血清热休克蛋白90α对肝细胞癌经肝动脉化疗栓塞术后生存的预测价值

陈乾; 姚辉华; 李波

doi:10.3969/j.issn.1001-5256.2022.03.016

血清热休克蛋白90α对肝细胞癌经肝动脉化疗栓塞术后生存的预测价值

DOI: 10.3969/j.issn.1001-5256.2022.03.016

陈乾^{1, 2},
姚辉华^{1, 3, , ,},
李波^{1, 2}

1.
西南医科大学临床医学院，四川泸州 646000
2.
西南医科大学附属医院肝胆外科，四川泸州 646000
3.
成都市第一人民医院肝胆外科，成都 610041

基金项目:

四川省医学会（青年创新）科研项目 (S20062)

伦理学声明：本研究方案于2021年4月16日经由西南医科大学附属医院伦理委员会批准，批号：KY2021109，所有患者均知情同意。

利益冲突声明：本研究不存在研究者、伦理委员会成员、受试者监护人以及与公开研究成果有关的利益冲突。

作者贡献声明：陈乾负责研究思路或设计，参与研究数据获取分析；陈乾、李波、姚辉华参与起草或修改文章关键内容。

详细信息

通信作者:
姚辉华，E-mail: yhhdrxp@hotmail.com

陈乾、姚辉华对本文贡献等同，同为第一作者

计量
- 文章访问数: 379
- HTML全文浏览量: 157
- PDF下载量: 53
- 被引次数: 0
出版历程
- 收稿日期: 2021-08-05
- 录用日期: 2021-10-08
- 出版日期: 2022-03-20

Influence of serum heat shock protein 90α on the prognosis of patients with hepatocellular carcinoma after transarterial chemoembolization

Qian CHEN^{1, 2},
Huihua YAO^{1, 3
, ,
,},
Bo LI^{1, 2}

1.
School of Clinical Medicine, Southwest Medical University, Luzhou, Sichuan 646000, China
2.
Department of Hepatobiliary Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China
3.
Department of Hepatobiliary Surgery, Chengdu First People's Hospital, Chengdu 610041, China

Research funding:

Scientific Research Project of Sichuan Medical Association (Youth Innovation) (S20062)

More Information

Corresponding author: YAO Huihua, yhhdrxp@hotmail.com (ORCID: 0000-0002-7803-8565)

摘要

摘要: 目的探讨术前血清热休克蛋白90α（HSP90α）水平对经肝动脉化疗栓塞术（TACE）治疗的肝细胞癌患者术后生存时间的影响。方法回顾性分析2019年1月1日—2020年6月1日于西南医科大学附属医院肝胆外科接受单一TACE治疗的97例肝细胞癌患者的临床资料。以患者血清HSP90α水平的中位数作为临界值，将入组病例分为高水平组（HSP90α＞135 ng/L，n=48）和低水平组（HSP90α≤135 ng/L，n=49）。计数资料2组间的比较采用χ²检验。采用Kaplan-Meier法计算中位生存时间，组间比较采用log-rank检验。通过log-rank单因素分析及Cox回归多因素分析探索患者术后生存时间的影响因素。结果血清HSP90α高水平组与低水平组患者的肝功能Child-Pugh分级（χ²=19.356，P<0.01）、肿瘤坏死(χ²=9.964，P=0.002)、BCLC分期(χ²=22.356，P<0.01)及ECOG评分(χ²=6.644，P<0.05)比较，差异均有统计学意义。HSP90α高水平组患者的中位生存时间比低水平组短，差异有统计学意义（χ²=15.551，P<0.01）；HSP90α水平（HR=1.690, P<0.05）及BCLC分期(HR=2.373, P<0.05)均是肝癌患者TACE术后生存时间的独立影响因素。结论术前血清HSP90α水平是影响肝癌患者TACE术后生存时间的独立因素，有望成为评估经TACE治疗肝癌患者预后的潜在指标之一。
- 癌, 肝细胞 /
- HSP90热休克蛋白质类 /
- 化学栓塞, 治疗性 /
- 预后
Abstract: Objective To investigate the influence of preoperative serum heat shock protein 90α (HSP90α) level on the survival time of patients with hepatocellular carcinoma treated by transarterial chemoembolization (TACE). Methods A retrospective analysis was performed for the clinical data of 97 patients with hepatocellular carcinoma who received TACE alone in Department of Hepatobiliary Surgery, The Affiliated Hospital of Southwest Medical University, from January 1, 2019 to June 1, 2020. With the median of serum HSP90α level as the cut-off value, the patients were divided into high-level group with 48 patients (HSP90α > 135 ng/L) and low-level group with 49 patients (HSP90α ≤135 ng/L). The chi-square test was used for comparison of categorical data between groups. The Kaplan-Meier method was used to calculate the median survival time, and the log-rank test was used for comparison between groups. The log-rank univariate analysis and multivariate Cox regression analysis were used to explore the influencing factors for the survival time of patients after surgery. Results There were significant differences between the high-level group and the low-level group in Child-Pugh class (χ²=19.356, P<0.01), tumor necrosis (χ²=9.964, P=0.002), BCLC staging (χ²=22.356, P<0.01), and ECOG score (χ²=6.644, P<0.05). The high-level group had a significantly shorter median survival time than the low-level group (χ²=15.551, P<0.01). HSP90α level (hazard ratio [HR]=1.690, P<0.05) and BCLC staging (HR=2.373, P<0.05) were independent influencing factors for the survival time of patients with hepatocellular carcinoma after TACE. Conclusion Preoperative serum HSP90α level is an independent influencing factor for the survival time of patients with hepatocellular carcinoma after TACE, and it is expected to become one of the potential indicators for evaluating the prognosis of patients with hepatocellular carcinoma treated by TACE.
- Carcinoma, Hepatocellular /
- HSP90 Heat-Shock Proteins /
- Chemoembolization, Therapeutic /
- Prognosis

