bar{x} \pm s$)]"

临床指标	敏感组 (n=36)	耐药组 (n=44)	χ²/t值	P值
性别
男	20(55.56)	27(61.36)	0.276	0.600
女	16(44.44)	17(38.64)
年龄(岁)
≤60	19(52.78)	24(54.55)	0.025	0.875
>60	17(47.22)	20(45.45)
吸烟
是	6(16.67)	18(40.91)	5.541	0.019
否	30(83.33)	26(59.09)
组织学分类
腺癌	33(91.67)	42(95.45)	0.054	0.817
其他	3(8.33)	2(4.55)
临床分期
Ⅲ期	26(72.22)	17(38.64)	8.984	0.003
Ⅳ期	10(27.78)	27(61.36)
分化程度
高分化	25(69.44)	16(36.36)	8.673	0.003
中、低分化	11(30.56)	28(63.64)
淋巴结转移
是	5(13.89)	17(38.64)	6.082	0.014
否	31(86.11)	27(61.36)
miR-200c	0.98±0.42	0.45±0.22	7.249	<0.001
miR-19a	0.27±0.13	0.10±0.04	8.222	<0.001
miR-155	1.07±0.49	0.27±0.12	10.467	<0.001

表1

图1

因素	β值	SE值	Wald值	OR值	95%CI	P值
吸烟	-1.036	0.316	10.751	0.355	0.149~0.845	<0.001
临床分期	-0.704	0.258	7.455	0.494	0.274~0.892	0.021
分化程度	1.802	0.374	23.216	6.062	3.258~11.279	0.013
淋巴结转移	-0.863	0.275	9.856	0.422	0.245~0.726	0.019
miR-200c	1.709	0.369	21.440	5.521	3.126~9.752	<0.001
miR-19a	1.683	0.324	26.996	5.384	2.947~9.836	<0.001
miR-155	1.672	0.319	27.488	5.325	3.058~9.274	<0.001

表2

表3

NSCLC患者临床病理特征与血清miR-200c、miR-19a、miR-155水平相关性($\bar{x} \pm s$)"

临床病理特征	例数	miR-200c	t值	P值	r值	miR-19a	t值	P值	r值	miR-155	t值	P值	r值
临床分期
Ⅲ期	43	0.78±0.30	3.230	0.002	-0.578	0.21±0.10	3.188	0.002	-0.612	0.72±0.32	3.123	0.003	-0.594
Ⅳ期	37	0.59±0.21				0.15±0.06				0.53±0.20
分化程度
高分化	41	0.77±0.35	2.586	0.012	0.610	0.22±0.11	4.009	<0.001	0.632	0.78±0.35	4.773	<0.001	0.594
中、低分化	39	0.60±0.22				0.14±0.06				0.47±0.21
淋巴结转移
是	22	0.53±0.25	2.902	0.005	-0.587	0.13±0.06	3.721	<0.001	-0.629	0.45±0.21	3.391	0.001	-0.614
否	58	0.75±0.32				0.20±0.08				0.70±0.32

表3

图2

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