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Caveolin—1在肺癌组织中的表达及临床意义

2018-11-30陈敏方陈福春

中国现代医生 2018年17期
关键词:淋巴免疫组化阳性率

陈敏方  陈福春

[摘要] 目的 分析Caveolin-1在不同組织学类型肺癌中的表达以及与肺癌病理的相关性。 方法 回顾性分析2016年7月~2017年7月来我院就诊的130例原发性肺癌患者,所有患者均行手术治疗,取肺癌组织及癌旁正常肺组织进行免疫组化,比较肺癌组织和正常肺组织及不同组织学类型肺癌组织、不同分期肺癌组织中Caveolin-1的表达。 结果 Caveolin-1在正常肺组织的支气管上皮细胞和肺泡上皮细胞中的阳性率为100.00%,显著高于肺癌组织中的58.46%,差异有统计学意义(P<0.05);Caveolin-1在非小细胞肺癌中的阳性率为61.67%,显著高于小细胞肺癌中的20.00%,差异有统计学意义(P<0.05);Caveolin-1在I、II期肺癌组织中的阳性率为47.37%,显著低于Ⅲ、Ⅳ期的60.71%,差异有统计学意义(P<0.05);Caveolin-1在有淋巴转移组中的阳性率显著高于无淋巴转移组,差异有统计学意义(P<0.05);Caveolin-1在腺癌、鳞癌、大细胞癌中的表达无显著差异。 结论 Caveolin-1在不同类型、分期、淋巴转移的肺癌中表达不同,可作为肺癌临床诊治的指标。

[关键词] Caveolin-1;肺癌;病理;分期;淋巴转移

[中图分类号] R734.2 [文献标识码] A [文章编号] 1673-9701(2018)17-0013-04

The significance and the expression of Caveolin-1 in the tissues of patients with lung cancer

CHEN Minfang1 CHEN Fuchun2

1.NO.1 Department of Surgery, Wenling Hospital of TCM in Zhejiang Province, Wenling 317500, China; 2.Department of Thoracic Surgery, Wenling Hospital of TCM in Zhejiang Province, Wenling 317500, China

[Abstract] Objective To analyze the expression of Caveolin-1 in different histological types of lung cancer and its correlation with lung cancer pathology. Methods 130 patients with primary lung cancer who came to our hospital for diagnosis from July 2016 to July 2017 were retrospectively analyzed. All patients were given surgical treatment. Lung cancer tissue and normal lung tissue next to the lung were given immunohistochemical tests. The expression of Caveolin-1 in lung cancer tissues and normal lung tissues, and different histological types of lung cancer tissues and different stages of lung cancer tissues were compared. Results The positive rate of Caveolin-1 in bronchial epithelial cells and alveolar epithelial cells in normal lung tissues was 100.0%, which was significantly higher than that in lung cancer tissues(58.46%). the difference was statistically significant(P<0.05); the positive rate of caveolin-1 in non-small cell lung cancer was 61.67%, which was significantly higher than that in small cell lung cancer(20.00%), the difference was statistically significant(P<0.05); the positive rate of caveolin-1 in stage Ⅰ and Ⅱ lung cancer tissues was 47.37%, which was significantly lower than that in stage Ⅲ and Ⅳ(60.71%), the difference was statistically significant(P<0.05); the positive rate of Caveolin-1 in patients with lymphatic metastasis was significantly higher than that in patients without lymphatic metastasis, and the difference was statistically significant(P<0.05); there was no significant difference in adenocarcinoma, squamous cell carcinoma and large cell carcinoma of expression of caveolin-1. Conclusion Caveolin-1 is expressed differently in the lung cancers with different types, stages, and lymphatic metastasis, which can be used as an indicator of clinical diagnosis and treatment of lung cancer.

