整合素αvβ6在结肠癌与甲状腺癌中的作用研究
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摘要
第一部分
整合素αvβ6在结肠癌细胞化疗耐药中的作用研究
研究背景
结直肠癌是世界范围内发病率居第三位,致死率居第四位的恶性消化道肿瘤。近年来随着环境污染日益严重和人们饮食结构的变化,结直肠癌的发病率和死亡率逐步上升。目前,手术切除仍然是治疗结直肠癌的主要方式。然而,在可切除的结直肠癌患者中,大约50%患者将会复发,其中绝大部分患者失去再治愈的机会。目前研究认为,Ⅲ期结直肠癌病人术后需全身辅助化疗以消灭体内的微小转移病变,减少肿瘤复发及改善生存。以5-氟尿嘧啶(5-fluorouracil,5-FU)为基础的多种化疗方案应用于临床已达30余年,但因原发性或获得性耐药的产生,化疗往往达不到满意效果甚至归于失败。虽然近年不断涌现一批新颖的化疗药物,如伊立替康、奥沙利铂等,耐药性的产生仍是目前结直肠癌化疗领域亟待解决的问题。
整合素是细胞表面粘附分子的一种,由α和β两种亚基结合而成,目前已发现由18种α亚基和8种β亚基组成的24种整合素成员。一方面,整合素在胞外连接基质蛋白或相邻细胞,在胞内连接细胞骨架系统,从而构成肿瘤细胞赖以生存发展的空间纽带；另一方面,整合素作为受体可与多种细胞因子结合,从而向细胞内外双向传导生物信息,构成肿瘤细胞感受外界刺激并作出相应反应的的信息枢纽。研究发现,整合素参与了肿瘤化疗耐药过程。在肿瘤耐药株已发现多种整合素亚型表达上调。另外,整合素可能参与了化疗药物诱导的肿瘤细胞凋亡过程。应用各种分子生物学技术,如抗体阻断,siRNA干扰等,阻断整合素与胞外基质及细胞之间的连接,可有效抑制肿瘤细胞的化疗耐药性。整合素成为解决肿瘤化疗耐药的极有潜力的靶向目标。在此基础上,应用微阵列技术分析肿瘤的整合素表型,可以选择最有效的化疗药物或化疗方案,而针对这些表型进行个体化治疗,将具有良好的临床应用前景。
整合素αvβ6仅在上皮组织表达,在胚胎形成、组织修复过程及某些癌组织表达增强,而在正常组织和良性肿瘤组织几无表达。我们前期研究发现：αvβ6在结肠癌侵袭转移、胞外基质降解等肿瘤恶性生物学行为发挥重要作用。另外,αvβ6与ERK2之间存在着生理性直接连接,该直接连接对αvβ6在结肠癌发挥调控功能起着关键作用。然而,αvβ6是否在结直肠癌化疗耐药过程发挥作用迄今尚不明确。在上述背景下,本研究拟选择两种结肠癌细胞系SW480和HT-29及结直肠癌化疗代表性药物-5-FU,在细胞水平深入研究αvβ6是否在结肠癌化疗耐药过程发挥作用并探索其作用机制。
第一节整合素αvβ6对5-FU作用下结肠癌细胞增殖和凋亡的影响
目的
研究整合素αvβ6对5-FU诱导的SW480和HT-29结肠癌细胞增殖抑制及凋亡的影响。
方法
1.SW480结肠癌细胞分为野生组(SW480wild-type)、已稳定转染含p6基因质粒组(SW480(36-transfectant)和转染空白质粒组(SW480Mock-transfectant),分别用流式细胞术、western blotting实验检测三组细胞αvβ6蛋白的表达情况。
2.利用pSIREN-DNR-DsRed-Express Vector质粒构建p6特异性shRNA表达载体及对照组载体,以脂质体法转染至HT-29结肠癌细胞,分别用流式细胞术、western blotting实验检钡HT-29wild-type、β6-shRNA、control-shRNA三组细胞αvβ6蛋白的表达情况。
3.以不同浓度5-FU(0.2、1、5、25、125μg/mL)作用于SW480和HT-29各组细胞48h,MTT法检测细胞增殖抑制情况,并计算比较IC50。
4.以48h IC50浓度的5-FU作用于SW480和HT-29各组细胞48h, Hoechst33258凋亡形态法和流式细胞术检测细胞凋亡情况。
结果
1.流式细胞术及western blotting实验均表明,稳定转染含β6基因质粒的SW480细胞(SW480β6-transfectant)显著表达整合素β6,而野生型细胞或转染空白质粒细胞不表达整合素β6,三组细胞整合素αv的表达无明显差异。
2.流式细胞术及western blotting实验均表明,与control-shRNA比较,β6-shRNA可显著降低HT-29细胞整合素p6的表达,但对整合素αv的表达无明显影响。
3.MTT实验表明,在不同浓度5-FU作用下,SW480β6-transfectant组细胞存活率均高于SW480wild-type及Mock-transfectant组；在HT-29细胞,p6-shRNA可显著降低5-FU作用下的细胞存活率。
4.Hoechst33258凋亡形态法和流式细胞术实验均标明,在不同浓度5-FU作用下,SW480p6-transfectant组细胞凋亡率均低于SW480wild-type及Mock-transfectant组;在HT-29细胞,p6-shRNA可显著提高5-FU作用下的细胞凋亡率。
结论及意义
本节研究揭示,在结肠癌SW480和HT-29细胞,整合素αvβ6均可保护细胞抑制5-FU诱导的增殖抑制及凋亡从而增强结肠癌细胞的化疗耐药能力,丰富了整合素αvβ6的理论知识,并为结肠癌的靶向治疗或辅助化疗研究提供了确切的理论依据。
第二节整合素αvβ6对5-FU诱导的结肠癌细胞线粒体凋亡途径的影响
目的
研究整合素αvβ6对5-FU诱导的SW480和HT-29结肠癌细胞线粒体凋亡途径的影响。
方法
1.细胞分组同第一节。
2.以48h IC50浓度的5-FU作用于SW480和HT-29各组细胞48h, western blotting实验检测胞浆cytochrome C表达情况。
3.以48h IC50浓度的5-FU作用于SW480和HT-29各组细胞48h,活性检测试剂盒检测caspase-3和caspase-9活性情况。
4.以48h IC50浓度的5-FU作用于SW480和HT-29各组细胞48h, western blotting实验检测Bcl-2和Bax蛋白表达情况。
结果
1.western blotting实验表明,在5-FU作用下,SW480三组细胞的胞浆cytochrome C表达均有增强,但β6-transfectant组细胞胞浆cytochrome C增强程度显著低于SW480wild-type及Mock-transfectant组；在HT-29细胞,与wild-type或control-shRNA组比较,β6-shRNA使5-FU介导的胞浆cytochrome C的表达进一步增强。
2.活性检测试剂盒实验表明,在5-FU作用下,SW480三组细胞的caspase-3和caspase-9活性均有增强,但β6-transfectant组细胞增强程度显著低于SW480wild-type及Mock-transfectant组；在HT-29细胞,与wild-type或control-shRNA组比较,β6-shRNA使5-FU介导的caspase-3和caspase-9活性增强进一步加剧。
3. western blotting实验表明,在5-FU作用前后,SW480p6-transfectant组细胞Bcl-2表达明显高于wild-type及Mock-transfectant组,而Bax表达低于后二组；在HT-29细胞,与wild-type或control-shRNA组比较,P6-shRNA可显著抑制Bcl-2表达而增强Bax表达,这种现象在5-FU作用前后均可发现。
结论及意义
本节实验揭示,在结肠癌SW480和HT-29细胞,整合素αvβ6均可有效抑制5-FU诱导的线粒体凋亡途径,包括抑制胞浆cytochrome C水平升高,抑制caspase-3和caspase-9活性增强,上调凋亡调节蛋白Bcl-2表达而下调Bax表达等。本节研究明确了整合素αvβ6抑制5-FU诱导的结肠癌细胞凋亡的具体机制,丰富了整合素αvβ6的理论知识,并为结肠癌的靶向治疗或辅助化疗研究提供了确切的理论依据。
第三节整合素αvβ6介导结肠癌化疗耐药的细胞信号通路研究
目的
研究整合素αvβ6增强SW480和HT-29结肠癌细胞化疗耐药能力的相关细胞信号传导通路。
方法
1.细胞分组同第一节,western blotting实验检测各组细胞MAPK信号传导通路关键因子磷酸化／总ERK (p/t-ERK)、磷酸化/总,fNK (p/t-JNK)和磷酸化/总p-p38(p/t-p38)的表达情况。
2.细胞分组同第一节,以PD98059阻断ERK/MAPK信号传导通路,以48h IC50浓度的5-FU作用于SW480和HT-29各组细胞48h,MTT实验检测细胞增殖,Annexin V/PI-流式细胞术检测细胞凋亡。