HTML全文

图 1 HSP90α高水平组与低水平组的生存曲线

下载: 全尺寸图片幻灯片

表 1 HSP90α高水平组与低水平组患者临床病理特征

临床特征	高水平组(n=48)	低水平组(n=49)	χ²值	P值
性别[例(%)]			1.101	0.294
男	42（87.5）	39（79.6）
女	6（12.5）	10（20.4）
年龄[例(%)]			0.112	0.738
≥60岁	18（37.5）	20（40.8）
<60岁	30（62.5）	29（59.2）
Child-Pugh分级[例(%)]			19.356	< 0.01
A级	30（62.5）	48（98.0）
B级	18（37.5）	1（2.0）
肿瘤坏死[例(%)]			9.964	0.002
有	29（60.4）	14（28.6）
无	19（39.6）	35（71.4）
BCLC分期[例(%)]			22.356	< 0.01
A+B期	7（14.6）	30（61.2）
C期	41（85.4）	19（38.8）
ECOG评分[例(%)]			6.644	0.010
0分	23（47.9）	36（73.5）
1+2分	25（52.1）	13（26.5）

下载: 导出CSV

表 2 影响患者生存时间的单因素分析

变量	例数	中位生存时间（95%CI）（月）	χ²值	P值
性别			2.713	0.100
男	81	12.00（9.999~14.001）
女	16	9.00（7.055~10.945）
年龄			3.099	0.078
≥60岁	38	13.00（5.062~20.938）
<60岁	59	10.00（8.327~11.673）
前白蛋白			0.197	0.658
<180 g/L	63	11.00（9.067~12.933）
≥180 g/L	34	12.00（6.435~17.565）
HSP90α			15.551	< 0.01
≤135 ng/mL	49	17.00（12.762~21.238）
＞135 ng/mL	48	8.00（5.739~10.261）
NLR			3.862	0.049
≤2.8	48	16.00（11.816~20.184）
＞2.8	49	10.00（7.110~12.890）
PLR			2.341	0.126
≤134.5	49	13.00（8.378~17.622）
＞134.5	48	10.00（7.745~12.255）
AFP			5.144	0.023
<400 ng/mL	51	15.00（11.379~18.621）
≥400 ng/mL	46	9.00（7.008~10.992）
Child-Pugh分级			4.747	0.029
A级	78	12.00（9.867~14.133）
B级	19	8.00（3.734~12.266）
肿瘤坏死			2.738	0.098
有	43	10.00（8.168~11.832）
无	54	12.00（9.645~14.355）
BCLC分期			21.433	< 0.01
A+B期	37	20.00（17.332~22.668）
C期	60	9.00（6.842~11.158）
ECOG评分			5.939	0.015
0分	59	13.00（8.560~17.440）
1+2分	38	8.00（4.979~11.021）

下载: 导出CSV

表 3 影响患者生存时间的Cox多因素分析

变量	B值	SE	HR	95%CI	P值
HSP90α(≤135 ng/mL vs＞135 ng/mL)	0.525	0.256	1.690	1.023~2.792	0.040
BCLC分期[(A+B)期vs C期]	0.864	0.275	2.373	1.383~4.069	0.002

下载: 导出CSV

参考文献(25)