[Key words] Caveolin-1; Lung cancer; Pathology; Staging; Lymphatic metastasis

胞膜窖(caveolae)是細胞膜上特定的[1-2],直径约50~100 nm的细颈瓶状微区域[3],其富含胆固醇、鞘磷脂、鞘糖脂,形成一个膜内陷区域[4],以存在窖蛋白分子为特征。caveolae广泛存在于内皮细胞、肺上皮细胞、脂肪细胞、成纤维细胞、血管平滑肌细胞等中,富含多种信号传导相关的酶、受体、连接蛋白,是信号转导途径中的枢纽,参与细胞内吞、信号传导[5]、肿瘤生成[6]、胆固醇运输等多种细胞生命活动[7]。微囊蛋白1(Caveolin-1)是caveolae中的主要膜结构蛋白[8],属于细胞膜上的整合膜蛋白,在保证caveolae的完整性、信号的传导方面发挥重要作用[9],具有激酶抑制活性,通过与caveolae分子结合而发挥调节作用。本实验通过免疫组化方法,分析Caveolin-1蛋白在正常肺组织、不同组织学类型肺癌中的表达及与肺癌病理的相关性,现报道如下。

1 资料与方法

1.1 一般资料

选取2016年7月~2017年7月来我院就诊的130例原发性肺癌患者为研究对象,所有患者均行手术治疗切除标本,术前均未接受放疗、化疗。其中,男94例,女36例;年龄27~74岁,平均(50.3±5.2)岁;非小细胞肺癌120例,小细胞肺癌10例;65例伴淋巴结转移,65例无淋巴结转移;患者的病理分型和临床分期见表1。所有患者诊断明确,病历、病理、随访资料完整,肿瘤的分期由两名有经验的医生共同确定。

1.2 主要试剂

兔抗人多克隆 Caveolin-1 抗体(sc-894),购自北京中杉金桥生物技术有限公司,辣根过氧化酶(HRP)标记的羊抗兔 IgG购自美国 Jackson 公司,免疫组织化学试剂盒(Kit-9710)购自福州迈新生物技术开发公司。

1.3 免疫组化方法

取肺癌组织以及癌旁正常肺组织进行免疫组化,将标本用4%的甲醛固定,石蜡包埋,制成切片,经脱蜡、脱苯、水化后,根据SP法试剂盒说明书进行抗Caveolin-1(1∶125)染色,阴性对照组用PBS代替一抗。染色后,Caveolin-1在血管内皮细胞、肺泡上皮细胞,胞膜和胞质处出现棕黄色颗粒为阳性对照。

1.4 结果判定

采用半定量积分法,Caveolin-1为膜/质蛋白,免疫组化染色反应阳性的标准为细胞膜和胞浆有棕黄色颗粒[10]。光镜下,从130例肺癌标本中随机选取不同的4个肺癌病灶视野,每个视野统计200个癌细胞,计算出阳性率为50.9%,以50%为界线,阳性率>50%为表达阳性,阳性率≤50%为表达阴性。

1.5 统计学处理

采用SPSS 17.0软件进行数据分析,计数资料采用χ2检验,P<0.05为差异有统计学意义。

2 结果

2.1 Caveolin-1在不同组织学类型肺癌中的表达

Caveolin-1在正常肺组织的支气管上皮细胞和肺泡上皮细胞中的阳性率为100.00%,显著高于肺癌组织中的58.46%,差异有统计学意义(P<0.05);Caveolin-1在非小细胞肺癌中的阳性率为61.67%,显著高于小细胞肺癌中的20.00%,差异有统计学意义(P<0.05);Caveolin-1在腺癌、鳞癌、大细胞癌中的表达无显著差异

2.2 Caveolin-1在不同分期肺癌中的表达

Caveolin-1在Ⅰ、Ⅱ期肺癌组织中的阳性率为47.37%,显著低于Ⅲ期、Ⅳ期的60.71%,差异有统计学意义(P<0.05)

2.3 Caveolin-1在有无淋巴结转移肺癌中的表达

Caveolin-1在有淋巴转移组中的阳性率为73.85%,显著高于无淋巴转移组的50.77%,差异有统计学意义(P<0.05)

