Levels and diagnostic value of TOP2A and ERBB2 in peripheral blood mononuclear cells of patients with early colorectal cancer

doi:10.3760/cma.j.cn371439-20230724-00135

Abstract

Abstract:

Objective To investigate the levels and diagnostic value of topoisomerase Ⅱα （TOP2A） and human epidermal growth factor receptor 2 （ERBB2） in early colorectal cancer （CRC）. Methods Ninty-three early CRC patients （CRC group） admitted to Shijiazhuang Hospital of Traditional Chinese Medicine were selected for the study from January 2019 to April 2022， and 93 healthy subjects during the same period were selected as the healthy group， and 93 colorectal polyps patients diagnosed and treated in the same period were selected as the colorectal polyp group. TOP2A and ERBB2 mRNA levels in peripheral blood mononuclear cell （PBMC） and serum carcinoembryonic antigen （CEA） level were detected and compared in each group. The value of TOP2A， ERBB2 mRNA and serum CEA level in the diagnosis of early CRC were evaluated by using receiver operating characteristic（ROC） curve. The relationship between TOP2A and ERBB2 levels and clinicopathological features of early CRC patients was analyzed. Results There were statistically significant differences in the PBMC TOP2A （1.04±0.35 vs. 1.72±0.57 vs. 2.83±0.71， F=246.73， P<0.001）， ERBB2 mRNA （1.01±0.34 vs. 1.64±0.55 vs. 2.75±0.71， F=234.80， P<0.001） levels and serum CEA levels （1.29±0.52 vs. 1.93±0.64 vs. 3.17±0.81， F=190.78， P<0.001） in healthy group， colorectal polyp group and CRC group. Compared with the healthy group and colorectal polyp group， the levels of TOP2A and ERBB2 mRNA in PBMC and serum CEA level in CRC group were significantly increased （all P<0.05）； Compared with the healthy group， the levels of TOP2A and ERBB2 mRNA in PBMC and serum CEA level in the colorectal polyp group were increased （all P<0.05）. The ROC curve showed that the area under curve （AUC） of TOP2A and ERBB2 mRNA levels in PBMC and serum CEA level for the diagnosis of early CRC were 0.85， 0.85 and 0.84， respectively， and the AUC for the combined diagnosis of early CRC was 0.96， which was higher than that of TOP2A， ERBB2 and CEA alone （Z=2.92， P=0.004； Z=3.16， P=0.002； Z=2.86， P=0.005）. The combination of the three diagnosed early CRC with a sensitivity of 94.64% and a specificity of 85.96%. There were statistically significant differences in PBMC TOP2A and ERBB2 mRNA levels in early CRC patients with different differentiation degrees （χ²=6.21， P=0.013； χ²=10.49， P=0.001）. Conclusion The expression levels of TOP2A， ERBB2 mRNA in PBMC in CRC patients are higher. The combination of TOP2A， ERBB2 mRNA levels in PBMC and serum CEA level may be more helpful for clinical diagnosis of early CRC.

Key words: Colorectal neoplasms, DNA topoisomerases， type Ⅱ, Genes， erbB-2

Liu Yujie, Zhao Zhiqiang, Wang Zicheng. Levels and diagnostic value of TOP2A and ERBB2 in peripheral blood mononuclear cells of patients with early colorectal cancer[J]. Journal of International Oncology, 2023, 50(12): 717-722.

