ADAM12在产前诊断中的的研究进展

ADAM12是新发现的细胞膜结合糖蛋白家族的一员，它在妊娠期妇女血清中水平显著增高，在胎儿染色体缺陷时降低，它的发现为临床筛查治疗疾病提供了新的靶点。     

ADAM12与PAPP-A联合检测与自然流产相关性研究

目的探讨解整合素-金属蛋白酶12(ADAM12)和妊娠相关血浆蛋白A(PAPP-A)联合检测与自然流产的相关性。方法利用时间分辨检测技术,对2756例孕妇血清中ADAM12和PAPP-A进行了检测,其中正常妊娠组2660例,自然流产96例。结果正常妊娠组血清中ADAM12和PAPP-A含量随孕龄的进展稳定增加,自然流产组ADAM12和PAPP-A含量明显低于同孕周正常妊娠组,差异有统计学意义(P0.01)。结论孕妇ADAM12和PAPP-A联合检测在预测自然流产方面有较高的准确性,在异常妊娠检测方面有较大的临床价值。     

孕妇血清ADAM12-S水平与妊娠结局的相关性研究

目的探讨妊娠早期孕妇血清解整合素-金属蛋白质酶12（ADAM12-S）水平变化与唐氏综合征等妊娠结局的关系。方法应用时间分辨荧光免疫分析法检测早孕期（8-11周）孕妇血清中ADAM12-S水平,并分析ADAM12-S水平变化与唐氏综合征等妊娠结局的关系。结果正常单胎血清ADAM12-S水平随孕周增加而逐渐上升的趋势,且呈线性相关（r=0.993,P〈0.01）。唐氏综合征等非整倍体染色体异常的ADAM12-S水平的明显低于正常单胎孕妇,差异有统计学意义（P〈0.05）.结论早孕期孕妇血清中ADAM12-S水平随孕周增加而上升,可用于非整倍体常染色体异常的筛查,预测胎停育、异位妊娠等早期妊娠丢失,可作为产前筛查指标。     

血清PAPP-A在正常孕妇及子痫前期患者中的研究

目的探讨正常孕妇各孕周血清妊娠相关蛋白A(PAPP-A)的变化,及其与子痫前期发病的关系.方法采用时间分辨荧光免疫分析技术(DELFIA)检测11w至足月孕妇3935例,统计分析子痫前期孕妇与正常孕妇外周血清PAPP-A的中位数的差异.结果在正常孕妇组,血清PAPP-A浓度值随着孕周的增加而不断增高,至孕晚期达到最高水平;而子痫前期组孕妇外周血清PAPP-A水平明显高于相应孕周正常孕妇组的中位数.结论正常孕妇血清PAPP-A浓度随妊娠进展而逐渐上升至足月;子痫前期患者血清PAPP-A浓度显著高于同孕周正常孕妇,PAPP-A与子痫前期发病存在相关关系.     

孕妇血清PAPP-A检测在产前筛查中的应用

目的对孕妇血清PAPP-A检测在产前筛查中的应用进行探讨.方法运用定量酶联免疫吸附(ELISA)法,对9～19w孕妇血清PAPP-A含量进行检测.结果流产、死胎及胎儿宫内发育迟缓、畸形、染色体异常、胸腹水、白化病、甲状腺功能低下等的孕妇血清PAPP-A的浓度降低.孕期PAPP-A浓度异常的孕妇易发生羊水过多或过少、胎儿宫内窘迫、羊水早破、妊高征等并发症.结论孕妇血清PAPP-A检测在产前筛查中有一定的意义.     

