Claudin蛋白在紧密连接中的作用机制及与疾病的关系

Claudin蛋白是组成细胞间紧密连接的一种跨膜蛋白,它的功能主要是调节屏障结构的渗透性。细胞间紧密连接的稳定性与Claudin蛋白间及Claudin蛋白与其他紧密连接蛋白间复杂的相互作用有关。Claudin蛋白的转录及表达的调节机制有磷酸化、去磷酸化等。人类很多疾病与Claudin蛋白的突变有关,至今为止,关于Claudin蛋白的了解不仅停留在紧密连接的组成部分,更多的是其调节方式及其与疾病发生的关系等方面的研究。本文作者对Claudin蛋白的结构、作用方式、与临床疾病的关系及其未来研究的展望作一综述。     

Claudin-1 expressions decrease in pterygium with respect to normal conjunctiva

Context: Pterygium is the fibrovascular growth of the limbal conjunctiva over cornea. This proliferative nature might have a pathogenesis associated with tight junction proteins.

Objective: To investigate the tight junction protein claudin-1 expressions in pterygium with respect to normal conjunctiva.

Materials and methods: This retrospective study included 28 patients who underwent pterygium surgery with autograft. Claudin-1 expressions were immunohistochemically evaluated in normal and lesional conjunctiva of the same eye. Immunohistochemical evaluation was done with regard of both the intensity and the extent of staining. The distribution of the immunohistochemical scores in pterygium and normal conjunctiva has been compared with using McNemar test.

Results: The mean age of the patients was 52.2?±?11.2 years and male/female ratio was 8/20. Among 28 samples of normal conjunctiva 25 (89.2%) demonstrated a strong immunohistochemical expression with claudin-1 whereas this rate was 10.8% for pterygium samples. Statistical analysis revealed a significant decrease in claudin-1 expressions in pterygium with respect to normal conjunctiva (p?<?0.001).

Discussion and conclusions: The loss of claudin-1 appears to be involved in the pathogenesis of pterygium and the future studies will elucidate the exact role of tight junction proteins in the invasive and recurrent nature of pterygium.     

Claudin-7与Slug在肺鳞癌和腺癌中的表达及其临床意义

背景与目的 Claudins是紧密连接的骨架蛋白,Claudin-7是Claudins家族成员之一。本研究旨在观察Claudin-7和Slug在肺鳞癌和腺癌中的表达及其与临床病理因素的关系,并探讨Claudin-7和Slug的相互关系。方法采用免疫组织化学SP法检测101例原发性肺鳞癌、腺癌组织中Claudin-7和Slug的表达,同时应用Westernblot检测30例新鲜肺癌组织及其配对的癌旁组织中Claudin-7和Slug的表达情况。结果 Claudin-7在肺癌中的表达明显低于正常肺组织,并且与分化程度和淋巴结转移有关(P<0.05),Slug在肺癌中的表达明显高于正常肺组织,除与分化程度和淋巴结转移有关外,还与TNM分期有关(P<0.05),肺鳞癌、腺癌中Claudin-7与Slug的表达具有负相关性(r=-0.566,8)。结论肺鳞癌、腺癌中Claudin-7的低表达与Slug的高表达可能是肺组织恶性转变和转移的有关标志物之一。     

Claudin expression in Barrett's esophagus and adenocarcinoma

Claudins (CLDNs) are key molecules in cell adhesion, polarity, and control of paracellular solute transport. Several studies suggested that changes in claudin pattern have a role in cancer development. This study aimed to detect alterations in CLDN 1, 2, 3, 4, and 7 expression patterns in Barrett's esophagus (BE) and adenocarcinoma (ACC) compared with that in foveolar epithelium (FOV), normal squamous epithelium (SQ), and squamous cell carcinoma (SQCC). One hundred twenty five surgically or endoscopically removed, paraffin-embedded cases were studied by immunohistochemistry and analyzed statistically. BE, ACC, and FOV were dissected from 30 paraffin-embedded samples for further mRNA expression analysis. CLDN 7 was the dominating type in all epithelia and carcinomas, but its expression did not differ in normal and altered tissues. CLDN 1 expression was significantly increased in SQCC compared with that in SQ. CLDNs 3 and 4 were significantly elevated both in BE and ACC compared with that in FOV. CLDN 2 expression increased significantly in ACCs compared with that in BE. This is the first report proving similarities and differences regarding claudin expression pattern in BE and ACC compared with that in FOV and SQ. Our data prove a close link in CLDN pattern between BE and ACC, adding further evidence that BE is an alteration preceding esophageal ACC.     

