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Chinese Journal of Lung Cancer logoLink to Chinese Journal of Lung Cancer
. 2013 Aug 20;16(8):411–416. [Article in Chinese] doi: 10.3779/j.issn.1009-3419.2013.08.04

检测肺癌患者血清Cathepsin X及Cystatin C的临床意义

Clinical Signifcance of Detection of Cathepsin X and Cystatin C in the Sera of Patients with Lung Cancer

Xuede ZHANG 1, Yanli HOU 1, Zequn NIU 1, Wei LI 1, Xia MENG 1, Na ZHANG 1, Shuanying YANG 1,*
PMCID: PMC6000661  PMID: 23945244

Abstract

Background and objective

Cathepsin X (Cat X) has been identifed as a member of cathepsin family. Studies have shown that Cat X is involved in tumorigenesis and tumor development of various cancers. The aim of this study is to investigate the relationship between the clinicopathological prognosis and the levels of Cat X and cystatin C in the serum of patients with lung cancer.

Methods

Blood samples were collected from 84 patients with lung cancer and 36 healthy control subjects. Cat X and cystatin C were determined by quantitative ELISA.

Results

Cat X and cystatin C levels were signifcantly higher in the patients with lung cancer than that in the healthy control subjects (P < 0.01). Cat X level was correlated with the pathological types of lung cancer (P=0.076). Cystatin C was positively correlated with TNM stage (P=0.01). Furthermore, cystatin C/Cat X was correlated with lymph node metastasis (P=0.058). The patients with high Cat X levels experienced signifcantly shorter overall survival rates compared with those with low Cat X. Univariate analysis indicated that Cat X and TNM stage were related to overall survival. Multivariate Cox analysis indicated that TNM stage may be used as an independent prognostic variable in patients with lung cancer.

Conclusion

Cat X and cystatin C levels were signifcantly higher in patients with lung cancer. Cat X and cystatin C detection in the sera may contribute to the diagnosis of lung cancer and may be used to evaluate the prognosis of patients with NSCLC.

Keywords: Cathepsin X, Cystatin C, Lung neoplasms, Sera

组织蛋白酶(Cathepsins, Cats)属于溶酶体半胱氨酸蛋白酶，最初发现涉及到溶酶体内蛋白转换，近年来研究[1, 2]表明，还参与肿瘤的发生、发展、转移，有希望成为新的肿瘤诊断和预后判断标记物。Cat B、Cat L等在肺癌、乳腺癌、头颈癌及结肠癌等肿瘤中表达明显增高，且高表达的患者预后更差，对预测肿瘤的复发和预后有潜在价值[3]。Cat X是最近发现的一种Cats家族成员，它的结构和功能特点明显不同于其它Cats，有一个区别于其它Cats的非常短的原区(pro-region)和一个独特的迷你环(mini-loop)，Cat X不像其它Cats作为肽链内切酶发挥生物学作用，而靠水解羧基端氨基酸起作用。Cat X表达主要局限于各类免疫细胞中，如单核、巨噬细胞及树突状细胞[4]。它涉及到细胞间信号传导、细胞粘附、增生以及迁移等作用[5-7]。研究表明Cat X表达上调与幽门螺旋杆菌感染[8]、多发创伤[9]、肺结核[10]有关，也有报道发现Cat X在前列腺癌[11]、胃癌[8]、恶性黑色素瘤[12]中表达明显增高。此外，已经在多种肿瘤中发现染色体20q13中编码Cat X基因明显扩增[13, 14]。

Cystatin C是半胱氨酸蛋白酶抑制剂蛋白质中的一种，在所有的有核细胞内以恒定速度持续转录与表达，无组织特异性，并存在于各种体液之中，不受年龄、性别、体重、炎症等因素影响，是一种反映肾小球滤过情况的重要指标。目前研究[15]表明，它作为Cats抑制剂与Cats互相作用参与肿瘤发生、发展。近期研究发现血液、体液中cystatin C高表达的患者预后差，有希望作为预测肿瘤预后标记物。

目前为止，我们尚未发现肺癌患者血清Cat X的研究，cystatin C在肺癌患者血清研究的报道也少见，cystatin C作为Cats强有力的抑制剂，它与Cat X血清表达水平之间可能存在相关性。目前已有cystatin C与Cat B、Cat L的相关性研究，但是尚无cystatin C与Cat X之间的研究。本研究旨在检测肺癌患者和健康人血清Cat X与cystatin C表达水平以及二者相关性和与肺癌临床病理、预后关系。