[1]	SUNG H, FERLAY J, SIEGEL RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2021, 71(3): 209-249. DOI: 10.3322/caac.21660.
[2]	SIEGHART W, HUCKE F, PECK-RADOSAVLJEVIC M. Transarterial chemoembolization: Modalities, indication, and patient selection[J]. J Hepatol, 2015, 62(5): 1187-1195. DOI: 10.1016/j.jhep.2015.02.010.
[3]	FU Y, XU X, HUANG D, et al. Plasma heat shock protein 90alpha as a biomarker for the diagnosis of liver Cancer: An official, large-scale, and multicenter clinical trial[J]. EBioMedicine, 2017, 24: 56-63. DOI: 10.1016/j.ebiom.2017.09.007.
[4]	CHEN Y. Expression and clinical significance of HSP90α in hepatocellular carcinoma[D]. Tianjin: Tianjin Medical University, 2019. 陈影. HSP90α在原发性肝细胞癌中的表达特点及临床意义[D]. 天津: 天津医科大学, 2019.
[5]	HEIMBACH JK, KULIK LM, FINN RS, et al. AASLD guidelines for the treatment of hepatocellular carcinoma[J]. Hepatology, 2018, 67(1): 358-380. DOI: 10.1002/hep.29086.
[6]	LIN W, WANG H, ZHONG M, et al. Effect and molecular mechanisms of jiedu recipe on hypoxia-induced angiogenesis after transcatheter arterial chemoembolization in hepatocellular carcinoma[J]. Evid Based Complement Alternat Med, 2021, 2021: 6529376. DOI: 10.1155/2021/6529376.
[7]	YAN YZ, TANG H, YOU J. Meta-analysis of efficacy of Ganfule combined with TACE in the treat-ment of hepatocellular carcinoma[J]. China Med Herald, 2020, 562(32): 87-91. https://www.cnki.com.cn/Article/CJFDTOTAL-YYCY202032024.htm 晏远智, 唐恒, 游晶. 肝复乐联合肝动脉化疗栓塞术治疗肝细胞癌有效性的Meta分析[J]. 中国医药导报, 2020, 562(32): 87-91. https://www.cnki.com.cn/Article/CJFDTOTAL-YYCY202032024.htm
[8]	DING Y, HUANG RG. Survival analysis of radiofrequency ablation combined with hepatic artery chemoembolization in the treatment of early liver cancer in the elderly[J]. Chin J Gerontol, 2021, 41(18): 3953-3955. DOI: 10.3969/j.issn.1005-9202.2021.18.021. 丁一, 黄汝刚. 射频消融术后联合肝动脉化疗栓塞治疗老年早期肝癌的生存分析[J]. 中国老年学杂志, 2021, 41(18): 3953-3955. DOI: 10.3969/j.issn.1005-9202.2021.18.021.
[9]	LIANG D, YANG B. Short-term efficacy of oral low-dose Tegafur chemotherapy after transarterial chemoembolization in primary hepatic carcinoma[J]. J BUON, 2019, 24(1): 171-177. http://www.ncbi.nlm.nih.gov/pubmed/30941967
[10]	CHEN MY, JUENGPANICH S, HU JH, et al. Prognostic factors and predictors of postoperative adjuvant transcatheter arterial chemoembolization benefit in patients with resected hepatocellular carcinoma[J]. World J Gastroenterol, 2020, 26(10): 1042-1055. DOI: 10.3748/wjg.v26.i10.1042.
[11]	LI J, ZHU WL, KANG XX, et al. Prognostic factors and model of primary liver cancer treated with transcatheter arterial chemoembolization combined with radiofrequency ablation[J]. Chin J Oncol, 2017, 39(10): 787-791. DOI: 10.3760/cma.j.issn.0253-3766.2017.10.013. 李靖, 朱文良, 康鑫鑫, 等. 经肝动脉化疗栓塞联合射频消融治疗原发性肝癌的预后影响因素及预测模型[J]. 中华肿瘤杂志, 2017, 39(10): 787-791. DOI: 10.3760/cma.j.issn.0253-3766.2017.10.013.
[12]	ZHAO SJ, YANG ZY, LEI SX, et al. Comparison of prognostic value between Child-Pugh score and albumin-bilirubin grading for patients with BCLC-B stage hepatocellular carcinoma[J/CD]. Chin J Hepat Surg(Electronic Edition), 2021, 10(1): 38-42. DOI: 10.3877/cma.j.issn.2095-3232.2021.01.009. 赵首捷, 杨振宇, 雷世雄, 等. Child-Pugh评分和ALBI分级对BCLC-B期肝癌生存预后预测价值比较[J/CD]. 中华肝脏外科手术学电子杂志, 2021, 10(1): 38-42. DOI: 10.3877/cma.j.issn.2095-3232.2021.01.009.
