Expression levels and clinical significance of miR-4262，NRG1 in non-small cell lung cancer tissues

doi:10.3760/cma.j.cn371439-20241021-00020

Abstract

Abstract:

Objective To investigate the expression of microRNA-4262 （miR-4262） and neuregulin 1 （NRG1） in non-small cell lung cancer （NSCLC） tissues and the relationship with prognosis. Methods A total of 102 NSCLC patients who underwent surgical resection from January 2017 to February 2021 in Tongren People's Hospital of Guizhou Province were selected. The expression levels of miR-4262 and NRG1 were detected using real-time fluorescence quantitative PCR. The expression levels of miR-4262 and NRG1 in NSCLC cancer tissues and adjacent tissues， as well as NSCLC cancer tissues with different clinicopathological characteristics were analyzed. TargetScan database was used to predict the binding sites of miR-4262 and NRG1， and Pearson correlation coefficient was used to analyze the correlation between miR-4262 and NRG1 expression in NSCLC cancer tissues. Based on the mean expression levels of miR-4262 and NRG1 in NSCLC cancer tissues， the patients were divided into high miR-4262 expression group （miR-4262≥1.52， n=54） and low miR-4262 expression group （miR-4262<1.52， n=48）， high NRG1 expression group （NRG1≥0.79， n=54） and low NRG1 expression group （NRG1<0.79， n=48）. Kaplan-Meier survival curves were plotted to compare the 3-year overall survival （OS） rates between groups. Cox proportional risk regression model was used to analyze the influencing factors for the prognosis of NSCLC patients. Results The expression level of miR-4262 was significantly higher in NSCLC tumor tissues compared to adjacent tissues （1.52±0.21 vs. 1.11±0.20）， while NRG1 expression level was lower （0.79±0.11 vs. 1.06±0.11）， there were statistically significant differences （t=14.22， P<0.001； t=-15.13， P<0.001）. The expression of miR-4262 was negatively correlated with NRG1 in cancer tissues of NSCLC patients （r=-0.74， P<0.001）. There were statistically significant differences in the expression levels of miR-4262 and NRG1 of NSCLC patients in tumor differentiation （t=2.80， P=0.006； t=-2.80， P=0.006）， TNM stage （F=24.36， P<0.001； F=17.66， P<0.001）， and lymph node metastasis （t=4.02， P<0.001； t=-3.98， P<0.001）. At the end of the follow-up period， 57 patients survived， and 45 died， with a 3-year OS rate of 55.88%. Patients with high miR-4262 expression had a significantly lower 3-year OS rate compared to those with low miR-4262 expression （35.19% vs. 79.17%）， patients with high NRG1 expression had a significantly higher 3-year OS rate than those with low NRG1 expression （77.78% vs. 31.25%）， there were statistically significant differences （χ²=22.58， P<0.001； χ²=27.26， P<0.001）. Univariate analysis showed that， age （HR=2.47， 95%CI：1.05-5.80， P=0.038）， maximum tumor diameter （HR=3.75， 95%CI：1.61-8.74， P=0.002）， differentiation degree （HR=3.03， 95%CI：1.32-6.96， P=0.009）， TNM stage （stage Ⅱ， HR=3.45， 95%CI：1.10-10.83， P=0.034； stage Ⅲ， HR=6.72， 95%CI：2.03-22.26， P=0.002）， lymph node metastasis （HR=3.00， 95%CI：1.29-6.96， P=0.010）， miR-4262 expression （HR=3.72， 95%CI：1.48-9.35， P=0.005）， and NRG1 expression （HR=0.30， 95%CI：0.13-0.73， P=0.008） were all influencing factors for OS in NSCLC patients. Multivariate analysis showed that， differentiation degree （HR=5.47， 95%CI：1.63-18.34， P=0.006）， TNM stage （stage Ⅲ， HR=5.56， 95%CI：1.23-25.14， P=0.026）， lymph node metastasis （HR=3.72， 95%CI：1.19-11.60， P=0.024）， miR-4262 expression （HR=8.56， 95%CI：2.26-32.41， P=0.002）， and NRG1 expression （HR=0.26， 95%CI：0.09-0.76， P=0.014） were all independent influencing factors for OS in NSCLC patients. Conclusions The expression of miR-4262 is high and the expression of NRG1 is low in cancer tissues of NSCLC patients. The 3-year OS rate of patients with high miR-4262 expression is lower than that of patients with low miR-4262 expression， and the 3-year OS rate of patients with high NRG1 expression is higher than that of patients with low NRG1 expression. Differentiation degree， TNM stage， lymph node metastasis， miR-4262 and NRG1 are all independent influencing factors for the prognosis of NSCLC patients.

Key words: Carcinoma, non-small-cell lung, Neuregulin-1, Prognosis, MicroRNA-4262

Yang Shengjun, Ren Jiang, Yang Dan, Long Yu, Shang Qunxian. Expression levels and clinical significance of miR-4262，NRG1 in non-small cell lung cancer tissues[J]. Journal of International Oncology, 2025, 52(3): 129-135.