1. 材料与方法

1.1. 研究对象

选择2007年3月-9月西安交大二附院84例肺癌患者，其中男性50例，女性34例，年龄41岁-78岁，中位年龄61.5岁；鳞癌30例，腺癌40例，小细胞肺癌(small cell lung cancer, SCLC) 14例。临床分期(TNM分期)，Ⅰ期+Ⅱ期28例，Ⅲ期+Ⅳ期56例。所有患者均经过组织学或病理学检查确诊为肺癌，采血前均未行手术、放化疗以及中成药等其它抗肿瘤治疗。另外，选取健康查体者36例作为对照组，男性20例，女性16例；年龄40岁-79岁，中位年龄60.4岁。本研究得到西安交大二附院伦理委员会许可，患者均签署知情同意书。

1.2. 标本采集

所有肺癌患者和健康体检者分别抽取晨间空腹静脉血3 mL，抽取后1 h内，4 ℃，3, 000 g离心10 min，分离的血清-80 ℃冻存待检。

1.3. 检测方法

Cat X及cystatin C水平均采用酶联免疫吸附法测定。严格按照ELISA检测试剂盒(上海郎卡公司)的说明书操作，标准品孔各加不同浓度的标准品50 μL；然后样本孔先加待测样本10 μL，再加样本稀释液40 μL；后分别加入辣根过氧化物酶(HRP)标记的检测抗体100 μL，封板膜封孔，37 ℃恒温箱温育60 min。手工洗板法清洗，每孔加入底物A、B各50 μL，37 ℃避光孵育15 min，后每孔加入终止液50 μL，15 min内，在450 nm波长处测定各孔的OD值。实验重复3次。

1.4. 随访

84例患者术后均进行了随访，总生存期OS定义为首次确诊至患者死亡时间或末次随访时间。死于非肺癌相关原因的患者排除在本研究外。随访最长时间为60个月。

1.5. 统计学处理

数据采用SPSS 16.0软件进行统计分析。每组数据均采用Mean±SD表示。组间差异采取Mann-Whitney和Kruskal-Wallis检验。Pearson's相关系数评价Cat X和cystatin C之间的相关性。Kaplan-Meier法(组间生存率比较采用Log-rank检验)及Cox单因素以及多因素风险回归模型进行生存分析。双侧P < 0.05为差异有统计学意义。

2. 结果

2.1. 肺癌患者和健康人Cat X和cystatin C表达水平比较

肺癌患者及健康人血清Cat X水平分别为(2.24±0.07) ng/mL、(1.85±0.09) ng/mL；cystatin C分别为(529.77 ±6.15) ng/mL、(476.76±13.95) ng/mL。肺癌患者血清Cat X和cystatin C水平明显高于健康人(P < 0.01)。此外，肺癌患者cystatin C/Cat X比值与健康人相比，差异无统计学意义(P=0.372)。Pearson相关分析显示，肺癌患者血清Cat X与cystatin C水平无明显相关性(r=-0.049, P=0.66)。

2.2. 肺癌患者Cat X和cystatin C表达水平与临床病理特征的关系

Cat X和cystatin C/Cat X与肺癌患者性别、年龄、病理类型、淋巴结转移、细胞分化及TNM分期无明显相关，但Cat X与病理类型有相关趋势(P=0.076)，cystatin C/Cat X与淋巴结转移有相关趋势(P=0.058)。cystatin C水平与肺癌分期相关，Ⅲ期+Ⅳ期肺癌患者cystatin C水平明显高于Ⅰ期+Ⅱ期(P=0.01)，与其它临床病理特征无关(表 1)。

1.