3.SW480结肠癌细胞分为已稳定转染含p6基因质粒组(SW480β6-transfectant)、转染空白质粒组(SW480Mock-transfectant)和转染含β6突变基因质粒组(转染表达的β6蛋白缺失与ERK2的结合位点)(SW480p6Mutant-transfectant);以48h IC50浓度的5-FU作用于SW480各组细胞48h,MTT实验检测细胞增殖,Annexin V/PI-流式细胞术检测细胞凋亡,western blotting实验检测凋亡相关分子Bcl-2和Bax表达情况。
结果
1.western blotting实验表明,转染表达β6可明显增强SW480细胞p-ERK的表达,而β36-shRNA可明显抑制HT-29细胞p-ERK的表达；p6表达对t-ERK、p/t-JNK、p/t-p38的表达无显著影响。
2.MTT增殖抑制实验及流式细胞术标明,以PD98059阻断ERK/MAPK信号传导通路,可有效抑制整合素αvβ6介导的结肠癌细胞对5-FU的化疗耐药。
3.整合素p6缺失与ERK2的结合位点,可显著抑制整合素αvβ6介导的p-ERK、Bcl-2表达增强及Bax表达降低,有效抑制整合素αvβ6介导的结肠癌细胞对5-FU的化疗耐药。
结论及意义
本节实验揭示,整合素αvβ6通过ERK/MAPK信号传导通路介导结肠癌SW480和HT-29细胞对5-FU的化疗耐药,并在很大程度上依赖于p6与ERK2的直接结合。本节研究明确了整合素αvβ6介导结肠癌化疗耐药的具体信号传导通路,丰富了整合素αvβ6的理论知识,并为结肠癌的靶向治疗或辅助化疗研究提供了确切的理论依据。
第二部分
整合素αvβ6在甲状腺组织的表达及与甲状腺癌临床病理特征的关系
研究背景
甲状腺癌发病率在人类全部癌症不超过2%,但几十年来其发病率一直在上升。目前,大多数甲状腺癌为低度恶性,可用手术治愈的并对放射性碘具有良好的反应性。然而甲状腺癌的诊断治疗仍然存在一些问题。首先,细针抽吸活检(fine needle aspiration, FNA)是目前甲状腺癌最准确的诊断方法,但多达30%的病例仍然存在诊断困难。原因是许多乳头和滤泡状甲状腺癌在结构上类似于正常甲状腺滤泡组织而使人无法做出确切判断。出于避免遗漏恶性肿瘤的目的,在很多诊断困难情况下往往施行大范围的手术切除,而术后才发现为良性肿瘤。其次,一些甲状腺癌具有侵袭转移倾向,包括淋巴结转移和远处转移,而这一点可能影响患者治疗和预后。例如,占甲状腺癌绝大多数的乳头状癌具有特征性的早期淋巴结转移倾向。有研究表明,甲状腺癌患者年龄45岁以上且合并纵隔或颈部淋巴结转移者,其死亡风险显著增加。在上述情况下,需要寻找一种合适的分子标志物,以增加诊断的准确性和预测甲状腺癌转移潜能。
整合素是细胞表面粘附分子的一种,由α和β两种亚基结合而成,目前已发现由18种α亚基和8种β亚基组成的24种整合素成员。一方面,整合素在胞外连接基质蛋白或相邻细胞,在胞内连接细胞骨架系统,从而构成肿瘤细胞赖以生存发展的空间纽带；另一方面,整合素作为受体可与多种细胞因子结合,从而向细胞内外双向传导生物信息,构成肿瘤细胞感受外界刺激并作出相应反应的的信息枢纽。
αvβ6属于整合素的一种亚型,仅在上皮组织表达,在胚胎形成、组织修复过程及某些癌组织表达增强,而在正常组织和良性肿瘤组织几无表达。研究发现,αvβ6参与了多种恶性肿瘤侵袭转移、增殖凋亡、肿瘤免疫、EMT等生物学功能。值得注意的是,整合素αvβ6表达与多种肿瘤的临床病理特征及病人预后密切相关。在结肠癌,高表达αvβ6的结肠癌患者,与不表达或低表达者相比,其中位生存期明显缩短；对早期结肠癌患者,高表达β6的患者其5年和10年生存率明显降低。在胃癌,αvβ6的表达与Lauren分型、细胞分化、N分期及TNM分期密切相关。重要的是,αvβ6阳性患者其生存期明显短于αvβ6阴性者。另外,在口腔鳞癌,乳腺癌及卵巢癌等,αvβ6表达与肿瘤的临床病理特征及病人预后的关系也得到研究证实。
然而,αvβ6在甲状腺癌的表达情况迄今未明。本研究利用免疫组织化学方法检测了一系列恶性和非恶性的甲状腺组织中αvβ6的表达。此外,我们利用统计学方法研究了αvβ6表达与甲状腺癌患者临床病理特征之间的关系。
目的
检测整合素αvβ6在各种甲状腺组织中的表达,研究整合素αvβ6与甲状腺癌临床病理特征的关系。
方法
1.购买含有多种甲状腺组织的微阵列芯片,从齐鲁医院病理科收集甲状腺癌组织标本及病人临床病理信息。在研究之前,所有病例均邀请病理科专家进行确诊。
2.免疫组织化学方法检测标本中αvβ6表达情况,并按确定的标准进行评分。
3.比较不同甲状腺组织的αvβ6表达差异；研究αvβ6表达与甲状腺癌患者临床病理特征之间的相关性,包括年龄、性别、病理类型、TNM分期等。
结果
1.整合素αvβ6在不同甲状腺组织的表达存在显著差异。在正常甲状腺组织,癌旁组织,甲状腺腺瘤,整合素αvβ6表达一般为阴性或弱阳性。其中,10例(10/10)正常甲状腺组织均未检测出αvβ6表达,只有1例(1/10)癌旁组织和3例(3/10)甲状腺腺瘤组织αvβ6表达阳性。整合素αvβ6在甲状腺肿组织和甲状腺炎组织多有广泛而较强表达,其中7例(7/10)甲状腺肿组织及8例(8/10)甲状腺炎组织αvβ6表达阳性。在甲状腺癌,有71例(71/90)αvβ6表达阳性。此外,10例(10/10)甲状腺乳头状癌淋巴结转移灶均检测有αvβ6的表达。
2.αvβ6表达区别甲状腺癌和非恶性甲状腺组织的灵敏度为78.89%,特异度为62%,预测阳性值为78.89%,而预测值阴性率为62%。检测αvβ6表达可成功区别甲状腺癌与正常甲状腺组织、癌旁正常组织和甲状腺腺瘤,但不能区别甲状腺癌与结节性甲状腺肿和甲状腺炎组织。此外,乳头状甲状腺癌和滤泡状甲状腺癌之间的αvβ6表达无显著差异。
3.αvβ6表达与甲状腺癌患者的性别、肿瘤组织学形态、T分期和TNM分期之间无相关性,但和患者的年龄和N分期有相关性。
结论及意义
本研究表明整合素αvβ6在不同甲状腺组织的表达存在显著差异,检测avβ6表达以区别非恶性甲状腺组织和甲状腺癌具有良好的灵敏度和特异性。此外,整合素avβ6的表达与甲状腺癌淋巴结转移有密切相关性。在这个意义上,检测整合素avβ6的表达可能有助于补充FNA活检以提高诊断的准确性,并帮助预测甲状腺癌潜在的淋巴转移倾向。
Part Ⅰ
Role of Integrin αvβ6in Chemo Resistance of Colon Carcinoma
Background
Colorectal cancer (CRC) is the third most prevalent cancer and the fourth leading cause of cancer deaths worldwide. With the increasingly serious environmental pollution and the change of people's diet in recent years, the incidence and mortality rates of colorectal cancer have gradually increased. Currently, surgical resection is still the main treatment for colorectal cancer. However, tumor recurrence was found in about50%of resectable colorectal cancers, and most patients lose the opportunity of cure. Present study suggests that, CRC patients with stage III need systemic adjuvant chemotherapy to destroy the body's tiny metastases, reducing tumor recurrence and prolonging life. Multiple chemotherapy regimens based on5-fluorouracil (5-FU) have been applied to the treatment of CRC patients for30years. Due to the generation of the primary or acquired drug resistance, chemotherapy often did not show good results, even failed. In recent years, a number of novel chemotherapy drugs are emerging, such as irinotecan and oxaliplatin, however, the generation of drug resistance is still the urgent problem in chemotherapy for colorectal cancer.
