Changes of serum HAS2 and CD44 levels in breast cancer patients and their clinical significance

doi:10.3969/j.issn.1673-8640.2023.05.004

Abstract

Abstract:

Objective To investigate the changes of serum hyaluronan synthase 2（HAS2） and differentiated antigen cluster 44（CD44）levels and the clinical values in patients with breast cancer. Methods From January 2020 to June 2021，52 patients with breast cancer（breast cancer group），40 patients with benign breast diseases（benign disease group）and 34 healthy subjects（healthy control group）from Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine were enrolled. The clinical data were collected，and serum HAS2 and CD44 levels were determined. Pearson correlation analysis was used to evaluate the correlation between serum HAS2 and CD44 levels. Receiver operating characteristic（ROC） curve was used to evaluate the efficacy of single and combined determinations of serum HAS2，CD44，carcinoembryonic antigen（CEA） and carbohydrate antigen（CA）15-3 in the diagnosis of breast cancer. Results Serum HAS2 and CD44 in healthy control group，benign disease group and breast cancer group were increased successively（P<0.000 1）. Pearson correlation analysis showed that serum HAS2 and CD44 levels were positively correlated in healthy control group，benign disease group and breast cancer group（r values were 0.364 4，0.415 2 and 0.290 5，respectively，P<0.05）. ROC curve analysis showed that the areas under curves（AUC） of serum HAS2，CD44，CEA and CA15-3 by single and combined determinations in the diagnosis of breast cancer were 0.800，0.805，0.560，0.621 and 0.883，respectively. The AUC of combined determination in the diagnosis of early stage（TNM stage Ⅰ to Ⅱ） and late stage（TNM stage Ⅲ to Ⅳ）were 0.860 and 0.919，respectively. There was statistical significance in serum HAS2 level among breast cancer patients with different tumor sizes，histological grades，human epidermal growth factor receptor 2（HER2） expressions and lymphatic metastasis（P<0.05）. There was no statistical significance in serum HAS2 level among breast cancer patients with different ages，estrogen receptor（ER） expressions，progesterone receptor（PR） expressions，Ki67 expressions and vascular invasions（P>0.05）. There was no statistical significance in serum CD44 level among breast cancer patients with different clinicopathologic characteristics（P>0.05）. The AUC of serum HAS2 in the diagnosis of lymphatic metastasis of breast cancer was 0.739. Conclusions Serum HAS2 and CD44 are potential as auxiliary diagnostic indicators for breast cancer. Serum HAS2 level is related to breast cancer malignant progression，which may be used as one of the prognostic indicators.

Key words: Hyaluronan synthase 2, Differentiated antigen cluster 44, Breast cancer, Lymphatic metastasis

CLC Number:

R446.1

ZHANG Guoliang, LIU Yiwen, HE Yiqing, XU Jing, YANG Cuixia, GAO Feng, LIU Hua. Changes of serum HAS2 and CD44 levels in breast cancer patients and their clinical significance[J]. Laboratory Medicine, 2023, 38(5): 424-429.

Figures/Tables 7

References 13

[1]	CAON I, BARTOLINI B, PARNIGONI A, et al. Revisiting the hallmarks of cancer:the role of hyaluronan[J]. Semin Cancer Biol, 2020, 62:9-19. DOI URL
[2]	LI P, XIANG T, LI H, et al. Hyaluronan synthase 2 overexpression is correlated with the tumorigenesis and metastasis of human breast cancer[J]. Int J Clin Exp Pathol, 2015, 8(10):12101-12114.
[3]	LIAGHATI P, MOMENI P, ESFANDI F, et al. Expression analysis of CD24 and CD44 transcripts in Iranian breast cancer patients[J]. Breast Dis, 2020, 39(3-4):143-148. DOI PMID
[4]	XU H, WU K, TIAN Y, et al. CD44 correlates with clinicopathological characteristics and is upregulated by EGFR in breast cancer[J]. Int J Oncol, 2016, 49(4):1343-1350. DOI PMID
[5]	AUVINEN P, RILLA K, TUMELIUS R, et al. Hyaluronan synthases(HAS1-3) in stromal and malignant cells correlate with breast cancer grade and predict patient survival[J]. Breast Cancer Res Treat, 2014, 143(2):277-286. DOI URL
[6]	UDABAGE L, BROWNLEE G R, NILSSON S K, et al. The over-expression of HAS2,Hyal-2 and CD44 is implicated in the invasiveness of breast cancer[J]. Exp Cell Res, 2005, 310(1):205-217. DOI URL
[7]	KOLLIOPOULOS C, LIN C Y, HELDIN C H, et al. Has2 natural antisense RNA and Hmga2 promote Has2 expression during TGFβ-induced EMT in breast cancer[J]. Matrix Biol, 2019, 80:29-45. DOI PMID
[8]	YANG C, CAO M, LIU Y, et al. Inducible formation of leader cells driven by CD44 switching gives rise to collective invasion and metastases in luminal breast carcinomas[J]. Oncogene, 2019, 38(46):7113-7132. DOI PMID
[9]	盛雨梦, 许静, 刘鷖雯, 等. 血清HA、HAS2在骨肿瘤辅助诊断及疗效监测中的价值[J]. 检验医学, 2021, 36(2):162-166.
[10]	DASARI S, RAJENDRA W, VALLURU L. Evaluation of soluble CD44 protein marker to distinguish the premalignant and malignant carcinoma cases in cervical cancer patients[J]. Med Oncol, 2014, 31(9):139. DOI PMID
[11]	SAWANT S, AHIRE C, DONGRE H, et al. Prognostic significance of elevated serum CD44 levels in patients with oral squamous cell carcinoma[J]. J Oral Pathol Med, 2018, 47(7):665-673. DOI PMID
[12]	NOTTEGAR A, VERONESE N, SENTHIL M, et al. Extra-nodal extension of sentinel lymph node metastasis is a marker of poor prognosis in breast cancer patients:a systematic review and an exploratory meta-analysis[J]. Eur J Surg Oncol, 2016, 42(7):919-925. DOI URL
[13]	MERIC-BERNSTAM F, JOHNSON A M, DUMBRAVA E E I, et al. Advances in HER2-targeted therapy:novel agents and opportunities beyond breast and gastric cancer[J]. Clin Cancer Res, 2019, 25(7):2033-2041. DOI URL

