Levels of serum HMGB2 and HMGB3 and clinical significance in non-small cell lung cancer patients

doi:10.3760/cma.j.cn371439-20231110-00073

Abstract

Abstract:

Objective To investigate the levels of serum high mobility group box （HMGB） 2 and HMGB3 and clinical significance in patients with non-small cell lung cancer （NSCLC）. Methods A total of 137 NSCLC patients admitted to the First Affiliated Hospital of Xi'an Medical University from January 2020 to January 2022 were selected as the NSCLC group， and another 90 cases who underwent healthy medical checkups during the same period were selected as the healthy group. Serum HMGB2 and HMGB3 levels were compared between the two groups. The relationship between serum HMGB2 and HMGB3 levels and the clinical and pathological characteristics of NSCLC patients was analyzed. NSCLC patients were divided into a good prognosis group （n=86） and a poor prognosis group （n=51） according to the prognosis， and the clinical data of the two groups were compared. Multivariate logistic regression was used to analyze the influencing factors of the prognosis of NSCLC patients. Receiver operator characteristic （ROC） curve was used to analyze the predictive value of serum HMGB2 and HMGB3 on the prognosis of NSCLC patients. Results Serum HMGB2 [（6.35±1.66） ng/ml vs. （2.58±0.76） ng/ml， t=20.19， P<0.001] and HMGB3 [（2.48±0.56） ng/ml vs. （1.09±0.13） ng/ml， t=23.13， P<0.001] levels in NSCLC group were higher than those in healthy group. Serum HMGB2 and HMGB3 levels of NSCLC patients with a history of smoking （t=2.80， P=0.006； t=5.04， P<0.001）， lymph node metastasis （t=3.53， P=0.001； t=4.02， P<0.001）， and TNM stage Ⅲ-Ⅳ （t=2.58， P=0.011； t=3.82， P<0.001） were significantly higher than those of patients with no history of smoking， no lymph node metastasis， and TNM stage Ⅰ-Ⅱ. The serum levels of HMGB2 [（7.80±1.83） ng/ml vs. （5.49±1.56） ng/ml， t=7.85， P<0.001] and HMGB3 [（2.91±0.78） ng/ml vs. （2.23±0.43） ng/ml， t=6.58， P<0.001）] in the poor prognosis group were higher than those in the good prognosis group， and the proportion of patients with lymph node metastasis （χ²=4.81， P=0.028）， history of smoking （χ²=11.67， P=0.001）， and TNM stage Ⅲ-Ⅳ （χ²=6.18， P=0.013） was significantly higher than that in the good prognosis group. Multivariate logistic regression analysis showed that lymph node metastasis （OR=1.96， 95%CI： 1.14-3.36， P=0.015）， smoking history （OR=2.02， 95%CI： 1.33-3.06， P=0.001）， TNM stage （OR=2.28， 95%CI： 1.35-3.86， P=0.002）， HMGB2 （OR=2.01， 95%CI： 1.40-2.91， P<0.001）， and HMGB3 （OR=1.99， 95%CI： 1.25-3.15， P=0.003） levels were independent influencing factors of prognosis of NSCLC patients. ROC curve analysis showed that the area under the curve （AUC） of serum HMGB2 and HMGB3 alone and in combination to predict the prognosis of NSCLC patients were 0.833， 0.862 and 0.922， respectively， and the AUC predicted by the combination was significantly higher than that predicted by serum HMGB2 （Z=2.44， P=0.015） and HMGB3 （Z=2.54， P=0.011） alone. Conclusion Serum HMGB2 and HMGB3 levels are up-regulated in NSCLC patients and are closely associated with poor prognosis， and the combined detection of the two has certain predictive efficacy for prognosis of NSCLC patients.

Key words: Carcinoma, non-small-cell lung, HMGB2 protein, HMGB3 protein

Liu Hao, Jin Ermei, Ding Hongjuan, Jin Lei. Levels of serum HMGB2 and HMGB3 and clinical significance in non-small cell lung cancer patients[J]. Journal of International Oncology, 2024, 51(7): 448-452.