葡萄糖调节蛋白94在人胚胎发育中的表达

目的 为探讨葡萄糖调节蛋白９４（ＧＲＰ９４）在胚胎发育中的作用,研究了１０－３１周人胎组织ＧＲＰ９４的定位及表达。方法 用ＳＰ免疫组织化学方法。结果 结肠粘膜上皮,肾小管上皮及肝细胞的胞质内,在１０周已有ＧＲＰ９４的表达,１８－２０周时表达增多,一直维持较高水平。胃粘膜上皮及心肌细胞也有较强的表达。     

ADAM17在膜蛋白胞外结构域剪切机制中的作用

ADAM17蛋白属于解聚素金属蛋白酶家族,是Ⅰ型多结构域跨膜蛋白,表达于多种组织及肿瘤细胞中。该蛋白是剪切跨膜蛋白胞外结构域的关键蛋白,对膜结合型蛋白的翻译后修饰及蛋白活性的产生具有重要的调节作用,与免疫反应、肿瘤的发生发展、神经发育、病毒传播及衰老等过程密切相关。对ADAM17跨膜蛋白胞外段的剪切功能及其生物学意义进行深入研究,对相关疾病的诊断与治疗具有重要的理论与临床应用价值。     

孕酮及PAPP-A在先兆流产预测中的应用

目的 探讨孕酮及妊娠相关血浆蛋白A(PAPP-A)对先兆流产的预测价值.方法 分别测定96例先兆流产患者血清中孕酮及PAPP-A的含量.结果 患者组孕酮16.24±6.13 ng/ml明显低于正常妊娠组26.30±6.91 ng/ml(P＜0.05),患者组PAPP-A的含量为26.31±9.26IU/L与对照组结果相比32.1±11.2 IU/L具有显著性差异(P＜0.05).结论 孕酮及PAPP-A在对先兆流产的预测上有一定意义.     

sFlt-1、IGFBP-3、PAPP-A在稽留流产中的表达及意义

目的研究可溶性FMS样酪氨酸激酶-1(sFlt-1)、胰岛素样生长因子结合蛋白3(IGFBP-3)、妊娠相关血浆蛋白A(PAPP-A)在稽留流产中的表达及意义。方法选取2015年6月至2017年6月在重庆市两江新区第一人民医院接受治疗的稽留流产患者40例纳入稽留流产组;早期流产患者40例纳入早期流产组;另外选取进行体检的健康妊娠期产妇20例作为正常组。收集3组研究对象的绒毛组织,采用免疫组化染色处理,酶联免疫吸附测定sFlt-1、IGFBP-3、PAPP-A表达,并在显微镜下观察其阳性表达情况。结果正常组sFlt-1表达水平显著低于早期流产组和稽留流产组(P<0.05);稽留流产组sFlt-1表达水平低于早期流产组(P<0.05)。正常组IGFBP-3、PAPP-A表达水平显著高于早期流产组和稽留流产组(P<0.05);稽留流产组患者IGFBP-3、PAPP-A表达水平高于早期流产患者(P<0.05)。sFlt-1、IGFBP-3、PAPP-A三项联合检测敏感度、准确度高于sFlt-1、IGFBP-3、PAPP-A单一检测,特异度低于sFlt-1、IGFBP-3、PAPP-A单一检测(P<0.05)。结论sFlt-1、IGFBP-3、PAPP-A联合检测对稽留流产的诊断价值较高,sFlt-1、IGFBP-3、PAPP-A的异常表达参与了稽留流产的发展,为稽留流产的治疗提供一定的理论基础。     

PAPP-A与动脉粥样硬化的关系

急性冠状动脉综合征的形成机制是斑块不稳定发生破裂并发血栓形成,如何识别不稳定斑块成为目前的研究热点。最新研究显示,在男,女两性体内均存在的妊娠相关血浆蛋白A(PAPP A)。该蛋白酶是金属蛋白酶超家族中的一员,通过激活胰岛素样生长因子,介导动脉粥样硬化形成。PAPP A血清水平增高是局部炎症状态增加的潜在标记因子,有助于早期诊断急性冠状动脉综合征,且与斑块病变的复杂程度和冠状动脉介入术后再狭窄有关,能一定程度上提示预后。     