肺癌患者血清Cat X和cystatin C表达水平与临床病理特征的关系

Relationship of Cat X and cystatin C in the sera of patients with lung cancer on the clinicopathological parameters

Characteristic n Cat X Cystatin C Cystatin C/Cat X
Mean±SD P Mean±SD P Mean±SD P
Cat X: Cathepsin X; Cats, Cathepsins; SCC: squamous cell carcinoma; ADC: adenocarcinoma; SCLC: small cell lung cancer.
Gender Male 50 2.34±0.941 0.222 531.73±8.33 0.483 245.30±10.80 0.196
Female 34 2.08±0.108 526.88±9.10 276.33±14.75
Age (yr) ≥61.5 42 2.13±0.099 0.137 526.61±10.02 0.308 267.77±12.78 0.137
< 61.6 42 2.34±0.103 532.92 ±7.22 247.95±12.29
Pathological type SCC 30 2.34± 0.125 0.076 537.14±9.53 0.575 251.45±15.42 0.076
ADC 40 2.05 ±0.774 527.99±9.47 273.21±11.97
SCLC 14 2.56 ±0.233 519.05±15.03 227.69±22.92
Lymph node metastasis Yes 50 2.16±0.902 0.279 537.37±8.33 0.126 269.33±10.83 0.058
No 34 2.38±0.117 516.09±8.03 237.21±14.94
Grade G1+G2 42 2.23±0.10 0.694 536.54±8.80 0.376 259.65±12.16 0.741
G3 42 2.24±0.105 523.00±8.46 256.08±13.08
Stage Ⅰ+Ⅱ 28 2.22±0.148 0.232 507.99±8.94 0.01 258.23±17.72 0.992
Ⅲ+Ⅳ 56 2.25± 0.08 540.66±7.71 257.68±10.07
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2.3. 肺癌患者Cat X和cystatin C水平与预后的关系

2.3.1. Kaplan-Meier生存分析

将患者性别、淋巴结状态、分化程度、分期分组，以及根据年龄、Cat X、cystatin C、cystatin C/Cat X的中位数以二分法的方式分 < 中位数组以及≥中位数组，进行Kaplan-Meier生存分析，生存差异的统计学意义用Log-rank法判定。结果示低Cat X和高Cat X患者中位OS分别为22.9个月和15.8个月，差异有统计学意义(P=0.019, RR=1.678)，低Cat X患者和高Cat X患者相比OS更长(图 1)。Ⅰ期+Ⅱ期和Ⅲ期+Ⅳ期肺癌患者中位OS分别为23.8个月和15.4个月，差异有统计学意义(P=0.011, RR=1.827)，晚期肺癌患者预后更差(图 2)。高、低cystatin C/Cat X值患者中位OS分别为23.5个月和18.5个月，差异无统计学意义，但有一定的差异趋势(P=0.069)。性别、年龄、淋巴结状态、分化程度以及cystatin C对肺癌患者OS无明显影响(表 2)。

1.

1

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血清Cat X高表达组和低表达组肺癌患者Kaplan-Meier生存曲线

Kaplan-Meier survival curves of lung cancer patients with low or high levels of Cat X in sera

2.

2

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TNM Ⅰ+Ⅱ组和Ⅲ+Ⅳ组肺癌患者生存曲线

Kaplan-Meier survival curves of lung cancer patients with TNM stage Ⅰ+Ⅱ or stage Ⅲ+Ⅳ

2.

单因素和多因素分析肺癌Cat X、cystatin C及其它因素与预后的情况

Univariate and multivariate analysis of Cat X, cystatin C, and other potential factors for prognosis in patients with lung cancer

Characteristic n Overall survival (month) Univariate analysis Multivariate analysis
P RR P RR
Cat X < 2.30 44 22.9 0.019 1.678 0.768 1.131
≥2.30 30 15.8
Cystatin C < 523.18 45 22.6 0.105 1.436 0.152 0.89
≥523.18 39 17.3
Cystatin C/Cat X < 233.00 42 18.5 0.069 0.665 0.582 0.783
≥233.00 42 23.5
Gender Male 50 17.3 0.103 0.688 0.358 0.789
Female 34 22.3
Age (yr) < 61.5 42 21.1 0.177 1.357 0.376 1.26
≥61.5 42 17.9
Pathological type SCC 30 17.6 0.638 1.078 0.193 1.25
ADC 40 20.5
SCLC 14 17.9
Lymph node metastasis Yes 54 18.2 0.409 0.827 0.994 1.002
No 30 20.3
Grade G1+G2 42 20.6 0.345 1.232 0.072 1.634
G3 42 16.8
Stage Ⅰ+Ⅱ 28 23.8 0.011 1.827 0.009 2.25
Ⅲ+Ⅳ 56 15.4
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2.3.2. Cox比例风险回归模型分析