Figures/Tables 6

References 19

[1]	Massafra M, Passalacqua MI, Gebbia V, et al. Immunotherapeutic advances for NSCLC[J]. Biologics, 2021, 15: 399-417. DOI: 10.2147/BTT.S295406. pmid: 34675481
[2]	Aird KM, Iwasaki O, Kossenkov AV, et al. HMGB2 orchestrates the chromatin landscape of senescence-associated secretory phenotype gene loci[J]. J Cell Biol, 2016, 215(3): 325-334. DOI: 10.1083/jcb.201608026. pmid: 27799366
[3]	Pu J, Tan C, Shao ZS, et al. Long noncoding RNA PART1 promotes hepatocellular carcinoma progression via targeting miR-590-3p/HMGB2 axis[J]. Onco Targets Ther, 2020, 13: 9203-9211. DOI: 10.2147/OTT.S259962.
[4]	Xie XJ, Pan JJ, Han X, et al. Downregulation of microRNA-532-5p promotes the proliferation and invasion of bladder cancer cells through promotion of HMGB3/Wnt/β-catenin signaling[J]. Chem Biol Interact, 2019, 300: 73-81. DOI: 10.1016/j.cbi.2019.01.015.
[5]	Guo SN, Wang YY, Gao Y, et al. Knockdown of high mobility group-box 3 (HMGB3) expression inhibits proliferation, reduces migration, and affects chemosensitivity in gastric cancer cells[J]. Med Sci Monit, 2016, 22: 3951-3960. DOI: 10.12659/msm.900880.
[6]	中华医学会, 中华医学会肿瘤学分会, 中华医学会杂志社. 中华医学会肺癌临床诊疗指南(2019版)[J]. 肿瘤研究与临床, 2020, 32(4): 217-249. DOI: 10.3760/cma.j.cn115355-20200202-00036.
[7]	顾剑峰, 毛卫军, 张健, 等. 单向式全腔镜肺叶切除术治疗外周型早期非小细胞肺癌的疗效及对预后的影响[J]. 癌症进展, 2019, 17(22): 2673-2675. DOI: 10.11877/j.issn.1672-1535.2019.17.22.17.
[8]	Ye RF, Tang RX, Gan SY, et al. New insights into long non-coding RNAs in non-small cell lung cancer[J]. Biomed Pharmacother, 2020, 131: 110775. DOI: 10.1016/j.biopha.2020.110775. pmid: 33152934
[9]	Siegel RL, Miller KD, Fuchs HE, et al. Cancer statistics, 2022[J]. CA Cancer J Clin, 2022, 72(1): 7-33. DOI: 10.3322/caac.21708.
[10]	Chaft JE, Rimner A, Weder W, et al. Evolution of systemic therapy for stages Ⅰ-Ⅲ non-metastatic non-small-cell lung cancer[J]. Nat Rev Clin Oncol, 2021, 18(9): 547-557. DOI: 10.1038/s41571-021-00501-4.
[11]	Niu LR, Yang WL, Duan LL, et al. Biological functions and theranostic potential of HMGB family members in human cancers[J]. Ther Adv Med Oncol, 2020, 12: 1758835920970850. DOI: 10.1177/1758835920970850.
[12]	Fu DY, Li J, Wei JL, et al. HMGB2 is associated with malignancy and regulates Warburg effect by targeting LDHB and FBP1 in breast cancer[J]. Cell Commun Signal, 2018, 16(1): 8. DOI:10.1186/s12964-018-0219-0. pmid: 29463261
[13]	Han QR, Xu LJ, Lin WH, et al. Long noncoding RNA CRCMSL suppresses tumor invasive and metastasis in colorectal carcinoma through nucleocytoplasmic shuttling of HMGB2[J]. Oncogene, 2019, 38(16): 3019-3032. DOI: 10.1038/s41388-018-0614-4. pmid: 30575817
[14]	Lou N, Zhu TT, Qin DR, et al. High-mobility group box 2 reflects exacerbated disease characteristics and poor prognosis in non-small cell lung cancer patients[J]. Ir J Med Sci, 2022, 191(1): 155-162. DOI: 10.1007/s11845-021-02549-8.
[15]	Gu J, Xu T, Zhang CM, et al. HMGB3 small interfere RNA suppresses mammosphere formation of MDA-MB-231 cells by down-regulating expression of HIF1α[J]. Eur Rev Med Pharmacol Sci, 2019, 23(21): 9506-9516. DOI: 10.26355/eurrev_201911_19445.
[16]	Wen B, Wei YT, Zhao K. The role of high mobility group protein B3 (HMGB3) in tumor proliferation and drug resistance[J]. Mol Cell Biochem, 2021, 476(4): 1729-1739. DOI: 10.1007/s11010-020-04015-y. pmid: 33428061
[17]	Zheng XF, Wang X, He YD, et al. Systematic analysis of expression profiles of HMGB family members for prognostic application in non-small cell lung cancer[J]. Front Mol Biosci, 2022, 9: 844618. DOI: 10.3389/fmolb.2022.844618.
[18]	Zhang JN, Mao JJ. CircRNA hsa_circ_0075048 promotes the malignant progression of non-small cell lung cancer by up-regulating HMGB2 expression via targeting miR-1225-5p[J]. Histol Histopathol, 2023, 38(6): 709-724. DOI: 10.14670/HH-18-551.
[19]	Li YJ, Ma YF, Zhang T, et al. High-mobility group box 3 (HMGB3) silencing inhibits non-small cell lung cancer development through regulating Wnt/β-catenin pathway[J]. Biol Chem, 2020, 401(10): 1191-1198. DOI: 10.1515/hsz-2020-0144. pmid: 32386184

