激肽释放酶相关肽酶13作为口腔鳞状细胞癌同步放化疗预后标志物的临床研究-东南大学学报医学版

激肽释放酶相关肽酶13作为口腔鳞状细胞癌同步放化疗预后标志物的临床研究

单位：1. 聊城市第四人民医院口腔科, 山东聊城 252000;
2. 聊城市肿瘤医院肿瘤内科, 山东聊城 252000

分类号：R739.85

出版年·卷·期（页码）：2023·42·第一期（49-56）

摘要：

目的：评估口腔鳞状细胞癌（OSCC）患者血浆和组织中激肽释放酶相关肽酶13（KLK13）表达，及其与临床病理因素、同步放化疗反应和总生存期的相关性。方法：收集2016年1月至2019年4月聊城市第四人民医院96例OSCC活检组织样本和32例健康对照组志愿者的正常组织样本，用福尔马林固定后进行免疫组化和实时荧光定量PCR法检测KLK13蛋白和mRNA表达。采用酶联免疫吸附测定法对84例OSCC患者同步放化疗前后血浆样本和对照组血浆KLK13水平进行测定。对患者至少完成2年同步放化疗反应的随访。结果：OSCC肿瘤组织KLK13蛋白阳性率低于对照组正常组织（67.71%vs.93.75%，P=0.004）。OSCC患者同步放化疗前血浆KLK13水平[（1 307.91±566.71） pg·ml^-1 vs.（1 869.16±377.36） pg·ml^-1，P<0.001）]和组织KLK13 mRNA相对表达量[0.126±0.062 vs.1.00±0.082，P<0.001]均低于对照组。而且OSCC患者同步放化疗后血浆KLK13水平较治疗前有所升高[（1 533.83±725.04） pg·ml^-1 vs.（1 307.91±566.71） pg·ml^-1，P=0.026]。OSCC中KLK13蛋白表达阳性的患者对同步放化疗有更好的临床应答率（P<0.001），且2年总生存率更高（P<0.001）。Cox比例风险模型分析表明，同步放化疗反应（P=0.005）和组织KLK13蛋白表达（P=0.035）对总生存期的影响是独立的。结论：KLK13可能是OSCC患者预测同步放化疗反应性和预后的候选生物标志物。

Objective: To evaluate the expression of kallikrein-related peptidase 13(KLK13) in plasma and tissues of patients with oral squamous cell carcinoma(OSCC) and its correlation with clinicopathological factors, concurrent chemoradiotherapy and overall survival. Methods: From January 2016 to April 2019, biopsy tissue samples of 96 OSCC cases and normal tissue samples of 32 healthy volunteers were collected from Liaocheng Fourth Peoples Hospita. After formalin fixation, KLK13 protein and mRNA expression were detected by immunohistochemistry and real-time fluorescent quantitative PCR. The levels of KLK13 in plasma samples from 84 patients with OSCC before and after concurrent chemoradiotherapy and plasma samples in the control group were measured by enzyme-linked immunosorbent assay. The patients were followed up for at least 2 years. Results: The positive rate of KLK13 protein in tumor tissue of the OSCC group was lower than that in the normal tissue of control group(67.71% vs. 93.75%, P=0.004). The plasma KLK13 level[(1 307.91±566.71) pg·ml^-1 vs.(1 869.16±377.36) pg·ml^-1, P<0.001] and the relative expression of tissue KLK13 mRNA(0.126±0.062 vs. 1.00±0.082, P<0.001) in the OSCC patients before concurrent chemoradiotherapy were lower than those in the control group. Moreover, the plasma KLK13 level of the OSCC patients after concurrent chemoradiotherapy was higher than that before treatment[(1 533.83±725.04) pg·ml^-1 vs.(1 307.91±566.71) pg·ml^-1, P=0.026]. Patients with positive expression of KLK13 protein in OSCC had better clinical response rate to concurrent chemoradiotherapy(P<0.001), and the 2-year overall survival rate was higher(P<0.001). Cox proportional hazard model analysis showed that the effects of concurrent chemoradiotherapy(P=0.005) and tissue KLK13 protein expression(P=0.035) on overall survival were independent. Conclusion: KLK13 may be a candidate biomarker for predicting the response and prognosis of concurrent chemoradiotherapy in OSCC patients.