采取单因素及多因素Cox回归法分析影响肺癌患者预后的独立危险因素。利用Cox单因素回归分析发现Cat x高表达以及tnm分期是影响肺癌预后独立因素，继续将各个变量引入Cox多因素回归模型，结果显示，仅有TNM分期是患者预后的独立危险因素(表 2)。

3. 讨论

肺癌是目前发病率高的恶性肿瘤之一，大部分发现时已经是中晚期，失去了手术机会，患者生存期短，5年生存率约15%[16]。因此肺癌的早诊断、早治疗至关重要。血清肿瘤标记物具有取材方便、方法易行等独特优势，在肺癌早期诊断、预后判断中有重要价值，因此人们一直在寻找有价值的血清肿瘤标记物。

Cat X是近年来发现一种新的Cats，通常以酶原形式存在于免疫细胞的溶酶体内，受到激活后，转化为有活性的酶释放到血液和细胞外基质中[17]。Cat X在恶性肿瘤患者血清和细胞外基质中也有表达，Vizin等[18]研究了Cat X在结肠癌、腺瘤、其它结肠良性病变以及健康者血清中的表达情况，虽未发现Cat X在4组中表达有差异，但Cat X水平高的结肠癌患者OS更短。Decock等[19]比较了早期乳癌和炎性乳癌中血清Cat X水平，发现炎性乳癌患者中血清Cat X中水平低，有可能为炎性乳癌的诊断提供一定的参考价值。本研究检测了肺癌患者和健康人血清Cat X水平，结果提示肺癌患者Cat X水平明显高于健康人，提示Cat X可能与肺癌发生有关，有希望作为肺癌的肿瘤标记物。

Cystatin C是Cats抑制剂，可能会减轻Cats在肿瘤侵袭、转移过程中作用[20]。Nishikawa等[21]用ELISA法检测良、恶性卵巢瘤患者和健康人的血清cystatin C，发现卵巢癌患者血清cystatin C水平明显高于良性肿瘤及健康人。Saleh等[22]也发现在结直肠癌组织中cystatin C高表达，特别是在腺癌中达到100%。然而也有研究[23]表明在肺鳞癌和正常肺组织中表达无明显差异。Wegiel等[24]则发现前列腺癌中cystatin C表达减低。我们检测了肺癌患者和健康人血清cystatin C水平，结果示肺癌患者血清cystatin C水平明显高于健康人。究其原因可能是肺癌患者中Cats升高，cystatin C为了抑制其活性也随之升高，但是仍然无法有效抑制蛋白水解酶的活性，导致肿瘤发生。

Cystatin C与Cats之间的失衡可能与肿瘤发生有关。Zore等[25]发现结肠癌患者血清Cat B的含量增加，cystatin C也随之增加，但Cat B的活性并未被相应增加的cystatin C抑制，提示随着肿瘤的进展，两者改变的同时伴随Cat B和cystatin C之间的失平衡。故有人把cystatin C与Cats的比值作为诊断肿瘤恶性程度的指标。本研究提示肺癌患者cystatin C/Cat X比值与健康人相比，无统计学差异，未见到cystatin C和Cat X失衡与肺癌相关。我们研究发现肺癌患者血清cystatin C和Cat X之间无相关性。Chen等[26]报道cystatin C与Cat B、Cat L之间无明显相关。原因可能是由于cystatin C并不是Cats唯一的抑制剂，其它抑制剂如stefn A也可能涉及到Cats的抑制。

本研究显示，Cat X与肺癌患者性别、年龄、病理类型、淋巴结转移、细胞分化及TNM分期之间无明显相关。Sevenich等[27]研究提示，在基因敲除的乳腺癌小鼠模型中，Cat X在肿瘤发展的初期表达增高，而在进展期及转移瘤中表达降低。此外Hidaka等[13]研究结果提示20q13.2扩增与结肠癌进展和转移有关。Wang等[28]研究也发现Cat X与晚期肝癌有关。而Lines等[29]报道了相反的结论，提示Cat X降低了细胞粘附，并减少胰腺癌转移。这些不同研究结果可能由于样本量偏小、检测方法以及检测标本不同或Cat X在不同肿瘤中表达不同所致。