解整合素-金属蛋白酶12与自然流产的相关性研究

目的探讨解整合素-金属蛋白酶12与自然流产的相关性。方法利用时间分辨检测技术,对1160例孕妇血清中ADAM12进行了检测,其中正常妊娠组1064例,自然流产96例。结果正常妊娠组血清中ADAM12含量随孕龄的进展稳定增加,自然流产组ADAM12含量明显低于同孕周正常妊娠组,差异有统计学意义(P0.05)。结论孕妇ADAM12的检测在预测自然流产方面有较高的准确性,在异常妊娠检测方面有较大的临床价值。     

ADAM12: a potential target for the treatment of chronic wounds

Wound healing is a complex process involving multiple cellular events, including cell proliferation, migration, and tissue remodeling. A disintegrin and metalloprotease 12 (ADAM12) is a membrane-anchored metalloprotease, which has been implicated in activation-inactivation of growth factors that play an important role in wound healing, including heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF) and insulin growth factor (IGF) binding proteins. Here, we report that expression of ADAM12 is fivefold upregulated in the nonhealing edge of chronic ulcers compared to healthy skin, based on microarrays of biopsies taken from five patients and from healthy controls (p = 0.013). The increase in ADAM12 expression in chronic ulcers was confirmed by quantitative real-time polymerase chain reaction (RT-PCR). Moreover, immunohistochemical analysis demonstrated a pronounced increase in the membranous and intracellular signal for ADAM12 in the epidermis of chronic wounds compared to healthy skin. These findings, coupled with our previous observations that lack of keratinocyte migration contributes to the pathogenesis of chronic ulcers, prompted us to evaluate how the absence of ADAM12 affects the migration of mouse keratinocytes. Skin explants from newborn ADAM12-/- or wild-type (WT) mice were used to quantify keratinocyte migration out of the explants over a period of 7 days. We found a statistically significant increase in the migration of ADAM12-/- keratinocytes compared to WT control (p = 0.0014) samples. Taken together, the upregulation of ADAM12 in chronic wounds and the increased migration of keratinocytes in the absence of ADAM12 suggest that ADAM12 is an important mediator of wound healing. We hypothesize that increased expression of ADAM12 in chronic wounds impairs wound healing through the inhibition of keratinocyte migration and that topical ADAM12 inhibitors may therefore prove useful for the treatment of chronic wounds.     

ADAM12 expression predicts clinical outcome in estrogen receptor-positive breast cancer

Objectives: Our study was aimed to make sure whether ADAM12 could serve as a prognostic biomarker of estrogen receptor (ER) -positive breast cancer. Methods: 127 patients with ER-positive breast cancer were included in the present study. The level of ADAM12 was assayed through real-time quantitative PCR (RT-qPCR). Levels of ADAM12 in tumor tissues and adjacent normal tissues were compared with paired t-test. The association of ADAM12 expression with clinical characteristics was analyzed via χ² test. Kaplan-Meier survival curve was used to evaluate the role of ADAM12 expression in overall survival (OS) of patients. Cox-regression analysis was performed to judge if ADAM12 could serve as a prognostic marker in breast cancer. Results: The level of ADAM12 was upregulated in tumor tissues of breast cancer compared to that of adjacent normal tissues (P < 0.05). The expression of ADAM12 was closely related to the Ki-67 and HER2 status (P < 0.05 for both). The results of Kaplan-Meier survival curve showed that patients with higher level of ADAM12 exhibited shorter survival time compared to that of low level of ADAM12 (P < 0.001). Cox regression analysis showed that ADAM12 might be a biomarker in predicting prognosis of patients with ER-positive breast cancer (HR = 7.116, 95% CI = 3.329-15.212). Conclusion: ADAM12 appears to be a prognostic marker in ER-positive breast cancer.     