Integrins belong to cell surface adhesion molecular family, which are composed of a and β subunits associated noncovalently. On the one hand, integrins combine with extracellular matrix proteins or adjacent cells, thus connecting extracellular matrix to cell skeletal system, and finally constituting the physical bracket of the tumor microenvironment. On the other hand, integrins combine with a variety of cytokines, and transduct cellular signals in a bidirectionally way, thus constituting the information transduction center for tumor microenvironment. Evidence has implicated that integrins may be involved in chemo resistance of cancers for increased expression of some integrin subunits and/or heterodimers have been found in drug resistant cells. In addition, integrins may participate in apoptosis of cancer cells induced by chemotherapeutic drugs. Blocking the link between integrins and extracellular matrix or adjacent cells, by molecular biology techniques, such as blocking antibodies and siRNA interference, can effectively inhibit drug resistance of tumors to chemotherapy. Integrins have become extremely potential targets for solving the problem of drug resistance of tumors. On this basis, doctors can analyze integrin phenotype of tumors by microarray technology and determine the most effective chemotherapy regimens. Especially, individualized treatments against specific integrin phenotype will have good prospects for clinical application.
Integrin avβ6is a subtype of integrins, which expresses strictly in epithelia and is up-regulated in parallel with embryo formation, oncogenesis and epithelial repair,whereas it ismostly undetectable in normal tissue. We have reported that avβ6plays an important role in invasion, metastasis and degradation of extracellular matrix of colon cancer. In addition, we demonstrated a direct link between avβ36and the extracellular signal-regulated kinase (ERK2), and this direct link plays a key role in regulatory function of avβ6. However, it was not known about the role of avβ6in chemo resistance of colonic or other cancers.
In the present study, we used two colon cancer cell lines SW480and HT-29and used5-FU, the representative of colorectal cancer chemotherapeutic drugs, to investigate whether avβ6participated in5-FU resistance and explored the mechanisms involved.
Section1Role of Integrin avP6in Proliferation and Apoptosis of Colon Cancer Cells with5-FU Treatment Objective This study was to investigate the role of integrin avβ6in proliferation and apoptosis of SW480and HT-29colon cancer cells with5-FU treatment.
Methods
1. SW480colon cancer cells were divided into three groups:wild-type,β6-transfectant and Mock-transfectant, Flow cytometry and western blotting were used to examine the expression of β6-integrin in three groups.
2. We generated the β6-integrin-specific shRNA expression vectors and control vectors by using pSIREN-DNR-DsRed-Express Vector plasmid, then transfected them into HT-29colon cancer cells in liposome way. HT-29colon cancer cells were divided into three groups: wild-type,β6-shRNA and control-shRNA. Flow cytometry and western blotting were used to examine the expression of β6-integrin in three groups.
3. Both SW480and HT-29colon cancer cells were exposed to5-FU under various concentrations for48h, then cell proliferation were examined by MTT assay, and IC50values at48h were also determined and compared.
4. Both SW480and HT-29colon cancer cells were exposed to5-FU under IC50concentrations for48h, and subjected to Hoechst33258nuclear staining assay and AnnexinV-FITC/PI cell apoptosis assay combined with a flow cytometer.
Results
1. Results of flow cytometry and western blotting showed that, in SW480cells, β6-transfected cells showed obvious expression of β6-integrin, while mock-transfected or wild type cells did not show obvious expression. In HT-29cells, plasmid vector based shRNA effectively down-regulated β6-integrin expression. As to av-integrin, the transfection did not result in obvious effects.
2. Results of MTT assay showed that, the survival rate was higher in SW480β6-transfected cells, compared to the wild type and mock-transfected cells in all dose points. Besides, suppression of β6-integrin by the specific siRNA resulted in markedly lower survival rate in HT-29cells.
3. Results of Hoechst33258assay and AnnexinV-FITC/PI cell apoptosis assay both showed that, apoptotic cells were fewer in SW480β6-transfected cells than the wild type or mock-transfected cells. In HT-29cells, more apoptosis occurred when β6-integrin was suppressed.
Conclusions
This part of the study revealed that, integrin avβ6protected SW480and HT-29colon cancer cells from5-FU-induced growth inhibition and apoptosis. The result provides precise theory for the study of targeted therapy or adjuvant chemotherapy for colon cancer.
Section2Effects of integrin avβ6on5-FU-related mitochondrial apoptotic pathway in colon carcinoma
Objective
This study was to investigate the effects of integrin avβ6on5-FU-related mitochondrial apoptotic pathway in colon carcinoma.
Methods
1. Cells were grouped in the same way as part I.
2. Both SW480and HT-29colon cancer cells were exposed to5-FU under IC50concentrations for48h, the expression of cytoplasmic cytochrome C, Bcl-2and Bax were examined by western blotting, the activity of caspase-3and caspase-9were examined by caspase activity detection kit.
Results
1. In SW480cells with5-FU treatment, cytochrome C released from mitochondria was evidently lower in β6-transfected cells compared to the wild type or mock-transfected cells. Both the caspase-3and caspase-9activities were lower in β6-transfected cells. In HT-29cells with5-FU treatment, suppression of β6-integrin induced higher expression of cytosolic cytochrome C and higher activities of caspase-3and caspase-9.
2. Western blotting analysis demonstrated that in SW480β6-transfected cells, theexpression of Bcl-2was higher and Bax was lower compared withthose in mock-transfected and wild type cells. Upon treatmentwith5-FU, Bcl-2expression also increased in P6-transfected cellsand remained low in mock-transfected and wild type cells. Meanwhile, Bax expression decreased in SW480β6-transfected cells andalmost remained unchanged in mock-transfected and wild typecells. This Bcl-2up-regulation and Bax down-regulation both, preand post5-FU treatment, which associated with β6-integrinexpression, was also found in HT-29cells.
Conclusions
This part of the study revealed that, integrin avβ6effectively inhibited cytochrome C releasing from the mitochondria and activating of caspase-3and caspase-9. Moreover, β6-integrin resulted in up-regulation of Bcl-2and down-regulation of Bax. Thus integrin avβ6effectively inhibited5-FU-induced mitochondrial apoptotic pathway in colon carcinoma. This part of the study identified the specific mechanism of integrin avβ6inhibition of5-FU-induced apoptosis in colon cancer, and provided precise theory for the study of targeted therapy or adjuvant chemotherapy for colon cancer.