3 讨论

肺癌是发生于支气管黏膜上皮的恶性肿瘤,其发病率居恶性肿瘤的首位,严重影响患者的生命健康[11]。早期肺癌患者多无症状,超过2/3的患者发现时已处于中晚期,发生远处转移和浸润,丧失了手术治疗的机会[12],而肺癌的转移和浸润是多因子调控的复杂过程,原癌基因的激活和抑癌基因的失活密切相关,因此,深入了解肺癌侵袭、转移的分子机制将有助于揭示肺癌发生、发展的实质。为寻找预防、早期诊断和治疗肺癌侵袭和转移提供有效的途径,因此,研究肺癌转移和浸润的机制是目前研究的重点,本研究旨在为临床肺癌转移和浸润的预测寻找有效指标。Caveolin 在 caveolae 的表面表达,分子量为 21~24 kd,属于小分子膜整合蛋白,由于其免疫学特性的不同,目前研究发现有 1、2、3 三种类型。其中Caveolin-1型又有α、β两种分型。Caveolae主要存在于高度分化的细胞,Caveolin-1、Caveolin-2主要表达于成纤维细胞、内皮细胞、脂肪细胞;Caveolin-3主要表达于平滑肌细胞、骨胳肌细胞、心肌细胞。Caveolae也参与了多种生物活性分子从细胞外向细胞内转移的过程。目前研究结果显示Caveolin-1在肿瘤中的作用并不一致[13-14],一些学者认为,Caveolin-1在肿瘤中发挥抑瘤作用[15],一方面,Caveolin-1通过其架构区发挥其抑癌作用,Caveolin-1架构区能够抑制内皮生长因子受体Raf、c-Src、EGF-R、MEK-1、G蛋白和ERK-2活性,而这些因子是激活p42/44MAPK及其下游核转录因子cyclin D、Fos、Jun的活化因子。在肿瘤发生过程中,Caveolin-1表达下降,则降低了Caveolin-1架构区对这些活化因子的抑制,导致核转录因子活性异常增高,从而影响肿瘤的发生;另一方面,Caveolin-1可通过下调 PDGF 受体及抑制 PI3K 通路抑制细胞生长,促进细胞凋亡。而另外一部分学者研究发现,Caveolin-1的高表达与肿瘤的转移和预后不良密切相关[16],Caveolin-1通过下调凋亡抑制蛋白survivin的表达,使得G2/M期细胞减少,增加细胞对凋亡的易感性,说明Caveolin-1不仅具有肿瘤抑制因子的作用,还具有促进肿瘤转移的活性[17]。起初,Caveolin-1被认为是抑癌基因,在正常肺部组织中高表达,而在肺癌中表达下降,通过Caveolin-1的重新表达可抑制肿瘤细胞的生长。但也有研究证实,Caveolin-1的高表达与肿瘤进展和淋巴结转移相关,Caveolin-1参与细胞增殖、新生血管生成,与肿瘤预后密切相关,进展期肺癌及有淋巴结转移的肺癌标本中,Caveolin-1的表达升高可能与Caveolin-1架构区外的氨基酸突变[18]或磷酸化相关。

本研究回顧性分析来我院就诊的130例原发性肺癌患者,所有患者均行手术治疗,取肺癌组织及癌旁正常肺组织进行免疫组化,比较肺癌组织和正常肺组织及不同组织学类型肺癌组织、不同分期肺癌组织中Caveolin-1的表达,结果显示:Caveolin-1在正常肺组织的支气管上皮细胞和肺泡上皮细胞中的阳性率为100.00%,显著高于肺癌组织中的58.46%,差异有统计学意义;Caveolin-1在非小细胞肺癌中的阳性率为61.67%,显著高于小细胞肺癌中的20.00%,差异有统计学意义;Caveolin-1在Ⅰ、Ⅱ期肺癌组织中的阳性率为47.37%,显著低于Ⅲ、Ⅳ期的60.71%,差异有统计学意义;Caveolin-1在有淋巴转移组中的阳性率显著高于无淋巴转移组,差异有统计学意义;Caveolin-1在腺癌、鳞癌、大细胞癌中的表达无显著差异。

综上所述,Caveolin-1在不同类型、分期、淋巴转移的肺癌中表达不同[19],可作为评价肺癌转移趋势的指标,通过检测Caveolin-1的表达,可实现对肺癌的早期诊断[19-20]、疗效评价及预后判断[21],为肺癌诊断和治疗提供新思路。

[参考文献]

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[2] Yeow I,Howard G,Chadwick J,et al. EHD proteins cooperate to generate caveolar clusters and to maintain caveolae during repeated mechanical stress[J].Curr Biol,2017,27(19):2951-2962 e5.

[3] Vrapciu AD,Rusu MC.PV-1 expression could distinguish the subset of caveolae-presenting telocytes that are endothelial progenitors[J].Rom J Morphol Embryol,2017,58(3):749-752.

[4] Hirama T,Das R,Yang Y,et al. Phosphatidylserine dictates the assembly and dynamics of caveolae in the plasma membrane[J]. J Biol Chem,2017,292(34):14292-14307.