临床病理特征	例数	HMGB2	t/F值	P值	HMGB3	t/F值	P值
年龄（岁）
<50	69	6.17±1.23	1.23	0.222	2.40±0.39	1.60	0.111
≥50	68	6.53±2.10	1.23	0.222	2.56±0.73	1.60	0.111
性别
男	76	6.43±2.06	0.61	0.544	2.53±0.64	1.13	0.261
女	61	6.25±1.16	0.61	0.544	2.42±0.46	1.13	0.261
吸烟史
有	82	6.68±1.87	2.80	0.006	2.68±0.55	5.04	<0.001
无	55	5.86±1.35	2.80	0.006	2.19±0.57	5.04	<0.001
TNM分期
Ⅰ~Ⅱ	59	5.93±1.56	2.58	0.011	2.26±0.33	3.82	<0.001
Ⅲ~Ⅳ	78	6.67±1.74	2.58	0.011	2.65±0.73	3.82	<0.001
病理类型
腺癌	88	6.21±2.02	1.20	0.232	2.41±0.55	1.90	0.059
鳞状细胞癌	49	6.58±1.01	1.20	0.232	2.60±0.58	1.90	0.059
淋巴结转移
有	72	6.83±1.86	3.53	0.001	2.67±0.42	4.02	<0.001
无	65	5.82±1.44	3.53	0.001	2.27±0.72	4.02	<0.001
分化程度
高分化	33	6.52±1.58			2.61±0.63
中分化	56	6.31±1.42	0.33	0.718	2.52±0.41	2.20	0.114
低分化	48	6.28±1.20			2.35±0.69

临床病理特征	预后良好组（n=86）	预后不良组（n=51）	χ²/t值	P值
性别
男	51（59.30）	25（49.02）	1.37	0.242
女	35（40.70）	26（50.98）	1.37	0.242
年龄（岁）	52.45±12.83	53.16±10.66	0.33	0.740
吸烟史
有	42（48.84）	40（78.43）	11.67	0.001
无	44（51.16）	11（21.57）	11.67	0.001
淋巴结转移
有	39（45.35）	33（64.71）	4.81	0.028
无	47（54.65）	18（35.29）	4.81	0.028
病理类型
腺癌	51（59.30）	37（72.55）	2.45	0.118
鳞状细胞癌	35（40.70）	14（27.45）	2.45	0.118
TNM分期
Ⅰ~Ⅱ	44（51.16）	15（29.41）	6.18	0.013
Ⅲ~Ⅳ	42（48.84）	36（70.59）	6.18	0.013
分化程度
高分化	17（19.77）	16（31.37）	2.48	0.290
中分化	38（44.18）	18（35.29）
低分化	31（36.05）	17（33.34）
HMGB2（ng/ml）	5.49±1.56	7.80±1.83	7.85	<0.001
HMGB3（ng/ml）	2.23±0.43	2.91±0.78	6.58	<0.001

变量	β值	SE值	Wald χ²值	OR值	95%CI	P值
淋巴结转移	0.670	0.276	5.90	1.96	1.14~3.36	0.015
吸烟史	0.701	0.213	10.83	2.02	1.33~3.06	0.001
TNM分期	0.825	0.268	9.49	2.28	1.35~3.86	0.002
HMGB2	0.700	0.187	14.02	2.01	1.40~2.91	<0.001
HMGB3	0.687	0.235	8.54	1.99	1.25~3.15	0.003

指标	截断值（ng/ml）	特异性（%）	敏感性（%）	AUC	95%CI	约登指数
HMGB2	6.97	86.05	64.71	0.833^a	0.759~0.891	0.508
HMGB3	2.64	90.70	78.43	0.862^b	0.793~0.915	0.691
二者联合		83.72	88.24	0.922	0.863~0.961	0.720