Section3Cell signaling pathway of integrin avβ6-mediated chemoresistance of colon carcinoma
Objective
This study was to investigate the cell signaling pathway of integrin avβ6-mediated chemoresistance of colon carcinoma.
Methods
1. Cells were grouped in the same way as part Ⅰ. Expression of MAPK signal transduction pathway critical factors, such as phosphorylated/total ERK (p/t-ERK), phosphorylated/total JNK (p/t-JNK) and phosphorylated/total p-p38(p/t-p38) were examined by western blotting.
2. Cells were grouped in the same way as part I. After ERK/MAPK signal transduction pathway was blocked, both SW480and HT-29colon cancer cells were exposed to5-FU under IC50concentrations for48h, then cell proliferation were examined by MTT assay, cell apoptosis were examined by AnnexinV-FITC/PI cell apoptosis assay combined with a flow cytometer.
3. SW480colon cancer cells were divided into three groups:β6-transfectant, Mock-transfectant and β6Mutant-transfectant(in which β6-integrin lost the ERK2binding site). Cells were exposed to5-FU under IC50concentrations for48h, then cell proliferation were examined by MTT assay, cell apoptosis were examined by AnnexinV-FITC/PI cell apoptosis assay combined with a flow cytometer, and expression of Bcl-2and Bax were examined by western blotting.
Results
1. Western blotting analysis demonstrated that higher expression of p-ERK1/2was associated with β6-integrin expression in both SW480and HT-29cells. The expression of t-ERK1/2, same as p/t-JNK and p/t-p38, were not obviously affected by β6-integrin expression.
2. Results of MTT assay and AnnexinV-FITC/PI cell apoptosis assay showed that, PD98059effectively reverted β6-integrin-mediated chemo resistance to5-FU.
3. When β6-integrin lost the ERK2binding site, β6-integrin-mediated chemoresistance to5-FU was markedly inhibited. In addition, β6-integrin-mediated Bcl-2up-regulation and Bax down-regulation both pre and post5-FU treatment, were also inhibited.
Conclusions
This part of the study revealed that, integrin avβ6induced5-FU resistance in colon cancer cells through the ERK/MAPK pathway and largely depending on the b6-ERK2direct binding. This part of the study identified the specific cell signaling pathway of integrin avβ6-mediated5-FU resistance in colon cancer, and provided precise theory for the study of targeted therapy or adjuvant chemotherapy for colon cancer.
Part Ⅱ
Expression of Integrin αvβ6in Different Thyroid Tissues and its Relationship with Clinicopathological Features of Thyroid Carcinoma Patients
Background
Thyroid carcinoma accounts for no more than2%of all human carcinomas, but the incidence rate over the past decades has consistently increased. Although most thyroid carcinomas have a low malignancy potential, are curable with surgery, and have a good responsiveness to radioiodine, diagnostic difficulties still remain. Fine needle aspiration (FNA) biopsy is currently the most accurate diagnostic method for thyroid carcinoma, but doctors or pathologists are unable to reach a consensus on the pathological diagnosis for as many as30%of these FNA biopsies. This low yield consensus is due to many papillary and follicular tumors appearing structurally similar to normal follicular tissue. In many cases, an unnecessary thyroidectomy was performed that in retrospect was a benign tumor. Additionally, some patients develop more aggressive forms of the disease including lymphatic and distant metastasis. Papillary carcinoma, which accounts for the majority of thyroid carcinomas, has a characteristic early stage lymph node metastasis. Studies have shown that patients over the age of45with lateral or mediastinal cervical lymph node metastasis have an increased risk of death from this disease. Thus, it is needed to identify new molecular markers to increase diagnostic accuracy and predict the metastatic potential for thyroid carcinoma.
As members of the cell adhesion molecular family, integrins are composed of a and β subunits associated noncovalently. Integrins are not only receptors for extracellular matrix protein cell adhesion but also transmembrane connections for bidirectional cellular signal pathway transduction.αvβ6is a subtype of integrins, expressed strictly in epithelia, up-regulated in parallel with embryo formation, oncogenesis and epithelial repair, and rarely expressed in normal tissue. Previously studies showed that integrin αvβ6played an important role in invasion, prolifration, apoptosis, tumor immunity and EMT of malignant tumors. It is worth noting that avP6expression was closely related with clinicopathological features of many carcinomas, as well as patients prognosis. In colon cancer, the median survival time of patients with high expression of avβ6, compared with patients with no or low expression of avβ6, was significantly shorter. In stomach carcinoma, avP6expression is closely associated with Lauren type, differentiation, N stage and TNM stage. More importantly, avP6expression is linked to significantly reduced survival times. In addition, in oral squamous cell carcinoma, breast carcinoma and ovarian carcinoma, the relationship between avP6expression and the clinicopathological features of carcinomas, as well as patients prognosis, has also been confirmed by studies.
There is still mystery about avβ6expression in the thyroid. In this study, we examined avP6expression in a series of malignant and non-malignant thyroid tissue. Furthermore, we investigated the relationship between avβ6expression and the clinicopathological features of patients with thyroid carcinoma.
Objective
This study was to examine integrin avP6expression in different thyroid tissues by immunohistochemistry and investigated the relationship between avβ6and clinicopathological features of thyroid carcinoma patients.
Methods
1. Purchased microarray containing a variety of thyroid tissues, and collectted thyroid cancer tissue samples and patient information from the Department of Pathology, QiLu Hospital. Before the study, all cases were reviewed for diagnostic confirmation.
2. avβ6expression in different thyroid tissues was examined by immunohistochemistry, and the results were evaluated according to the criteria established.
3. Compared avβ6expression in different thyroid tissues, and explored the relationship between avβ6expression and clinicopathological characteristics of patients with thyroid cancer, including age, gender, histological type, TNM stage, etc.
Results
1. avβ6expression was significantly different among tissues with different histopathological types. In normal thyroid tissue, carcinoma adjacent normal tissue, and thyroid adenomas, avP6expression was generally negative or weak. Among them,10cases of normal thyroid tissue were consistently avβ6-negative. Only1out of10cases in carcinoma adjacent normal tissue and3out of10cases in thyroid adenomas were avβ6-positive. Thyroid goiters and thyroiditis tissue both showed wide and strong avβ6expression with7out of10cases in thyroid goiters and8out of10cases in thyroiditis tissue as avβ6-positive. In thyroid carcinomas, expression was positive and strong in71out of90cases. In addition,10cases of metastatic lymph node tissue from papillary thyroid carcinoma showed consistent and strong avP6expression
2. avβ6expression distinguished thyroid carcinoma from non-malignant tissues with a sensitivity of78.89%and specificity of62%. The predictive positive value was78.89%and the predictive negative value was62%. avβ6expression differentiated thyroid carcinoma from normal thyroid tissue, carcinoma adjacent normal tissue, and thyroid adenoma. According to the level of avβ6expression, it is impossible to differentiate thyroid carcinoma from thyroid nodular goiter and thyroiditis tissue. There was no significant difference in avβ6expression between papillary and follicular thyroid carcinoma.
3. Analysis showed that there was no statistical difference between avβ6-positive and avP6-negative tumors regarding gender, histopathological patterns, T stage and TNM stage, but statistical differences existed regarding patient age and N stage.
Conclusions
This study showed that avβ6expression was significantly different among tissues with different histopathological types. avβ6expression distinguished thyroid carcinoma from non-malignant thyroid tissues with a good sensitivity and specificity. Additionally, avP6expression was closely related to lymph node metastasis from thyroid carcinoma. A potentially consequence of our work is that detection of avβ6expression may help supplement FNA biopsy to increase diagnostic accuracy and help predict the potential lymph node metastasis of thyroid carcinoma.
