International Journal of Clinical Research
International Journal of Clinical Research. 2022; 6: (6) ; 10.12208/j.ijcr.20220255 .
总浏览量: 587
潍坊市中医院肿瘤外科 山东潍坊
潍坊医学院 山东潍坊
潍坊市人民医院肿瘤内科 山东潍坊
*通讯作者： 于渊,单位：潍坊市人民医院肿瘤内科 山东潍坊；
目的 探讨血清基质金属蛋白酶11（MMP-11）在诊断小细胞肺癌（SCLC）及评估预后中的应用价值。方法 收集110例SCLC患者和60例健康人的血清，采用酶联免疫吸附法（ELISA）检测两组间MMP-11的差异，并分析血清MMP-11与小细胞肺癌临床病理特征、化疗疗效及总生存时间（OS）的相关性。结果 治疗前SCLC患者血清MMP-11水平（28.2±13.8 ng/ml）明显高于健康对照组（12.1±5.5ng/ml；p < 0.001），ROC曲线分析显示：曲线下面积（AUC）为0.849，95% CI（0.7930-0.9050），p<0.01。当截断值为18.35 ng/ml时，血清MMP-11诊断SCLC的敏感性、特异性、阳性预测值（PPV）和阴性预测值（NPV）分别为73.6%、83.3%、81.9%和76.0%。Kaplan-Meier（K-M）生存分析显示：小细胞肺癌化疗后血清MMP-11较高者（≥25ng/mL）的OS劣于较低者（<25ng/mL）的OS（中位OS：15.0 vs 23.3个月，P =0.024）。多因素Cox回归分析显示，化疗后血清MMP-11水平是OS的独立影响因素。（风险比[HR] = 1.617 [95% CI，1.126-2.648]，P =0.026）。结论 血清MMP-11有望成为SCLC诊断及评估预后的一种新的血清肿瘤标志物。
Objective To explore the value of serum matrix metalloproteinase-11 (MMP-11) in the diagnosis and prognosis of small cell lung cancer (SCLC). Methods The serum of 110 patients with SCLC and 60 healthy people were collected. The difference of MMP-11 between the two groups was detected by enzyme-linked immunosorbent assay (ELISA), and the correlation between serum MMP-11 and clinicopathological features, chemotherapy efficacy, overall survival time (OS) of small cell lung cancer was analyzed. Results The level of serum MMP-11 in SCLC patients before treatment (28.2 ± 13.8 ng/ml) was significantly higher than that in healthy control group (12.1 ± 5.5 ng/ml; P < 0.001). ROC curve analysis showed that the area under the curve (AUC) was 0.849, 95% CI (0.7930-0.9050), P < 0.01. When the cutoff value was 18.35 ng/ml, the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of serum MMP-11 in the diagnosis of SCLC were 73.6%, 83.3%, 81.9% and 76.0%, respectively. Kaplan Meier (K-M) survival analysis demonstrated that the OS of patients with high serum MMP-11 (≥ 25ng/ml) was worse than that of patients with low serum MMP-11 (< 25ng/ml) (median OS: 15.0 vs 23.3 months, P=0.024). Multivariate Cox regression analysis indicated that the level of serum MMP-11 after chemotherapy was an independent influencing factor of OS. (hazard ratio [HR] = 1.617 [95% CI, 1.126-2.648], P = 0.026). Conclusion Serum MMP-11 could become a new serum tumor marker for the diagnosis and prognosis of SCLC in prospect.