[13]	YOO YG, YEO MG, KIM DK, et al. Novel function of orphan nuclear receptor Nur77 in stabilizing hypoxia-inducible factor-1alpha[J]. J Biol Chem, 2004, 279(51): 53365-53373. DOI: 10.1074/jbc.M408554200.
[14]	SONG X, WANG X, ZHUO W, et al. The regulatory mechanism of extracellular Hsp90{alpha} on matrix metalloproteinase-2 processing and tumor angiogenesis[J]. J Biol Chem, 2010, 285(51): 40039-40049. DOI: 10.1074/jbc.M110.181941.
[15]	WANG X, SONG X, ZHUO W, et al. The regulatory mechanism of Hsp90alpha secretion and its function in tumor malignancy[J]. Proc Natl Acad Sci U S A, 2009, 106(50): 21288-21293. DOI: 10.1073/pnas.0908151106.
[16]	ZOU M, BHATIA A, DONG H, et al. Evolutionarily conserved dual lysine motif determines the non-chaperone function of secreted Hsp90alpha in tumour progression[J]. Oncogene, 2017, 36(15): 2160-2171. DOI: 10.1038/onc.2016.375.
[17]	WEI W, LIU M, NING S, et al. Diagnostic value of plasma HSP90α levels for detection of hepatocellular carcinoma[J]. BMC Cancer, 2020, 20(1): 6. DOI: 10.1186/s12885-019-6489-0.
[18]	TANG Y, LI K, CAI Z, et al. HSP90α combined with AFP and TK1 improved the diagnostic value for hepatocellular carcinoma[J]. Biomark Med, 2020, 14(10): 869-878. DOI: 10.2217/bmm-2019-0484.
[19]	TAN LL, BAI WY. The Phosphatidylinositol 3-kinase/AKt pathway in hepatocelluar carcinoma[J]. Int J Dig Dis, 2008, 28(2): 120-122. DOI: 10.3969/j.issn.1673-534X.2008.02.011. 谭莉莉, 白文元. PI3K/AKt信号通路与肝细胞癌[J]. 国际消化病杂志, 2008, 28(2): 120-122. DOI: 10.3969/j.issn.1673-534X.2008.02.011.
[20]	WANG N, CHEN S, ZHANG B, et al. 8u, a pro-apoptosis/cell cycle arrest compound, suppresses invasion and metastasis through HSP90α downregulating and PI3K/Akt inactivation in hepatocellular carcinoma cells[J]. Sci Rep, 2018, 8(1): 309. DOI: 10.1038/s41598-017-18701-3.
[21]	CHUNG TW, LEE YC, KIM CH. Hepatitis B viral HBx induces matrix metalloproteinase-9 gene expression through activation of ERK and PI-3K/AKT pathways: Involvement of invasive potential[J]. FASEB J, 2004, 18(10): 1123-1125. DOI: 10.1096/fj.03-1429fje.
[22]	SIDERA K, GAITANOU M, STELLAS D, et al. A critical role for HSP90 in cancer cell invasion involves interaction with the extracellular domain of HER-2[J]. J Biol Chem, 2008, 283(4): 2031-2041. DOI: 10.1074/jbc.M701803200.
[23]	LI H, LI WH, ZHANG ZX, et al. Expression of heat shock protein 90α in HBV-related hepatocellular carcinoma[J]. Academic J Guangzhou Med Univ, 2014, 42(6): 21-24. DOI: 10.3969/j.issn.1008-1836.2014.06.008. 李慧, 李卫华, 张志翔, 等. 热休克蛋白90α在HBV相关性肝细胞癌中表达的意义[J]. 广州医科大学学报, 2014, 42(6): 21-24. DOI: 10.3969/j.issn.1008-1836.2014.06.008.
[24]	LUO XH, GUI PG, DU YH. Evaluation of prognostic value of HSP90α combined with tumor marker level in prognosis evaluation of patients with hepatocellular carcinoma[J]. Pract J Cancer, 2019, 34(9): 1405-1408. DOI: 10.3969/j.issn.1001-5930.2019.09.004. 罗小怀, 桂普国, 杜一鸿. HSP90α联合肿瘤标志物水平检测对肝癌患者预后的评估价值[J]. 实用癌症杂志, 2019, 34(9): 1405-1408. DOI: 10.3969/j.issn.1001-5930.2019.09.004.
[25]	ZHANG B, CHEN RH, YANG W, et al. Application of serum HSP90α and PIVKA-Ⅱ levels in prognosis of patients with hepatocellular carcinoma[J]. J Clin Hepatol, 2021, 24(4): 548-551. DOI: 10.3969/j.issn.1672-5069.2021.04.024. 张兵, 陈瑞红, 杨威, 等. 肝细胞癌患者血清HSP90α和PIVKA-Ⅱ水平变化及其临床意义探讨[J]. 实用肝脏病杂志, 2021, 24(4): 548-551. DOI: 10.3969/j.issn.1672-5069.2021.04.024.