整合素αvβ6在结肠癌细胞化疗耐药中的作用研究
研究背景
结直肠癌是世界范围内发病率居第三位,致死率居第四位的恶性消化道肿瘤。近年来随着环境污染日益严重和人们饮食结构的变化,结直肠癌的发病率和死亡率逐步上升。目前,手术切除仍然是治疗结直肠癌的主要方式。然而,在可切除的结直肠癌患者中,大约50%患者将会复发,其中绝大部分患者失去再治愈的机会。目前研究认为,Ⅲ期结直肠癌病人术后需全身辅助化疗以消灭体内的微小转移病变,减少肿瘤复发及改善生存。以5-氟尿嘧啶(5-fluorouracil,5-FU)为基础的多种化疗方案应用于临床已达30余年,但因原发性或获得性耐药的产生,化疗往往达不到满意效果甚至归于失败。虽然近年不断涌现一批新颖的化疗药物,如伊立替康、奥沙利铂等,耐药性的产生仍是目前结直肠癌化疗领域亟待解决的问题。
整合素是细胞表面粘附分子的一种,由α和β两种亚基结合而成,目前已发现由18种α亚基和8种β亚基组成的24种整合素成员。一方面,整合素在胞外连接基质蛋白或相邻细胞,在胞内连接细胞骨架系统,从而构成肿瘤细胞赖以生存发展的空间纽带；另一方面,整合素作为受体可与多种细胞因子结合,从而向细胞内外双向传导生物信息,构成肿瘤细胞感受外界刺激并作出相应反应的的信息枢纽。研究发现,整合素参与了肿瘤化疗耐药过程。在肿瘤耐药株已发现多种整合素亚型表达上调。另外,整合素可能参与了化疗药物诱导的肿瘤细胞凋亡过程。应用各种分子生物学技术,如抗体阻断,siRNA干扰等,阻断整合素与胞外基质及细胞之间的连接,可有效抑制肿瘤细胞的化疗耐药性。整合素成为解决肿瘤化疗耐药的极有潜力的靶向目标。在此基础上,应用微阵列技术分析肿瘤的整合素表型,可以选择最有效的化疗药物或化疗方案,而针对这些表型进行个体化治疗,将具有良好的临床应用前景。
整合素αvβ6仅在上皮组织表达,在胚胎形成、组织修复过程及某些癌组织表达增强,而在正常组织和良性肿瘤组织几无表达。我们前期研究发现：αvβ6在结肠癌侵袭转移、胞外基质降解等肿瘤恶性生物学行为发挥重要作用。另外,αvβ6与ERK2之间存在着生理性直接连接,该直接连接对αvβ6在结肠癌发挥调控功能起着关键作用。然而,αvβ6是否在结直肠癌化疗耐药过程发挥作用迄今尚不明确。在上述背景下,本研究拟选择两种结肠癌细胞系SW480和HT-29及结直肠癌化疗代表性药物-5-FU,在细胞水平深入研究αvβ6是否在结肠癌化疗耐药过程发挥作用并探索其作用机制。
第一节整合素αvβ6对5-FU作用下结肠癌细胞增殖和凋亡的影响
目的
研究整合素αvβ6对5-FU诱导的SW480和HT-29结肠癌细胞增殖抑制及凋亡的影响。
方法
1.SW480结肠癌细胞分为野生组(SW480wild-type)、已稳定转染含p6基因质粒组(SW480(36-transfectant)和转染空白质粒组(SW480Mock-transfectant),分别用流式细胞术、western blotting实验检测三组细胞αvβ6蛋白的表达情况。
2.利用pSIREN-DNR-DsRed-Express Vector质粒构建p6特异性shRNA表达载体及对照组载体,以脂质体法转染至HT-29结肠癌细胞,分别用流式细胞术、western blotting实验检钡HT-29wild-type、β6-shRNA、control-shRNA三组细胞αvβ6蛋白的表达情况。
3.以不同浓度5-FU(0.2、1、5、25、125μg/mL)作用于SW480和HT-29各组细胞48h,MTT法检测细胞增殖抑制情况,并计算比较IC50。
4.以48h IC50浓度的5-FU作用于SW480和HT-29各组细胞48h, Hoechst33258凋亡形态法和流式细胞术检测细胞凋亡情况。
结果
1.流式细胞术及western blotting实验均表明,稳定转染含β6基因质粒的SW480细胞(SW480β6-transfectant)显著表达整合素β6,而野生型细胞或转染空白质粒细胞不表达整合素β6,三组细胞整合素αv的表达无明显差异。
2.流式细胞术及western blotting实验均表明,与control-shRNA比较,β6-shRNA可显著降低HT-29细胞整合素p6的表达,但对整合素αv的表达无明显影响。
3.MTT实验表明,在不同浓度5-FU作用下,SW480β6-transfectant组细胞存活率均高于SW480wild-type及Mock-transfectant组；在HT-29细胞,p6-shRNA可显著降低5-FU作用下的细胞存活率。
4.Hoechst33258凋亡形态法和流式细胞术实验均标明,在不同浓度5-FU作用下,SW480p6-transfectant组细胞凋亡率均低于SW480wild-type及Mock-transfectant组;在HT-29细胞,p6-shRNA可显著提高5-FU作用下的细胞凋亡率。
结论及意义
本节研究揭示,在结肠癌SW480和HT-29细胞,整合素αvβ6均可保护细胞抑制5-FU诱导的增殖抑制及凋亡从而增强结肠癌细胞的化疗耐药能力,丰富了整合素αvβ6的理论知识,并为结肠癌的靶向治疗或辅助化疗研究提供了确切的理论依据。
第二节整合素αvβ6对5-FU诱导的结肠癌细胞线粒体凋亡途径的影响
目的
研究整合素αvβ6对5-FU诱导的SW480和HT-29结肠癌细胞线粒体凋亡途径的影响。
方法
1.细胞分组同第一节。
2.以48h IC50浓度的5-FU作用于SW480和HT-29各组细胞48h, western blotting实验检测胞浆cytochrome C表达情况。
3.以48h IC50浓度的5-FU作用于SW480和HT-29各组细胞48h,活性检测试剂盒检测caspase-3和caspase-9活性情况。
4.以48h IC50浓度的5-FU作用于SW480和HT-29各组细胞48h, western blotting实验检测Bcl-2和Bax蛋白表达情况。
结果
1.western blotting实验表明,在5-FU作用下,SW480三组细胞的胞浆cytochrome C表达均有增强,但β6-transfectant组细胞胞浆cytochrome C增强程度显著低于SW480wild-type及Mock-transfectant组；在HT-29细胞,与wild-type或control-shRNA组比较,β6-shRNA使5-FU介导的胞浆cytochrome C的表达进一步增强。
2.活性检测试剂盒实验表明,在5-FU作用下,SW480三组细胞的caspase-3和caspase-9活性均有增强,但β6-transfectant组细胞增强程度显著低于SW480wild-type及Mock-transfectant组；在HT-29细胞,与wild-type或control-shRNA组比较,β6-shRNA使5-FU介导的caspase-3和caspase-9活性增强进一步加剧。
3. western blotting实验表明,在5-FU作用前后,SW480p6-transfectant组细胞Bcl-2表达明显高于wild-type及Mock-transfectant组,而Bax表达低于后二组；在HT-29细胞,与wild-type或control-shRNA组比较,P6-shRNA可显著抑制Bcl-2表达而增强Bax表达,这种现象在5-FU作用前后均可发现。
结论及意义
本节实验揭示,在结肠癌SW480和HT-29细胞,整合素αvβ6均可有效抑制5-FU诱导的线粒体凋亡途径,包括抑制胞浆cytochrome C水平升高,抑制caspase-3和caspase-9活性增强,上调凋亡调节蛋白Bcl-2表达而下调Bax表达等。本节研究明确了整合素αvβ6抑制5-FU诱导的结肠癌细胞凋亡的具体机制,丰富了整合素αvβ6的理论知识,并为结肠癌的靶向治疗或辅助化疗研究提供了确切的理论依据。
第三节整合素αvβ6介导结肠癌化疗耐药的细胞信号通路研究
目的
研究整合素αvβ6增强SW480和HT-29结肠癌细胞化疗耐药能力的相关细胞信号传导通路。
方法
1.细胞分组同第一节,western blotting实验检测各组细胞MAPK信号传导通路关键因子磷酸化／总ERK (p/t-ERK)、磷酸化/总,fNK (p/t-JNK)和磷酸化/总p-p38(p/t-p38)的表达情况。
2.细胞分组同第一节,以PD98059阻断ERK/MAPK信号传导通路,以48h IC50浓度的5-FU作用于SW480和HT-29各组细胞48h,MTT实验检测细胞增殖,Annexin V/PI-流式细胞术检测细胞凋亡。
3.SW480结肠癌细胞分为已稳定转染含p6基因质粒组(SW480β6-transfectant)、转染空白质粒组(SW480Mock-transfectant)和转染含β6突变基因质粒组(转染表达的β6蛋白缺失与ERK2的结合位点)(SW480p6Mutant-transfectant);以48h IC50浓度的5-FU作用于SW480各组细胞48h,MTT实验检测细胞增殖,Annexin V/PI-流式细胞术检测细胞凋亡,western blotting实验检测凋亡相关分子Bcl-2和Bax表达情况。