[5] Copeland CA,Han B,Tiwari A,et al. A disease-associated frameshift mutation in Caveolin-1 disrupts caveolae formation and function through introduction of a de novo ER retention signal[J]. Mol Biol Cell,2017,28(22):3095-3111.

[6] Liao L,Zheng B,Yi B,et al. Annexin A2-modulated proliferation of pulmonary arterial smooth muscle cells depends on caveolae and Caveolin-1 in hepatopulmonary syndrome[J]. Exp Cell Res,2017,359(1):266-274.

[7] Sung M,Tan X,Lu B,et al. Caveolae-mediated endocytosis as a novel mechanism of resistance to trastuzumab emtansine(T-DM1)[J]. Mol Cancer Ther,2018,17(1): 243-253.

[8] Williere Y,Borschewski A,Patzak A,et al.Caveolin 1 promotes renal water and salt reabsorption[J]. Sci Rep,2018,8(1):545.

[9] Alcala AC,Hernandez-Bravo R,Medina F,et al. The dengue virus non-structural protein 1(NS1) is secreted from infected mosquito cells via a non-classical Caveolin-1-dependent pathway[J]. J Gen Virol,2017,98(8):2088-2099.

[10] Joo HJ,Oh DK,Kim YS,et al. Increased expression of Caveolin-1 and microvessel density correlates with metastasis and poor prognosis in clear cell renal cell carcinoma[J]. BJU Int,2004,93(3):291-296.

[11] Stephans KL,Woody NM,Reddy CA,et al. Tumor control and toxicity for common stereotactic body radiation therapy dose-fractionation regimens in stage I non-small cell lung cancer[J]. Int J Radiat Oncol Biol Phys,2018, 100(2):462-469.

[12] Zhao B,Zhang W,Yu D,et al.Adoptive immunotherapy shows encouraging benefit on non-small cell lung cancer:A systematic review and meta-analysis[J]. Oncotarget,2017,8(68):113105-113119.

[13] Kuo A,Lee MY,Yang K,et al.Caveolin-1 regulates lipid droplet metabolism in endothelial cells via autocrine prostacyclin-stimulated,cAMP-mediated lipolysis[J].J Biol Chem,2018,293(3):973-983.

[14] Park SY,Park JW,Lee GW,et al. Inhibition of neddylation facilitates cell migration through enhanced phosphorylation of Caveolin-1 in PC3 and U373MG cells[J]. BMC Cancer,2018,18(1):30.

[15] Ruan H,Li X,Yang H,et al. Enhanced expression of Caveolin-1 possesses diagnostic and prognostic value and promotes cell migration,invasion and sunitinib resistance in the clear cell renal cell carcinoma[J]. Exp Cell Res,2017,358(2):269-278.

[16] Ruan H,Li X,Yang H,et al.Corrigendum to "Enhanced expression of Caveolin-1 possesses diagnostic and prognostic value and promotes cell migration,invasion and sunitinib resistance in the clear cell renal cell carcinoma"[Exp. Cell Res. (2017) 269-278][J]. Exp Cell Res,2018,362(1):244.

[17] Glukhova XA,Trizna JA,Proussakova OV,et al.Impairment of Fas-ligand-Caveolin-1 interaction inhibits Fas-ligand translocation to rafts and Fas-ligand-induced cell death[J]. Cell Death Dis,2018,9(2):73.

[18] Cui Y,Zhu T,Song X,et al.Downregulation of Caveolin-1 increased EGFR-TKIs sensitivity in lung adenocarcinoma cell line with EGFR mutation[J].Biochem Biophys Res Commun,2018,495(1):733-739.

[19] Basourakos SP,Davis JW,Chapin BF,et al.Baseline and longitudinal plasma Caveolin-1 level as a biomarker in active surveillance for early-stage prostate cancer[J]. BJU Int,2018,121(1):69-76.

[20] Yeong J,Thike AA,Ikeda M,et al. Caveolin-1 expression as a prognostic marker in triple negative breast cancers of Asian women[J]. J Clin Pathol,2018,71(2):161-167.

[21] Eliyatkin N,Aktas S,Diniz G,et al. Expression of Stromal Caveolin-1 May Be a Predictor for Aggressive Behaviour of Breast Cancer[J]. Pathol Oncol Res,2018,24(1):59-65.

(收稿日期:2018-01-16)

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