[1] Siegel RL, Miller KD, Fuchs HE, Jemal A (2021) Cancer Statistics, 2021. CA Cancer J Clin 71 (1):7-33. doi:10.3322/caac.21654
[2] Harmsma M, Schutte B, Ramaekers FC (2013) Serum markers in small cell lung cancer: opportunities for improvement. Biochim Biophys Acta 1836 (2):255-272. doi:10.1016/j.bbcan.2013.06.002
[3] Itoh Y, Nagase H (2002) Matrix metalloproteinases in cancer. Essays Biochem 38:21-36. doi:10.1042/bse0380021
[4] Gialeli C, Theocharis AD, Karamanos NK (2011) Roles of matrix metalloproteinases in cancer progression and their pharmacological targeting. FEBS J 278 (1):16-27. doi:10.1111/j.1742-4658.2010.07919.x
[5] Chen P, Cescon M, Bonaldo P (2013) Collagen VI in cancer and its biological mechanisms. Trends Mol Med 19 (7):410-417.doi:10.1016/j.molmed.2013.04.001
[6] Zhang X, Huang S, Guo J, Zhou L, You L, Zhang T, Zhao Y (2016) Insights into the distinct roles of MMP-11 in tumor biology and future therapeutics (Review). Int J Oncol 48 (5):1783-1793. doi:10.3892/ijo.2016.3400
[7] Greco M, Arcidiacono B, Chiefari E, Vitagliano T, Ciriaco AG, Brunetti FS, Cuda G, Brunetti A (2018) HMGA1 and MMP-11 Are Overexpressed in Human Non-melanoma Skin Cancer. Anticancer Res 38 (2):771-778. doi:10.21873/anticanres.12283
[8] Kettunen E, Anttila S, Seppanen JK, Karjalainen A, Edgren H, Lindstrom I, Salovaara R, Nissen AM, Salo J, Mattson K, Hollmen J, Knuutila S, Wikman H (2004) Differentially expressed genes in nonsmall cell lung cancer: expression profiling of cancer-related genes in squamous cell lung cancer. Cancer Genet Cytogenet 149 (2):98-106. doi:10.1016/S0165-4608(03)00300-5
[9] von Marschall Z, Riecken EO, Rosewicz S (1998) Stromelysin 3 is overexpressed in human pancreatic carcinoma and regulated by retinoic acid in pancreatic carcinoma cell lines. Gut 43 (5):692-698. doi:10.1136/gut.43.5.692
[10] Cheng CW, Yu JC, Wang HW, Huang CS, Shieh JC, Fu YP, Chang CW, Wu PE, Shen CY (2010) The clinical implications of MMP-11 and CK-20 expression in human breast cancer. Clin Chim Acta 411 (3-4):234-241. doi:10.1016/j.cca.2009.11.009
[11] Fu J, Khaybullin R, Zhang Y, Xia A, Qi X (2015) Gene expression profiling leads to discovery of correlation of matrix metalloproteinase 11 and heparanase 2 in breast cancer progression. BMC Cancer 15:473. doi:10.1186/s12885-015-1410-y
[12] Mueller J, Brebeck B, Schmalfeldt B, Kuhn W, Graeff H, Hofler H (2000) Stromelysin-3 expression in invasive ovarian carcinomas and tumours of low malignant potential. Virchows Arch 437 (6):618-624. doi:10.1007/s004280000261
[13] Nonsrijun N, Mitchai J, Brown K, Leksomboon R, Tuamsuk P (2013) Overexpression of matrix metalloproteinase 11 in Thai prostatic adenocarcinoma is associated with poor survival. Asian Pac J Cancer Prev 14 (5):3331-3335. doi:10.7314/apjcp.2013.14.5.3331
[14] Soni S, Mathur M, Shukla NK, Deo SV, Ralhan R (2003) Stromelysin-3 expression is an early event in human oral tumorigenesis. Int J Cancer 107 (2):309-316. doi:10.1002/ijc.11366
[15] Arora S, Kaur J, Sharma C, Mathur M, Bahadur S, Shukla NK, Deo SV, Ralhan R (2005) Stromelysin 3, Ets-1, and vascular endothelial growth factor expression in oral precancerous and cancerous lesions: correlation with microvessel density, progression, and prognosis. Clin Cancer Res 11 (6):2272-2284. doi:10.1158/1078-0432.CCR-04-0572
[16] Zhao ZS, Chu YQ, Ye ZY, Wang YY, Tao HQ (2010) Overexpression of matrix metalloproteinase 11 in human gastric carcinoma and its clinicopathologic significance. Hum Pathol 41 (5):686-696. doi:10.1016/j.humpath.2009.10.010
[17] Wlodarczyk J, Stolte M, Mueller J (2001) E-cadherin, beta-catenin and stromelysin-3 expression in de novo carcinoma of the colorectum. Pol J Pathol 52 (3):119-124
[18] Xu CJ, Xu F (2014) MMP-11 and VEGF-C expression correlate with clinical features of colorectal adenocarcinoma. Int J Clin Exp Med 7 (9):2883-2888