结果
1.western blotting实验表明,转染表达β6可明显增强SW480细胞p-ERK的表达,而β36-shRNA可明显抑制HT-29细胞p-ERK的表达；p6表达对t-ERK、p/t-JNK、p/t-p38的表达无显著影响。
2.MTT增殖抑制实验及流式细胞术标明,以PD98059阻断ERK/MAPK信号传导通路,可有效抑制整合素αvβ6介导的结肠癌细胞对5-FU的化疗耐药。
3.整合素p6缺失与ERK2的结合位点,可显著抑制整合素αvβ6介导的p-ERK、Bcl-2表达增强及Bax表达降低,有效抑制整合素αvβ6介导的结肠癌细胞对5-FU的化疗耐药。
结论及意义
本节实验揭示,整合素αvβ6通过ERK/MAPK信号传导通路介导结肠癌SW480和HT-29细胞对5-FU的化疗耐药,并在很大程度上依赖于p6与ERK2的直接结合。本节研究明确了整合素αvβ6介导结肠癌化疗耐药的具体信号传导通路,丰富了整合素αvβ6的理论知识,并为结肠癌的靶向治疗或辅助化疗研究提供了确切的理论依据。
第二部分
整合素αvβ6在甲状腺组织的表达及与甲状腺癌临床病理特征的关系
研究背景
甲状腺癌发病率在人类全部癌症不超过2%,但几十年来其发病率一直在上升。目前,大多数甲状腺癌为低度恶性,可用手术治愈的并对放射性碘具有良好的反应性。然而甲状腺癌的诊断治疗仍然存在一些问题。首先,细针抽吸活检(fine needle aspiration, FNA)是目前甲状腺癌最准确的诊断方法,但多达30%的病例仍然存在诊断困难。原因是许多乳头和滤泡状甲状腺癌在结构上类似于正常甲状腺滤泡组织而使人无法做出确切判断。出于避免遗漏恶性肿瘤的目的,在很多诊断困难情况下往往施行大范围的手术切除,而术后才发现为良性肿瘤。其次,一些甲状腺癌具有侵袭转移倾向,包括淋巴结转移和远处转移,而这一点可能影响患者治疗和预后。例如,占甲状腺癌绝大多数的乳头状癌具有特征性的早期淋巴结转移倾向。有研究表明,甲状腺癌患者年龄45岁以上且合并纵隔或颈部淋巴结转移者,其死亡风险显著增加。在上述情况下,需要寻找一种合适的分子标志物,以增加诊断的准确性和预测甲状腺癌转移潜能。
整合素是细胞表面粘附分子的一种,由α和β两种亚基结合而成,目前已发现由18种α亚基和8种β亚基组成的24种整合素成员。一方面,整合素在胞外连接基质蛋白或相邻细胞,在胞内连接细胞骨架系统,从而构成肿瘤细胞赖以生存发展的空间纽带；另一方面,整合素作为受体可与多种细胞因子结合,从而向细胞内外双向传导生物信息,构成肿瘤细胞感受外界刺激并作出相应反应的的信息枢纽。
αvβ6属于整合素的一种亚型,仅在上皮组织表达,在胚胎形成、组织修复过程及某些癌组织表达增强,而在正常组织和良性肿瘤组织几无表达。研究发现,αvβ6参与了多种恶性肿瘤侵袭转移、增殖凋亡、肿瘤免疫、EMT等生物学功能。值得注意的是,整合素αvβ6表达与多种肿瘤的临床病理特征及病人预后密切相关。在结肠癌,高表达αvβ6的结肠癌患者,与不表达或低表达者相比,其中位生存期明显缩短；对早期结肠癌患者,高表达β6的患者其5年和10年生存率明显降低。在胃癌,αvβ6的表达与Lauren分型、细胞分化、N分期及TNM分期密切相关。重要的是,αvβ6阳性患者其生存期明显短于αvβ6阴性者。另外,在口腔鳞癌,乳腺癌及卵巢癌等,αvβ6表达与肿瘤的临床病理特征及病人预后的关系也得到研究证实。
然而,αvβ6在甲状腺癌的表达情况迄今未明。本研究利用免疫组织化学方法检测了一系列恶性和非恶性的甲状腺组织中αvβ6的表达。此外,我们利用统计学方法研究了αvβ6表达与甲状腺癌患者临床病理特征之间的关系。
目的
检测整合素αvβ6在各种甲状腺组织中的表达,研究整合素αvβ6与甲状腺癌临床病理特征的关系。
方法
1.购买含有多种甲状腺组织的微阵列芯片,从齐鲁医院病理科收集甲状腺癌组织标本及病人临床病理信息。在研究之前,所有病例均邀请病理科专家进行确诊。
2.免疫组织化学方法检测标本中αvβ6表达情况,并按确定的标准进行评分。
3.比较不同甲状腺组织的αvβ6表达差异；研究αvβ6表达与甲状腺癌患者临床病理特征之间的相关性,包括年龄、性别、病理类型、TNM分期等。
结果
1.整合素αvβ6在不同甲状腺组织的表达存在显著差异。在正常甲状腺组织,癌旁组织,甲状腺腺瘤,整合素αvβ6表达一般为阴性或弱阳性。其中,10例(10/10)正常甲状腺组织均未检测出αvβ6表达,只有1例(1/10)癌旁组织和3例(3/10)甲状腺腺瘤组织αvβ6表达阳性。整合素αvβ6在甲状腺肿组织和甲状腺炎组织多有广泛而较强表达,其中7例(7/10)甲状腺肿组织及8例(8/10)甲状腺炎组织αvβ6表达阳性。在甲状腺癌,有71例(71/90)αvβ6表达阳性。此外,10例(10/10)甲状腺乳头状癌淋巴结转移灶均检测有αvβ6的表达。
2.αvβ6表达区别甲状腺癌和非恶性甲状腺组织的灵敏度为78.89%,特异度为62%,预测阳性值为78.89%,而预测值阴性率为62%。检测αvβ6表达可成功区别甲状腺癌与正常甲状腺组织、癌旁正常组织和甲状腺腺瘤,但不能区别甲状腺癌与结节性甲状腺肿和甲状腺炎组织。此外,乳头状甲状腺癌和滤泡状甲状腺癌之间的αvβ6表达无显著差异。
3.αvβ6表达与甲状腺癌患者的性别、肿瘤组织学形态、T分期和TNM分期之间无相关性,但和患者的年龄和N分期有相关性。
结论及意义
本研究表明整合素αvβ6在不同甲状腺组织的表达存在显著差异,检测avβ6表达以区别非恶性甲状腺组织和甲状腺癌具有良好的灵敏度和特异性。此外,整合素avβ6的表达与甲状腺癌淋巴结转移有密切相关性。在这个意义上,检测整合素avβ6的表达可能有助于补充FNA活检以提高诊断的准确性,并帮助预测甲状腺癌潜在的淋巴转移倾向。
Part Ⅰ
Role of Integrin αvβ6in Chemo Resistance of Colon Carcinoma
Background
Colorectal cancer (CRC) is the third most prevalent cancer and the fourth leading cause of cancer deaths worldwide. With the increasingly serious environmental pollution and the change of people's diet in recent years, the incidence and mortality rates of colorectal cancer have gradually increased. Currently, surgical resection is still the main treatment for colorectal cancer. However, tumor recurrence was found in about50%of resectable colorectal cancers, and most patients lose the opportunity of cure. Present study suggests that, CRC patients with stage III need systemic adjuvant chemotherapy to destroy the body's tiny metastases, reducing tumor recurrence and prolonging life. Multiple chemotherapy regimens based on5-fluorouracil (5-FU) have been applied to the treatment of CRC patients for30years. Due to the generation of the primary or acquired drug resistance, chemotherapy often did not show good results, even failed. In recent years, a number of novel chemotherapy drugs are emerging, such as irinotecan and oxaliplatin, however, the generation of drug resistance is still the urgent problem in chemotherapy for colorectal cancer.