Tight junctions and human diseases

Tight junctions are intercellular junctions adjacent to the apical end of the lateral membrane surface. They have two functions, the barrier (or gate) function and the fence function. The barrier function of tight junctions regulates the passage of ions, water, and various macromolecules, even of cancer cells, through paracellular spaces. The barrier function is thus relevant to edema, jaundice, diarrhea, and blood-borne metastasis. On the other hand, the fence function maintains cell polarity. In other words, tight junctions work as a fence to prevent intermixing of molecules in the apical membrane with those in the lateral membrane. This function is deeply involved in cancer cell biology, in terms of loss of cell polarity. Of the proteins comprising tight junctions, integral membrane proteins occludin, claudins, and JAMs have been recently discovered. Of these molecules, claudins are exclusively responsible for the formation of tight-junction strands and are connected with the actin cytoskeleton mediated by ZO-1. Thus, both functions of tight junctions are dependent on the integrity of the actin cytoskeleton as well as ATP. Mutations in the claudin14 and the claudin16 genes result in hereditary deafness and hereditary hypomagnesemia, respectively. Some pathogenic bacteria and viruses target and affect the tight-junction function, leading to diseases. In this review, the relationship between tight junctions and human diseases is summarized.     

紧密连接蛋白claudin-10基因5′调控区序列的生物信息学分析

目的:拟对claudin-10基因转录起始位点和启动子区域进行预测,并对潜在的转录因子结合位点进行分析。方法:利用BLAST比对分析TATA-box、GC-box和CAAT-box;利用在线分析软件Neural Network Promoter Prediction、PROMOTER SCAN和PROMOTER 2.0分析claudin-10基因5′调控区序列中启动子;利用在线分析软件EMBOSS和CpG Island Searcher分析claudin-10基因5′调控区序列中CpG岛位置;利用在线分析软件TFSEARCH分析claudin-10基因5′调控区序列中潜在的转录因子结合位点。结果:claudin-10基因5′调控区序列中存在1个CAAT-box和3个GC-box,没有TATA-box;claudin-10基因可能存在4个启动子位点;CpG岛为444bp区间(1 700～2 143bp)或834bp区间(1 367～2 200bp);评分在85分以上时,该区域具有159个潜在的转录因子结合位点;评分在90分以上时,该区域具有48个潜在的转录因子结合位点;评分在95分以上时,该区域具有9个潜在的转录因子结合位点。结论:通过生物信息学的方法对于claudin-10基因转录起始位点、启动子区域和潜在的转录因子结合位点进行预测,对于科研具有十分重要的指导意义,但最终的结论还需要实验来证实。     

Diagnostic utility of expression of claudins in non-small cell lung cancer: Different expression profiles in squamous cell carcinomas and adenocarcinomas

The claudins, members of a large family of adherent junction proteins, regulate the integrity and function of tight junctions. At present, at least 23 different claudins are known to exist in humans, and claudin gene expression is frequently altered in several human cancers. However, few studies have examined the expression of claudins in lung cancer. This study examined the expression of claudin-1, claudin-3, claudin-4, and claudin-5 proteins using immunohistochemical analysis in 14 normal lung tissue samples and 171 NSCLC samples. All of the claudin proteins examined were expressed in normal bronchial epithelial cells. In the normal peripheral parenchyma, only claudin-5 strongly stained most of the pneumocytes. Claudin-1 expression was stronger in squamous cell carcinomas than in adenocarcinomas, whereas claudin-4 and claudin-5 expression was stronger in adenocarcinomas. Clinically, expression of claudin proteins was not found to be associated with patient survival. These data suggest that the disruption of tight junction protein might be involved in the development of these tumors. Immunohistochemical evaluation of the different expression patterns of claudins in NSCLC suggests that claudin-4, in addition to 1 and 5, might be a useful differential diagnostic marker in Korean people.