[19] Denys H, De Wever O, Nusgens B, Kong Y, Sciot R, Le AT, Van Dam K, Jadidizadeh A, Tejpar S, Mareel M, Alman B, Cassiman JJ (2004) Invasion and MMP expression profile in desmoid tumours. Br J Cancer 90 (7):1443-1449. doi:10.1038/sj.bjc.6601661
[20] Perret AG, Duthel R, Fotso MJ, Brunon J, Mosnier JF (2002) Stromelysin-3 is expressed by aggressive meningiomas. Cancer 94 (3):765-772. doi:10.1002/cncr.10270
[21] Hourihan RN, O'Sullivan GC, Morgan JG (2003) Transcriptional gene expression profiles of oesophageal adenocarcinoma and normal oesophageal tissues. Anticancer Res 23 (1A):161-165
[22] P OC, Rhys-Evans PH, Eccles SA (2001) Expression of matrix metalloproteinases and their inhibitors correlates with invasion and metastasis in squamous cell carcinoma of the head and neck. Arch Otolaryngol Head Neck Surg 127 (7):813-820
[23] Kren L, Goncharuk VN, Krenova Z, Stratil D, Hermanova M, Skrickova J, Sheehan CE, Ross JS (2006) Expression of matrix metalloproteinases 3, 10 and 11 (stromelysins 1, 2 and 3) and matrix metalloproteinase 7 (matrilysin) by cancer cells in non-small cell lung neoplasms. Clinicopathologic studies. Cesk Patol 42 (1):16-19
[24] Ahmad A, Hanby A, Dublin E, Poulsom R, Smith P, Barnes D, Rubens R, Anglard P, Hart I (1998) Stromelysin 3: an independent prognostic factor for relapse-free survival in node-positive breast cancer and demonstration of novel breast carcinoma cell expression. Am J Pathol 152 (3):721-728
[25] Yan D, Dai H, Liu JW (2011) Serum levels of MMP-11 correlate with clinical outcome in Chinese patients with advanced gastric adenocarcinoma. BMC Cancer 11:151. doi:10.1186/1471-2407-11-151
[26] Hsin CH, Chen MK, Tang CH, Lin HP, Chou MY, Lin CW, Yang SF (2014) High level of plasma matrix metalloproteinase-11 is associated with clinicopathological characteristics in patients with oral squamous cell carcinoma. PLoS One 9 (11):e113129. doi:10.1371/journal.pone.0113129
[27] Pang L, Wang DW, Zhang N, Xu DH, Meng XW (2016) Elevated serum levels of MMP-11 correlate with poor prognosis in colon cancer patients. Cancer Biomark 16 (4):599-607. doi:10.3233/CBM-160601
[28] Drac P, Klein J, Tichy T, Kolek V, Skarda J (2007) [Prognostic impact of matrix metalloproteinases 2,9, and 11 in stromal cells stage I non-small cell lung cancer]. Cas Lek Cesk 146 (1):45-47
[29] Michael M, Babic B, Khokha R, Tsao M, Ho J, Pintilie M, Leco K, Chamberlain D, Shepherd FA (1999) Expression and prognostic significance of metalloproteinases and their tissue inhibitors in patients with small-cell lung cancer. J Clin Oncol 17 (6):1802-1808. doi:10.1200/JCO.1999.17.6.1802
[30] Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45 (2):228-247. doi:10.1016/j.ejca.2008.10.026
[31] Ren H, Shen Z, Shen J, Zhang Y, Zhang Y (2020) Diagnostic value of Doppler ultrasound parameters combined with MMP-11 in early breast cancer and benign breast diseases. Oncol Lett 20 (2):1028-1032. doi:10.3892/ol.2020.11676
[32] Zhang X, Lu J, Zhou L, You L, Liang Z, Guo J, Zhao Y (2020) Matrix Metalloproteinase 11 as a Novel Tumor Promoter and Diagnostic and Prognostic Biomarker for Pancreatic Ductal Adenocarcinoma. Pancreas 49 (6):812-821. doi:10.1097/MPA.0000000000001583
[33] Huang X, Lan Y, Li E, Li J, Deng Q, Deng X (2021) Diagnostic values of MMP-7, MMP-9, MMP-11, TIMP-1, TIMP-2, CEA, and CA19-9 in patients with colorectal cancer. J Int Med Res 49 (5):3000605211012570. doi:10.1177/03000605211012570
[34] Yang YH, Deng H, Li WM, Zhang QY, Hu XT, Xiao B, Zhu HH, Geng PL, Lu YY (2008) Identification of matrix metalloproteinase 11 as a predictive tumor marker in serum based on gene expression profiling. Clin Cancer Res 14 (1):74-81. doi:10.1158/1078-0432.CCR-07-1179
[35] Gerstein ES, Sini L, Ryabov AB, Dvorova EK, Yurchenko AA, Stilidi IS, Kushlinskii NE, Davydov MI (2009) Comparative enzyme immunoassay of matrix metalloproteinases-2, -7, -9 and their tissue inhibitor-2 in tumors and plasma of patients with gastric cancer. Bull Exp Biol Med 148 (6):899-902. doi:10.1007/s10517-010-0847-x