组别	例数	HAS2/（pg/mL）	CD44/（pg/mL）
正常对照组	34	171.1±50.7	504.7±142.9
乳腺良性疾病组	40	203.5±59.1^*	584.8±111.1^**
乳腺癌组	52	238.7±60.7^***#	674.8±145.1^***#
F值		14.41	16.80
P值		<0.000 1	<0.000 1

组别	例数	HAS2/（pg/mL）	CD44/（pg/mL）
正常对照组	34	171.1±50.7	504.7±142.9
乳腺良性疾病组	40	203.5±59.1^*	584.8±111.1^**
乳腺癌组	52	238.7±60.7^***#	674.8±145.1^***#
F值		14.41	16.80
P值		<0.000 1	<0.000 1

指标	AUC（95%CI ^①）	最佳临界值	敏感性/%	特异性/%	P值
HAS2	0.800（0.706~0.894）	154.0 pg/mL	100.00	47.06	<0.000 1
CD44	0.805（0.709~0.901）	519.0 ng/mL	90.38	64.71	<0.000 1
CEA	0.560（0.437~0.683）	1.715 ng/mL	63.46	52.94	0.351 5
CA15-3	0.621（0.500~0.741）	7.840 U/mL	69.23	58.82	0.060 0
HAS2+CD44	0.865（0.785~0.945）	0.617 4	75.00	85.29	<0.000 1
HAS2+CD44+CEA	0.876（0.798~0.954）	0.580 9	84.60	79.41	<0.000 1
HAS2+CD44+CA15-3	0.874（0.800~0.949）	0.572 2	80.80	79.41	<0.000 1
HAS2+CD44+CEA+CA15-3	0.883（0.810~0.956）	0.500 0	90.40	76.47	<0.000 1

指标	AUC（95%CI ^①）	最佳临界值	敏感性/%	特异性/%	P值
HAS2	0.800（0.706~0.894）	154.0 pg/mL	100.00	47.06	<0.000 1
CD44	0.805（0.709~0.901）	519.0 ng/mL	90.38	64.71	<0.000 1
CEA	0.560（0.437~0.683）	1.715 ng/mL	63.46	52.94	0.351 5
CA15-3	0.621（0.500~0.741）	7.840 U/mL	69.23	58.82	0.060 0
HAS2+CD44	0.865（0.785~0.945）	0.617 4	75.00	85.29	<0.000 1
HAS2+CD44+CEA	0.876（0.798~0.954）	0.580 9	84.60	79.41	<0.000 1
HAS2+CD44+CA15-3	0.874（0.800~0.949）	0.572 2	80.80	79.41	<0.000 1
HAS2+CD44+CEA+CA15-3	0.883（0.810~0.956）	0.500 0	90.40	76.47	<0.000 1

临床病理特征	例数	HAS2/（pg/mL）	CD44/（pg/mL）
年龄^①
<49岁	25	254.8±54.3	705.6±146.7
≥49岁	27	223.8±63.5	646.3±140.2
t值		1.866 0	1.493 0
P值		0.065 0	0.142 2
肿瘤直径^①
<2 cm	23	215.9±50.5	672.5±142.0
≥2 cm	29	256.8±62.9	676.6±149.9
t值		2.573 0	0.101 0
P值		0.014 4	0.920 0
组织学分级
Ⅰ~Ⅱ级	33	223.3±51.7	664.4±130.3
Ⅲ级	19	264.8±67.6	692.9±170.0
t值		2.486 0	0.678 4
P值		0.017 1	0.500 6
淋巴转移
无	32	221.2±58.3	67.92±143.4
有	20	266.8±54.9	667.7±151.2
t值		2.864 0	0.274 5
P值		0.007 1	0.784 8
脉管侵犯
无	35	230.8±55.3	681.3±153.9
有	17	254.9±69.6	661.5±128.2
t值		1.354 0	0.458 1
P值		0.181 9	0.648 9
ER
阴性	15	232.8±60.3	681.3±153.9
阳性	37	241.1±61.6	661.5±128.2
t值		0.446 7	0.108 1
P值		0.651 0	0.914 3
PR
阴性	21	234.6±55.8	692.9±142.1
阳性	31	241.5±64.6	662.5±148.1
t值		0.395 1	0.737 8
P值		0.694 4	0.464 1
HER2
阴性	38	226.2±54.0	663.0±153.4
阳性	14	274.9±64.1	706.7±118.7
t值		2.137 0	0.865 6
P值		0.008 1	0.340 8
Ki67
<14%	16	222.4±53.9	650.8±142.2
≥14%	36	246.0±62.9	685.4±147.0
t值		1.099 0	0.939 7
P值		0.198 9	0.432 6