Figures/Tables 5

References 23

[1]	Jiang X, Wang J, Wang M, et al. ITGB4 as a novel serum diagnosis biomarker and potential therapeutic target for colorectal cancer[J]. Cancer Med, 2021, 10(19): 6823-6834. DOI: 10.1002/cam4.4216.
[2]	李淑婷, 刘楠, 李袁飞. 结直肠癌与结直肠息肉患者血清IGFBP7水平比较及其诊断价值分析[J]. 山东医药, 2021, 61(29): 67-69. DOI: 10.3969/j.issn.1002-266X.2021.29.018.
[3]	Chen X, Sun J, Wang X, et al. A meta-analysis of proteomic blood markers of colorectal cancer[J]. Curr Med Chem, 2021, 28(6): 1176-1196. DOI: 10.2174/0929867327666200427094054.
[4]	Yu D, Sun J, Weng Y, et al. Serum angiogenin as a potential biomarker for early detection of colorectal adenomas and colorectal cancer[J]. Anticancer Drugs, 2021, 32(7): 703-708. DOI: 10.1097/CAD.0000000000001047. pmid: 33661188
[5]	Iacuzzo C, Germani P, Troian M, et al. Serum carcinoembryonic antigen pre-operative level in colorectal cancer: revisiting risk stratification[J]. ANZ J Surg, 2021, 91(6): E367-E374. DOI: 10.1111/ans.16861. pmid: 33870621
[6]	Carvalho RF, do Canto LM, Cury SS, et al. Drug repositioning based on the reversal of gene expression signatures identifies TOP2A as a therapeutic target for rectal cancer[J]. Cancers (Basel), 2021, 13(21): 5492. DOI: 10.3390/cancers13215492.
[7]	潘坚慧, 奕天飞, 杭晨, 等. 结直肠癌患者HER-2表达与临床病理特征及预后的关系[J]. 浙江医学, 2020, 42(19): 2084-2088. DOI: 10.12056/j.issn.1006-2785.2020.42.19.2020-146.
[8]	张雪, 韩晶, 周欣亮, 等. DUOXA2在结直肠癌组织中表达及其与预后的关联[J]. 中华肿瘤防治杂志, 2021, 28(7): 502-507. DOI: 10.16073/j.cnki.cjcpt.2021.07.04.
[9]	Pączek S, Łukaszewicz-Zając M, Gryko M, et al. The clinical utility of serum CXCR-2 assessment in colorectal cancer (CRC) patients[J]. Anticancer Res, 2021, 41(3): 1421-1428. DOI: 10.21873/anticanres.14899. pmid: 33788733
[10]	Wang X, Wang J, Lyu L, et al. Oncogenic role and potential regulatory mechanism of topoisomerase Ⅱα in a pan-cancer analysis[J]. Sci Rep, 2022, 12(1): 11161. DOI: 10.1038/s41598-022-15205-7.
[11]	严龙君, 夏萌, 李明, 等. CDC20、TOP2A、NEK2的表达特征以及对食管鳞状细胞癌细胞增殖和迁移的影响[J]. 临床和实验医学杂志, 2022, 21(21): 2273-2277. DOI: 10.3969/j.issn.1671-4695.2022.21.009.
[12]	Liu T, Zhang H, Yi S, et al. Mutual regulation of MDM4 and TOP2A in cancer cell proliferation[J]. Mol Oncol, 2019, 13(5): 1047-1058. DOI: 10.1002/1878-0261.12457. pmid: 30672125
[13]	Dong Y, Sun X, Zhang K, et al. Type ⅡA topoisomerase (TOP2A) triggers epithelial-mesenchymal transition and facilitates HCC progression by regulating Snail expression[J]. Bioengineered, 2021, 12(2): 12967-12979. DOI: 10.1080/21655979.2021.2012069.
[14]	Piran M, Sepahi N, Moattari A, et al. Systems biomedicine of primary and metastatic colorectal cancer reveals potential therapeutic targets[J]. Front Oncol, 2021, 11: 597536. DOI: 10.3389/fonc.2021.597536.
[15]	Yu C, Chen F, Jiang J, et al. Screening key genes and signaling pathways in colorectal cancer by integrated bioinformatics analysis[J]. Mol Med Rep, 2019, 20(2): 1259-1269. DOI: 10.3892/mmr.2019.10336. pmid: 31173250
[16]	Sukanya JS, Raj PV, Thanka J. Role of HER2neu expression in gastric cancer[J]. Indian J Pathol Microbiol, 2021, 64(1): 58-64. DOI: 10.4103/IJPM.IJPM_835_19.
[17]	Zhang G, Ren C, Li C, et al. Distinct clinical and somatic mutational features of breast tumors with high-, low-, or non-expressing human epidermal growth factor receptor 2 status[J]. BMC Med, 2022, 20(1): 142. DOI: 10.1186/s12916-022-02346-9. pmid: 35484593
[18]	苏婷婷, 郑晋, 王硕, 等. 吡咯替尼抑制胆囊癌细胞增殖、迁移和侵袭并诱导凋亡的作用研究[J]. 中国普通外科杂志, 2020, 29(2): 161-170. DOI: 10.7659/j.issn.1005-6947.2020.02.007.
[19]	Huang YF, Zhang Y, Fu X. Long non-coding RNA DANCR promoted non-small cell lung cancer cells metastasis via modulating of miR-1225-3p/ErbB2 signal[J]. Eur Rev Med Pharmacol Sci, 2021, 25(2): 758-769. DOI: 10.26355/eurrev_202101_24637.
[20]	宋聚才, 巩跃生, 刘全林. 白头翁汤对结直肠癌小鼠肠道菌群、炎症因子及HER-2表达的影响[J]. 中医药信息, 2022, 39(3): 20-24. DOI: 10.19656/j.cnki.1002-2406.20220304.
[21]	朱婷, 步大成, 张英轶, 等. 结直肠癌组织Snail、pim-3、E-cadherin和Her-2的表达及与预后的关系[J]. 局解手术学杂志, 2019, 28(10): 778-781. DOI: 10.11659/jjssx.02E019010.
[22]	王小平, 王诺凡, 陈小翔, 等. 血清miR-23a、miR-27a联合CEA在结直肠癌诊断中的临床价值[J]. 南京医科大学学报(自然科学版), 2022, 42(1): 58-62. DOI: 10.7655/NYDXBNS20220110.
[23]	Brown I, Zammit AP, Bettington M, et al. Pathological features associated with metastasis in patients with early invasive (pT₁) colorectal carcinoma in colorectal polyps[J]. Histopathology, 2023, 83(4): 591-606. DOI: 10.1111/his.14970.