Figures/Tables 7

References 30

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基因	正向引物	反向引物
miR-4262	5′-CAGCCATCATCAAAGAGATCG-3′	5′-TTGTTCCTGTATACGCCTTCAA-3′
U6	5′-TGCACCACCAACTGCTTAGC-3′	5′-GGCATGGACTGTGGTCATGAG-3′
NRG1	5′-GTGTCCGGTGGTTGCTGT-3′	5′-AATAGGGCCTAGGGGCTTCTC-3′
GAPDH	5′-TCCCAGACATGACAGCCATC-3′	5′-TGCTTTGAATCCAAAAACCTT-3′

临床病理特征	例数	miR-4262	t/F值	P值	NRG1	t/F值	P值
性别
男	74	1.52±0.22	0.40	0.693	0.79±0.10	-0.28	0.778
女	28	1.50±0.17	0.40	0.693	0.80±0.12	-0.28	0.778
年龄（岁）
≥60	57	1.53±0.23	0.71	0.481	0.78±0.09	-0.67	0.506
<60	45	1.50±0.17	0.71	0.481	0.80±0.13	-0.67	0.506
TP53基因突变
有	56	1.54±0.21	1.51	0.133	0.78±0.10	-1.50	0.138
无	46	1.48±0.20	1.51	0.133	0.81±0.12	-1.50	0.138
EGFR基因突变
有	48	1.55±0.20	1.77	0.080	0.77±0.09	-1.75	0.083
无	54	1.48±0.21	1.77	0.080	0.81±0.12	-1.75	0.083
吸烟
是	45	1.55±0.23	1.29	0.199	0.78±0.08	-1.30	0.196
否	57	1.49±0.19	1.29	0.199	0.80±0.12	-1.30	0.196
病理类型
腺癌	33	1.54±0.23	1.75	0.179	0.77±0.08	0.82	0.446
鳞状细胞癌	60	1.52±0.20			0.79±0.11
腺鳞癌	9	1.40±0.17			0.82±0.16
肿瘤最大径（cm）
≥3	32	1.57±0.20	1.91	0.059	0.76±0.08	-1.96	0.053
<3	70	1.49±0.21	1.91	0.059	0.80±0.11	-1.96	0.053
肿瘤部位
左肺	38	1.50±0.24	-0.52	0.606	0.80±0.10	0.60	0.548
右肺	64	1.52±0.19	-0.52	0.606	0.79±0.11	0.60	0.548
分化程度
低分化	35	1.59±0.22	2.80	0.006	0.75±0.08	-2.80	0.006
中、高分化	67	1.48±0.19	2.80	0.006	0.81±0.12	-2.80	0.006
TNM分期
Ⅰ期	28	1.37±0.16	24.36	<0.001	0.87±0.11	17.66	<0.001
Ⅱ期	42	1.50±0.15			0.79±0.10
Ⅲ期	32	1.67±0.20			0.73±0.06
淋巴结转移
有	60	1.58±0.21	4.02	<0.001	0.75±0.07	-3.98	<0.001
无	62	1.43±0.17	4.02	<0.001	0.84±0.13	-3.98	<0.001

因素	β值	SE值	Wald χ²值	HR值	95%CI	P值
性别（男/女）	0.26	0.40	0.41	1.29	0.59~2.85	0.523
年龄（≥60岁/<60岁）	0.90	0.44	4.28	2.47	1.05~5.80	0.038
TP53基因突变（有/无）	-0.34	0.41	0.69	0.71	0.32~1.58	0.406
EGFR基因突变（有/无）	-0.29	0.41	0.51	0.75	0.34~1.66	0.477
吸烟（是/否）	0.15	0.47	0.11	1.16	0.47~2.90	0.745
病理类型
腺癌				Ref
鳞状细胞癌	0.35	0.84	0.17	1.42	0.27~7.42	0.677
腺鳞癌	-0.75	1.17	0.41	0.47	0.05~4.73	0.524
肿瘤最大径（≥3 cm/<3 cm）	1.32	0.43	9.39	3.75	1.61~8.74	0.002
肿瘤部位（左肺/右肺）	0.41	0.42	0.96	1.50	0.67~3.38	0.329
分化程度（低分化/中、高分化）	1.11	0.43	6.78	3.03	1.32~6.96	0.009
TNM分期
Ⅰ期				Ref
Ⅱ期	1.24	0.58	4.50	3.45	1.10~10.83	0.034
Ⅲ期	1.91	0.61	9.73	6.72	2.03~22.26	0.002
淋巴结转移（有/无）	1.10	0.43	6.56	3.00	1.29~6.96	0.010
miR-4262表达	1.31	0.47	7.79	3.72	1.48~9.35	0.005
NRG1表达	-1.20	0.45	7.13	0.30	0.13~0.73	0.008

因素	β值	SE值	Wald χ²值	HR值	95%CI	P值
年龄（≥60岁/<60岁）	0.95	0.56	2.87	2.58	0.86~7.75	0.090
肿瘤最大径（≥3 cm/<3 cm）	1.08	0.50	3.34	2.96	0.93~9.45	0.068
分化程度（低分化/中、高分化）	1.70	0.62	7.58	5.47	1.63~18.34	0.006
TNM分期
Ⅰ期				Ref
Ⅱ期	1.34	0.70	3.70	3.83	0.98~15.00	0.054
Ⅲ期	1.72	0.77	4.96	5.56	1.23~25.14	0.026
淋巴结转移（有/无）	1.31	0.58	5.10	3.72	1.19~11.60	0.024
miR-4262表达	2.15	0.68	9.99	8.56	2.26~32.41	0.002
NRG1表达	-1.35	0.55	6.06	0.26	0.09~0.76	0.014