Integrins belong to cell surface adhesion molecular family, which are composed of a and β subunits associated noncovalently. On the one hand, integrins combine with extracellular matrix proteins or adjacent cells, thus connecting extracellular matrix to cell skeletal system, and finally constituting the physical bracket of the tumor microenvironment. On the other hand, integrins combine with a variety of cytokines, and transduct cellular signals in a bidirectionally way, thus constituting the information transduction center for tumor microenvironment. Evidence has implicated that integrins may be involved in chemo resistance of cancers for increased expression of some integrin subunits and/or heterodimers have been found in drug resistant cells. In addition, integrins may participate in apoptosis of cancer cells induced by chemotherapeutic drugs. Blocking the link between integrins and extracellular matrix or adjacent cells, by molecular biology techniques, such as blocking antibodies and siRNA interference, can effectively inhibit drug resistance of tumors to chemotherapy. Integrins have become extremely potential targets for solving the problem of drug resistance of tumors. On this basis, doctors can analyze integrin phenotype of tumors by microarray technology and determine the most effective chemotherapy regimens. Especially, individualized treatments against specific integrin phenotype will have good prospects for clinical application.
Integrin avβ6is a subtype of integrins, which expresses strictly in epithelia and is up-regulated in parallel with embryo formation, oncogenesis and epithelial repair,whereas it ismostly undetectable in normal tissue. We have reported that avβ6plays an important role in invasion, metastasis and degradation of extracellular matrix of colon cancer. In addition, we demonstrated a direct link between avβ36and the extracellular signal-regulated kinase (ERK2), and this direct link plays a key role in regulatory function of avβ6. However, it was not known about the role of avβ6in chemo resistance of colonic or other cancers.
In the present study, we used two colon cancer cell lines SW480and HT-29and used5-FU, the representative of colorectal cancer chemotherapeutic drugs, to investigate whether avβ6participated in5-FU resistance and explored the mechanisms involved.
Section1Role of Integrin avP6in Proliferation and Apoptosis of Colon Cancer Cells with5-FU Treatment Objective This study was to investigate the role of integrin avβ6in proliferation and apoptosis of SW480and HT-29colon cancer cells with5-FU treatment.
Methods
1. SW480colon cancer cells were divided into three groups:wild-type,β6-transfectant and Mock-transfectant, Flow cytometry and western blotting were used to examine the expression of β6-integrin in three groups.
2. We generated the β6-integrin-specific shRNA expression vectors and control vectors by using pSIREN-DNR-DsRed-Express Vector plasmid, then transfected them into HT-29colon cancer cells in liposome way. HT-29colon cancer cells were divided into three groups: wild-type,β6-shRNA and control-shRNA. Flow cytometry and western blotting were used to examine the expression of β6-integrin in three groups.
3. Both SW480and HT-29colon cancer cells were exposed to5-FU under various concentrations for48h, then cell proliferation were examined by MTT assay, and IC50values at48h were also determined and compared.
4. Both SW480and HT-29colon cancer cells were exposed to5-FU under IC50concentrations for48h, and subjected to Hoechst33258nuclear staining assay and AnnexinV-FITC/PI cell apoptosis assay combined with a flow cytometer.
Results
1. Results of flow cytometry and western blotting showed that, in SW480cells, β6-transfected cells showed obvious expression of β6-integrin, while mock-transfected or wild type cells did not show obvious expression. In HT-29cells, plasmid vector based shRNA effectively down-regulated β6-integrin expression. As to av-integrin, the transfection did not result in obvious effects.
2. Results of MTT assay showed that, the survival rate was higher in SW480β6-transfected cells, compared to the wild type and mock-transfected cells in all dose points. Besides, suppression of β6-integrin by the specific siRNA resulted in markedly lower survival rate in HT-29cells.
3. Results of Hoechst33258assay and AnnexinV-FITC/PI cell apoptosis assay both showed that, apoptotic cells were fewer in SW480β6-transfected cells than the wild type or mock-transfected cells. In HT-29cells, more apoptosis occurred when β6-integrin was suppressed.
Conclusions
This part of the study revealed that, integrin avβ6protected SW480and HT-29colon cancer cells from5-FU-induced growth inhibition and apoptosis. The result provides precise theory for the study of targeted therapy or adjuvant chemotherapy for colon cancer.
Section2Effects of integrin avβ6on5-FU-related mitochondrial apoptotic pathway in colon carcinoma
Objective
This study was to investigate the effects of integrin avβ6on5-FU-related mitochondrial apoptotic pathway in colon carcinoma.
Methods
1. Cells were grouped in the same way as part I.
2. Both SW480and HT-29colon cancer cells were exposed to5-FU under IC50concentrations for48h, the expression of cytoplasmic cytochrome C, Bcl-2and Bax were examined by western blotting, the activity of caspase-3and caspase-9were examined by caspase activity detection kit.
Results
1. In SW480cells with5-FU treatment, cytochrome C released from mitochondria was evidently lower in β6-transfected cells compared to the wild type or mock-transfected cells. Both the caspase-3and caspase-9activities were lower in β6-transfected cells. In HT-29cells with5-FU treatment, suppression of β6-integrin induced higher expression of cytosolic cytochrome C and higher activities of caspase-3and caspase-9.
2. Western blotting analysis demonstrated that in SW480β6-transfected cells, theexpression of Bcl-2was higher and Bax was lower compared withthose in mock-transfected and wild type cells. Upon treatmentwith5-FU, Bcl-2expression also increased in P6-transfected cellsand remained low in mock-transfected and wild type cells. Meanwhile, Bax expression decreased in SW480β6-transfected cells andalmost remained unchanged in mock-transfected and wild typecells. This Bcl-2up-regulation and Bax down-regulation both, preand post5-FU treatment, which associated with β6-integrinexpression, was also found in HT-29cells.
Conclusions
This part of the study revealed that, integrin avβ6effectively inhibited cytochrome C releasing from the mitochondria and activating of caspase-3and caspase-9. Moreover, β6-integrin resulted in up-regulation of Bcl-2and down-regulation of Bax. Thus integrin avβ6effectively inhibited5-FU-induced mitochondrial apoptotic pathway in colon carcinoma. This part of the study identified the specific mechanism of integrin avβ6inhibition of5-FU-induced apoptosis in colon cancer, and provided precise theory for the study of targeted therapy or adjuvant chemotherapy for colon cancer.