本研究显示，cystatin C与肺癌分期有关，但是与其它临床特征之间无明显相关。Vigneswaran等[30]研究发现cystatin C与乳腺癌淋巴结转移无关，但与肿瘤大小有关。Saleh等[22]研究发现cystatin C在晚期结肠癌中表达高于早期结肠癌。本研究与上述研究一致，提示cystatin C升高可能与肿瘤浸润、转移有关。

本研究未发现cystatin C/Cat X比值与肺癌临床病理特征相关。Kolwijck等[31]报道cystatin C/Cat H和cystatin C/ Cat X比值与卵巢癌病理类型相关，在低分化癌中明显升高。cystatin C与Cat X失衡与肿瘤研究甚少，还需要进一步扩大样本量或在其它肿瘤上进一步研究。

本研究表明，Cat X低水平肺癌患者同高水平患者相比有更好的OS。Vizin等[18]报道了血清Cat X高水平的结肠癌患者OS更短，与结肠癌预后有关。本研究与Vizin等[18]研究一致，提示Cat X有希望作为判断肺癌预后的指标。

我们研究提示，血清cystatin C高水平的肺癌患者OS短于低水平者(22.6个月vs 13.7个月)，但差异无统计学意义(P=0.105)。Strojan等[32]研究报道cystatin C与头颈部肿瘤预后有关，cystatin C低表达的患者无病生存期更长。Kos等[33]研究了黑色素瘤患者中cystatin C与预后关系，未发现两者之间存在相关性。

我们用单因素Cox回归分析发现Cat X水平以及TNM分期是影响肺癌预后独立因素，Cat X高水平以及晚期肺癌患者预后更差。多因素回归分析表明分期是影响肺癌患者生存的独立危险因素，晚期患者预后更差、OS更短，死亡的风险是早期的2.250倍。我们的结果进一步佐证了晚期肺癌预后更差。

总之，我们的研究初步证明在肺癌患者中血清Cat X和cystatin C水平升高，可能与肺癌的发生、发展有关。cystatin C在晚期肺癌中表达增高，可能与肺癌转移、侵袭相关。Cat X高水平的患者OS更短，单因素Cox回归分析显示Cat X是影响肺癌患者预后的独立因素。但本研究样本量还不大，需要扩大样本量进一步研究Cat X等因子与肺癌临床特征及预后的关系。

Funding Statement

本研究受国家自然科学基金资助项目（No.81172234）资助

This study was supported by the grant from the National Natural Science Foundation of China (to Shuanying YANG)(No.81172234)