参考文献：

[1] PANARESE I, AQUINO G, RONCHI A, et al.Oral and oropharyngeal squamous cell carcinoma:prognostic and predictive parameters in the etiopathogenetic route[J].Expert Rev Anticancer Ther, 2019, 19(2):105-119.
[2] SOLOMON B, YOUNG R J, RISCHIN D.Head and neck squamous cell carcinoma:genomics and emerging biomarkers for immunomodulatory cancer treatments[J].Semin Cancer Biol, 2018, 52(Pt 2):228-240.
[3] KITAMURA N, SENTO S, YOSHIZAWA Y, et al.Current trends and future prospects of molecular targeted therapy in head and neck squamous cell carcinoma[J].Int J Mol Sci, 2020, 22(1):240.
[4] 霍玉荣, 康鹏, 宋伟霞.口腔鳞状细胞癌患者生存及复发的临床影响因素分析[J].实用癌症杂志, 2021, 36(7):1175-1177.
[5] KONTOS C K, SCORILAS A.Kallikrein-related peptidases(KLKs):a gene family of novel cancer biomarkers[J].Clin Chem Lab Med, 2012, 50(11):1877-1891.
[6] GRUBA N, BIELECKA E, WYSOCKA M, et al.Development of chemical tools to monitor human kallikrein 13(KLK13) activity[J].Int J Mol Sci, 2019, 20(7):1557.
[7] SHAW J L, DIAMANDIS E P.Distribution of 15 human kallikreins in tissues and biological fluids[J].Clin Chem, 2007, 53(8):1423-1432.
[8] LENGA-MA-BONDA W, IOCHMANN S, MAGNEN M, et al.Kallikrein-related peptidases in lung diseases[J].Biol Chem, 2018, 399(9):959-971.
[9] TOKAS T, AVGERIS M, ALAMANIS C, et al.Downregulated KLK13 expression in bladder cancer highlights tumor aggressiveness and unfavorable patients' prognosis[J].J Cancer Res Clin Oncol, 2017, 143(3):521-532.
[10] DETTMAR L, AHMED N, KOTZSCH M, et al.Advanced high-grade serous ovarian cancer:inverse association of KLK13 and KLK14 mRNA levels in tumor tissue and patients' prognosis[J].J Cancer Res Clin Oncol, 2018, 144(6):1109-1118.
[11] ISHIGE S, KASAMATSU A, OGOSHI K, et al.Decreased expression of kallikrein-related peptidase 13:possible contribution to metastasis of human oral cancer[J].Mol Carcinog, 2014, 53(7):557-565.
[12] LIN Q, MAO W, WU Q, et al.Downregulation of KLK13 promotes the invasiveness and metastasis of oesophageal squamous cell carcinoma[J].Biomed Pharmacother, 2017, 96:1008-1015.
[13] HUANG S H, O'SULLIVAN B.Overview of the 8th Edition TNM Classification for Head and Neck Cancer[J].Curr Treat Options Oncol, 2017, 18(7):40.
[14] SCHWARTZ L H, LITIèRE S, DE VRIES E, et al.RECIST 1.1-update and clarification:from the RECIST committee[J].Eur J Cancer, 2016, 62:132-137.
[15] MAEDA O, ANDO T, OHMIYA N, et al.Alteration of gene expression and DNA methylation in drug-resistant gastric cancer[J].Oncol Rep, 2014, 31(4):1883-1890.
[16] CHOU R H, LIN S C, WEN H C, et al.Epigenetic activation of human kallikrein 13 enhances malignancy of lung adenocarcinoma by promoting N-cadherin expression and laminin degradation[J].Biochem Biophys Res Commun, 2011, 409(3):442-447.
[17] KAPADIA C, GHOSH M C, GRASS L, et al.Human kallikrein 13 involvement in extracellular matrix degradation[J].Biochem Biophys Res Commun, 2004, 323(3):1084-1090.
[18] JIANG Y, ZHANG H, WANG J, et al.Targeting extracellular matrix stiffness and mechanotransducers to improve cancer therapy[J].J Hematol Oncol, 2022, 15(1):34.
[19] EKE I, CORDES N.Focal adhesion signaling and therapy resistance in cancer[J].Semin Cancer Biol, 2015, 31:65-75.
[20] 张海山, 赵军, 李丽媚, 等.单中心20年4068例口腔鳞状细胞癌发病状况的回顾性研究[J].广西医科大学学报, 2022, 39(3):484-487.
[21] 徐建华, 王玲, 刘怀勤, 等.新辅助化疗对晚期口腔癌患者术后预后的影响及相关影响因素分析[J].现代医生, 2017, 45(4):486-490.

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