Section3Cell signaling pathway of integrin avβ6-mediated chemoresistance of colon carcinoma
Objective
This study was to investigate the cell signaling pathway of integrin avβ6-mediated chemoresistance of colon carcinoma.
Methods
1. Cells were grouped in the same way as part Ⅰ. Expression of MAPK signal transduction pathway critical factors, such as phosphorylated/total ERK (p/t-ERK), phosphorylated/total JNK (p/t-JNK) and phosphorylated/total p-p38(p/t-p38) were examined by western blotting.
2. Cells were grouped in the same way as part I. After ERK/MAPK signal transduction pathway was blocked, both SW480and HT-29colon cancer cells were exposed to5-FU under IC50concentrations for48h, then cell proliferation were examined by MTT assay, cell apoptosis were examined by AnnexinV-FITC/PI cell apoptosis assay combined with a flow cytometer.
3. SW480colon cancer cells were divided into three groups:β6-transfectant, Mock-transfectant and β6Mutant-transfectant(in which β6-integrin lost the ERK2binding site). Cells were exposed to5-FU under IC50concentrations for48h, then cell proliferation were examined by MTT assay, cell apoptosis were examined by AnnexinV-FITC/PI cell apoptosis assay combined with a flow cytometer, and expression of Bcl-2and Bax were examined by western blotting.
Results
1. Western blotting analysis demonstrated that higher expression of p-ERK1/2was associated with β6-integrin expression in both SW480and HT-29cells. The expression of t-ERK1/2, same as p/t-JNK and p/t-p38, were not obviously affected by β6-integrin expression.
2. Results of MTT assay and AnnexinV-FITC/PI cell apoptosis assay showed that, PD98059effectively reverted β6-integrin-mediated chemo resistance to5-FU.
3. When β6-integrin lost the ERK2binding site, β6-integrin-mediated chemoresistance to5-FU was markedly inhibited. In addition, β6-integrin-mediated Bcl-2up-regulation and Bax down-regulation both pre and post5-FU treatment, were also inhibited.
Conclusions
This part of the study revealed that, integrin avβ6induced5-FU resistance in colon cancer cells through the ERK/MAPK pathway and largely depending on the b6-ERK2direct binding. This part of the study identified the specific cell signaling pathway of integrin avβ6-mediated5-FU resistance in colon cancer, and provided precise theory for the study of targeted therapy or adjuvant chemotherapy for colon cancer.
Part Ⅱ
Expression of Integrin αvβ6in Different Thyroid Tissues and its Relationship with Clinicopathological Features of Thyroid Carcinoma Patients
Background
Thyroid carcinoma accounts for no more than2%of all human carcinomas, but the incidence rate over the past decades has consistently increased. Although most thyroid carcinomas have a low malignancy potential, are curable with surgery, and have a good responsiveness to radioiodine, diagnostic difficulties still remain. Fine needle aspiration (FNA) biopsy is currently the most accurate diagnostic method for thyroid carcinoma, but doctors or pathologists are unable to reach a consensus on the pathological diagnosis for as many as30%of these FNA biopsies. This low yield consensus is due to many papillary and follicular tumors appearing structurally similar to normal follicular tissue. In many cases, an unnecessary thyroidectomy was performed that in retrospect was a benign tumor. Additionally, some patients develop more aggressive forms of the disease including lymphatic and distant metastasis. Papillary carcinoma, which accounts for the majority of thyroid carcinomas, has a characteristic early stage lymph node metastasis. Studies have shown that patients over the age of45with lateral or mediastinal cervical lymph node metastasis have an increased risk of death from this disease. Thus, it is needed to identify new molecular markers to increase diagnostic accuracy and predict the metastatic potential for thyroid carcinoma.
As members of the cell adhesion molecular family, integrins are composed of a and β subunits associated noncovalently. Integrins are not only receptors for extracellular matrix protein cell adhesion but also transmembrane connections for bidirectional cellular signal pathway transduction.αvβ6is a subtype of integrins, expressed strictly in epithelia, up-regulated in parallel with embryo formation, oncogenesis and epithelial repair, and rarely expressed in normal tissue. Previously studies showed that integrin αvβ6played an important role in invasion, prolifration, apoptosis, tumor immunity and EMT of malignant tumors. It is worth noting that avP6expression was closely related with clinicopathological features of many carcinomas, as well as patients prognosis. In colon cancer, the median survival time of patients with high expression of avβ6, compared with patients with no or low expression of avβ6, was significantly shorter. In stomach carcinoma, avP6expression is closely associated with Lauren type, differentiation, N stage and TNM stage. More importantly, avP6expression is linked to significantly reduced survival times. In addition, in oral squamous cell carcinoma, breast carcinoma and ovarian carcinoma, the relationship between avP6expression and the clinicopathological features of carcinomas, as well as patients prognosis, has also been confirmed by studies.
There is still mystery about avβ6expression in the thyroid. In this study, we examined avP6expression in a series of malignant and non-malignant thyroid tissue. Furthermore, we investigated the relationship between avβ6expression and the clinicopathological features of patients with thyroid carcinoma.
Objective
This study was to examine integrin avP6expression in different thyroid tissues by immunohistochemistry and investigated the relationship between avβ6and clinicopathological features of thyroid carcinoma patients.
Methods
1. Purchased microarray containing a variety of thyroid tissues, and collectted thyroid cancer tissue samples and patient information from the Department of Pathology, QiLu Hospital. Before the study, all cases were reviewed for diagnostic confirmation.
2. avβ6expression in different thyroid tissues was examined by immunohistochemistry, and the results were evaluated according to the criteria established.
3. Compared avβ6expression in different thyroid tissues, and explored the relationship between avβ6expression and clinicopathological characteristics of patients with thyroid cancer, including age, gender, histological type, TNM stage, etc.
Results
1. avβ6expression was significantly different among tissues with different histopathological types. In normal thyroid tissue, carcinoma adjacent normal tissue, and thyroid adenomas, avP6expression was generally negative or weak. Among them,10cases of normal thyroid tissue were consistently avβ6-negative. Only1out of10cases in carcinoma adjacent normal tissue and3out of10cases in thyroid adenomas were avβ6-positive. Thyroid goiters and thyroiditis tissue both showed wide and strong avβ6expression with7out of10cases in thyroid goiters and8out of10cases in thyroiditis tissue as avβ6-positive. In thyroid carcinomas, expression was positive and strong in71out of90cases. In addition,10cases of metastatic lymph node tissue from papillary thyroid carcinoma showed consistent and strong avP6expression
2. avβ6expression distinguished thyroid carcinoma from non-malignant tissues with a sensitivity of78.89%and specificity of62%. The predictive positive value was78.89%and the predictive negative value was62%. avβ6expression differentiated thyroid carcinoma from normal thyroid tissue, carcinoma adjacent normal tissue, and thyroid adenoma. According to the level of avβ6expression, it is impossible to differentiate thyroid carcinoma from thyroid nodular goiter and thyroiditis tissue. There was no significant difference in avβ6expression between papillary and follicular thyroid carcinoma.
3. Analysis showed that there was no statistical difference between avβ6-positive and avP6-negative tumors regarding gender, histopathological patterns, T stage and TNM stage, but statistical differences existed regarding patient age and N stage.
Conclusions
This study showed that avβ6expression was significantly different among tissues with different histopathological types. avβ6expression distinguished thyroid carcinoma from non-malignant thyroid tissues with a good sensitivity and specificity. Additionally, avP6expression was closely related to lymph node metastasis from thyroid carcinoma. A potentially consequence of our work is that detection of avβ6expression may help supplement FNA biopsy to increase diagnostic accuracy and help predict the potential lymph node metastasis of thyroid carcinoma.
引文
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