References

  • 1.Strojan P. Cysteine cathepsins and stefins in head and neck cancer: an update of clinical studies. http://dx.doi.org/10.2478/v10019-008-0006-4 Radiol Oncol. 2008;42(2):69–81. [Google Scholar]
  • 2.Ardebili SY, Zajc I, Gole B, et al. CD133/prominin1 is prognostic for GBM patient's survival, but inversely correlated with cysteine cathepsins' expression in glioblastoma derived spheroids. http://ojs.szd.si/index.php/ro/article/view/1071/847. Radiol Oncol. 2011;45(2):102–115. doi: 10.2478/v10019-011-0015-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Kos J, Lah TT. Cysteine proteinases and their endogenous inhibitors: target proteins for prognosis, diagnosis and therapy in cancer (review) http://www.ncbi.nlm.nih.gov/pubmed/9769367. Oncol Rep. 1998;5(6):1349–1361. doi: 10.3892/or.5.6.1349. [DOI] [PubMed] [Google Scholar]
  • 4.Kos J, Sekirnik A, Premzl A, et al. Carboxypeptidases cathepsins X and B display distinct protein profile in human cells and tissues. Exp Cell Res. 2005;306(1):103–113. doi: 10.1016/j.yexcr.2004.12.006. [DOI] [PubMed] [Google Scholar]
  • 5.Kos J, Jevnikar Z, Obermajer N. The role of cathepsin X in cell signaling. Cell Adh Migr. 2009;3(2):164–166. doi: 10.4161/cam.3.2.7403. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Obermajer N, Jevnikar Z, Doljak B, et al. CathepsinX-mediated β2-integrin activation results in nanotube outgrowth. Cell Mol Life Sci. 2009;66(6):1126–1134. doi: 10.1007/s00018-009-8829-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Nascimento FD, Rizzi CC, Nantes IL, et al. Cathepsin X binds to cell surface heparan sulfate proteoglycans. Arch Biochem Biophys. 2005;436(2):323–332. doi: 10.1016/j.abb.2005.01.013. [DOI] [PubMed] [Google Scholar]
  • 8.Krueger S, Kalinski T, Hundertmark T, et al. Up-regulation of cathepsin X in Helicobacter pylori gastritis and gastric cancer. http://onlinelibrary.wiley.com/doi/10.1002/path.1820/full. J Pathol. 2005;207(1):32–42. doi: 10.1002/path.1820. [DOI] [PubMed] [Google Scholar]
  • 9.Nägler DK, Lechner AM, Oettl A, et al. An enzyme-linked immunosorbent assay for human cathepsin X, a potential new inflammatory marker. J Immunol Methods. 2006;308(1-2):241–250. doi: 10.1016/j.jim.2005.11.002. [DOI] [PubMed] [Google Scholar]
  • 10.Baker AR, Zalwango S, Malone LL, et al. Genetic susceptibility to tuberculosis associated with cathepsin Z haplotype in a Ugandan household contact study. Hum Immunol. 2011;72(5):426–430. doi: 10.1016/j.humimm.2011.02.016. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Nagler DK, Kruger S, Kellner A, et al. Upregulation of Cathepsin X in prostate cancer and prostatic intraepithelial neoplasia. Prostate. 2004;60:109–119. doi: 10.1002/pros.v60:2. [DOI] [PubMed] [Google Scholar]
  • 12.Rumpler G, Becker B, Hafner C, et al. Identification of differentially expressed genes in models of melanoma progression by cDNA array analysis: SPARC, MIF and a novel cathepsin protease characterize aggressive phenotypes. Exp Dermatol. 2003;12(6):761–771. doi: 10.1111/exd.2003.12.issue-6. [DOI] [PubMed] [Google Scholar]
  • 13.Hidaka S, Yasutake T, Takeshita H, et al. Differences in 20q13.2 copy number between colorectal cancers with and without liver metastasis. http://clincancerres.aacrjournals.org/content/6/7/2712.short?cited-by=yes;6/7/2712. Clin Cancer Res. 2000;6(7):2712–2717. [PubMed] [Google Scholar]
  • 14.Bar-Shira A, Pinthus HJ, Rozovsky U, et al. Multiple genes in human 20q13 chromosomal region are involved in an advanced prostate cancer xenograft. http://cancerres.aacrjournals.org/content/62/23/6803.abstract?cited-by=yesl62/23/6803c62/23/6803. Cancer Res. 2002;62(23):6803–6807. [PubMed] [Google Scholar]
  • 15.Kos J, Werle B, Lah T, et al. Cysteine proteinases and their inhibitors in extracellular fluids: markers for diagnosis and prognosis in cancer. Int J Biol Markers. 2000;15(1):84–89. doi: 10.1177/172460080001500116. [DOI] [PubMed] [Google Scholar]
  • 16.Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012;62(1):10–29. doi: 10.3322/caac.20138. [DOI] [PubMed] [Google Scholar]
  • 17.Nägler DK, Zhang R, Tam W, et al. Human cathepsin X: A cysteine protea-se with unique carboxypeptidase activity. Biochemistry. 1999;38(39):12648–12654. doi: 10.1021/bi991371z. [DOI] [PubMed] [Google Scholar]