组别	性别（男/女）	年龄（岁）
健康组（n=93）	52/41	53.72±9.44
结直肠息肉组（n=93）	54/39	54.05±9.71
CRC组（n=93）	50/43	53.24±9.35
χ²/F值	0.35	0.17
P值	0.840	0.843

组别	TOP2A mRNA	ERBB2 mRNA	CEA（ng/ml）
健康组（n=93）	1.04±0.35	1.01±0.34	1.29±0.52
结直肠息肉组（n=93）	1.72±0.57^a	1.64±0.55^a	1.93±0.64^a
CRC组（n=93）	2.83±0.71^ab	2.75±0.71^ab	3.17±0.81^ab
F值	246.73	234.80	190.78
P值	<0.001	<0.001	<0.001

指标	最佳截断值	AUC	95%CI	敏感性（%）	特异性（%）	约登指数
TOP2A	2.23	0.85	0.72~0.92	81.71	87.09	0.69
ERBB2	2.15	0.85	0.78~0.92	74.16	89.24	0.63
CEA	2.77 ng/ml	0.84	0.75~0.92	74.21	88.19	0.62
三者联合	-	0.96	0.94~0.99	94.64	85.96	0.81

临床病理特征	TOP2A				ERBB2
临床病理特征	低水平组（n=46）	高水平组（n=47）	χ²值	P值	低水平组（n=48）	高水平组（n=45）	χ²值	P值
性别
男	24（52.17）	26（55.32）	0.09	0.761	28（58.33）	22（48.89）	0.83	0.361
女	22（47.83）	21（44.68）	0.09	0.761	20（41.67）	23（51.11）	0.83	0.361
年龄（岁）
<55	20（43.48）	19（40.43）	0.09	0.765	18（37.50）	21（46.67）	0.80	0.371
≥55	26（56.52）	28（59.57）	0.09	0.765	30（62.50）	24（53.33）	0.80	0.371
肿瘤大小（mm）
<15	23（50.00）	22（46.81）	0.10	0.758	26（54.17）	19（42.22）	1.33	0.249
15~30	23（50.00）	25（53.19）	0.10	0.758	22（45.83）	26（57.78）	1.33	0.249
肿瘤位置
直肠	19（41.30）	18（38.30）	1.80	0.406	21（43.75）	16（35.56）
右半结肠	14（30.43）	20（42.55）			16（33.33）	18（40.00）	0.70	0.706
左半结肠	13（28.26）	9（19.15）			11（22.92）	11（24.44）
分化程度
低分化	3（6.52）	12（25.53）	6.21	0.013	2（4.17）	13（28.89）	10.49	0.001
中、高分化	43（93.48）	35（74.47）	6.21	0.013	46（95.83）	32（71.11）	10.49	0.001