  • 18.Vizin T, Christensen IJ, Nielsen HJ, et al. Cathepsin X in serum from patients with colorectal cancer: relation to prognosis. http://www.ncbi.nlm.nih.gov/pubmed/23077459. Radiol oncol. 2012;46(3):207–212. doi: 10.2478/v10019-012-0040-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Decock J, Obermajer N, Vozelj S, et al. CathepsinB, cathepsin H, cathepsin X and cystatin C in sera of patients with early-stage and inflammatory breast cancer. Int J Biol Markers. 2008;23(3):161–168. doi: 10.1177/172460080802300305. [DOI] [PubMed] [Google Scholar]
  • 20.Cox JL, Sexton PS, Green TJ, et al. Inhibition of B16 melanoma metastasis by over expression of the cysteine proteinase inhibitor cystatin C. Melanoma Res. 1999;9(4):369–374. doi: 10.1097/00008390-199908000-00005. [DOI] [PubMed] [Google Scholar]
  • 21.Nishikawa H, Ozaki Y, Nakanishi T, et al. The role of Cathepsin B and Cystatin C in the mechanisms of invasion by ovarian cancer. Gynecol Oncol. 2004;92(3):881–886. doi: 10.1016/j.ygyno.2003.11.017. [DOI] [PubMed] [Google Scholar]
  • 22.Saleh Y, Sebzda T, Warwas M, et al. Expression of cystatin C in clinical human colorectal cancer tissues. http://www.ncbi.nlm.nih.gov/pubmed/16416601. J Exp Ther Oncol. 2005;5(1):49–53. [PubMed] [Google Scholar]
  • 23.Krepela E, Prochazka J, Karova B, et al. Cysteine proteases and cysteine protease inhibitors in non-small cell lung cancer. http://www.ncbi.nlm.nih.gov/pubmed/9921922. Neoplasma. 1998;45(4):318–331. [PubMed] [Google Scholar]
  • 24.Wegiel B, Jiborn T, Abrahamson M, et al. Cystatin C is downregulated in prostate cancer and modulates invasion of prostate cancer cells via MAPK/Erk and androgen receptor pathways. PLoS One. 2009;4(11):e7953. doi: 10.1371/journal.pone.0007953. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Zore I, Krasovec M, Cimerman N, et al. Cathepsin B/cystatin C complex levels in sera from patients with lung and colorectal cancer. http://med.wanfangdata.com.cn/Paper/Detail/PeriodicalPaper_JJ027731537. Biol Chem. 2001;382(5):805–810. doi: 10.1515/BC.2001.097. [DOI] [PubMed] [Google Scholar]
  • 26.Chen QY, Fei J, Wu L, et al. Detection of cathepsin B, cathepsin L, cystatin C, urokinase plasminogen activator and urokinase plasminogen activator receptor in the sera of lung cancer patients. Oncol Lett. 2011;2(4):693–699. doi: 10.3892/ol.2011.302. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Sevenich L, Schurigt U, Sachse K, et al. Synergistic antitumor effects of combined cathepsin B and cathepsin Z deficiencies on breast cancer progression and metastasis in mice. Proc Natl Acad Sci USA. 2010;107(6):2497–2502. doi: 10.1073/pnas.0907240107. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Wang J, Chen L, Li Y, et al. Overexpression of Cathepsin Z contributes to tumor metastasis by inducing epithelial-mesenchymal transition of hepatocellular carcinoma. PLoS One. 2011;6(9):e24967. doi: 10.1371/journal.pone.0024967. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Lines KE, Chelala C, Dmitrovic B, et al. S100P-binding protein, S100PBP, mediates adhesion through regulation of cathepsin Z in pancreatic cancer cells. Am J Pathol. 2012;180(4):1485–1494. doi: 10.1016/j.ajpath.2011.12.031. [DOI] [PubMed] [Google Scholar]
  • 30.Vigneswaran N, Wu J, Muller S, et al. Expression analysis of cystatin C and M in laser-capture microdissectioned human breast cancer cells-a preliminary study. Pathol Res Pract. 2005;200(11-12):753–762. doi: 10.1016/j.prp.2004.09.005. [DOI] [PubMed] [Google Scholar]
  • 31.Kolwijck E, Kos J, Obermajer N, et al. The balance between extracellular cathepsins and cystatin C is of importance for ovarian cancer. Eur J Clin Invest. 2010;40(7):591–599. doi: 10.1111/eci.2010.40.issue-7. [DOI] [PubMed] [Google Scholar]
  • 32.Strojan P, Svetic B, Smid L, et al. Serum cystatin C in patients with head and neck carcinoma. Clin Chim Acta. 2004;344(1-2):155–161. doi: 10.1016/j.cccn.2004.02.011. [DOI] [PubMed] [Google Scholar]
  • 33.Kos J, Stabuc B, Schweiger A, et al. Cathepsins B, H, and L and their inhibitors stefin A and cystatin C in sera of melanoma patients. http://clincancerres.aacrjournals.org/content/3/10/1815. Clin Cancer Res. 1997;3(10):1815–1822. [PubMed] [Google Scholar]

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