Association of single nucleotide polymorphisms in ADAM12 gene with susceptibility to knee osteoarthritis: a case-control study in a Chinese Han population

Objective: Genetic factors play an important role in osteoarthritis (OA) etiology and ADAM12 gene polymorphisms may be involved. This study tried to examine the single-nucleotide polymorphisms (SNPs) of ADAM12 for their association with knee OA susceptibility in a Chinese Han population. Methods: The rs3740199, rs1871054, rs1278279, and rs1044122 SNPs in ADAM12 gene were genotyped in 152 subjects who were diagnosed as knee osteoarthritis and in 179 healthy controls. Results: Rs1871054 was found to be significantly associated with increased risk of OA (C vs. T, OR 1.802 (1.308 to 2.483), P < 0.0001) after adjustment of age, gender, and BMI. For other SNPs, no statistically significant associations with OA were found. Conclusion: In conclusion, our data demonstrated the ADAM12 rs1871054 variant was found to be significantly associated with increased OA susceptibility in a Chinese Han population.     

Cellular reprogramming into a brown adipose tissue-like phenotype by co-expression of HB-EGF and ADAM 12S

Abstract

Abnormal adipogenesis leads to excessive fat accumulation and several health disorders. Mouse fibroblasts (MLC) transfected with ADAM 12S and HB-EGF promoted lipid accumulation. Addition of KBR-7785, an ADAM 12S inhibitor, to HB-EGF/ADAM 12S expressing cells suppressed adipogenesis. BrdU incorporation was attenuated and enhanced mitotracker staining was observed in HB-EGF/ADAM 12S cells. Quantitative real time RT-PCR resulted in elevated levels of expression of three brown adipose tissue (BAT) genes (PRDM16, PGC-1α, and UCP-1), while expression levels of the three white adipose tissue (WAT) genes (PPARγ, C/EBPα, and AKT-1) were unaltered in HB-EGF/ADAM 12S cells. Amino- or carboxy-terminal deletions of HB-EGF (HB-EGF_ΔN and HB-EGF_ΔC) co-expressed with ADAM 12S stimulated lipid accumulation. Human epidermoid carcinoma cells (A431) also exhibited lipid accumulation by HB-EGF/ADAM 12S co-expression. These studies suggest ADAM 12S and HB-EGF are involved in cellular plasticity resulting in the production of BAT-like cells and offers insight into novel therapeutic approaches for fighting obesity.     

TM4SF3 promotes esophageal carcinoma metastasis via upregulating ADAM12m expression

Esophageal cancer is characterized by rapid clinical progression and poor prognosis due to adjacent tissue invasion and distant organs metastasis at a very early stage. TM4SF3 (transmembrane 4 superfamily 3), a member of tetraspanin family, has been reported as a metastasis associated gene in many types of tumors. Herein, we described new properties of TM4SF3 in tumor metastasis, which suggested that this gene might be involved in esophageal carcinoma metastasis. Western blotting revealed that TM4SF3 was overexpressed in 57.1% (8/14) of esophageal carcinomas and esophageal carcinoma cell lines with high-invasive potential. Exogenous expression of TM4SF3 in two low-invasive esophageal carcinoma cell lines, KYSE150 and EC9706, significantly promoted cell migration and invasion. Upregulating TM4SF3 expression in EC9706 cells promoted xenograft tumor invading into surrounding tissues, enhanced lung metastasis, and shortened the lifespan of mice (median survival EC9706-TM4SF3 106.5 days versus EC9706-Vector 169.0 days, P < 0.0001) in a spontaneous metastasis model. Further studies demonstrated that ADAM12m was upregulated by TM4SF3 overexpression in vitro and in vivo. Abrogating up-expression of ADAM12m by siRNA significantly suppressed TM4SF3-mediated invasion. Together, these data from our studies indicated that overexpression of TM4SF3 in esophageal cancer conferred advantage to the invasion and metastasis of this destructive disease. Upregulated expression of ADAM12m by TM4SF3 might play a key role in TM4SF3-mediated invasion and metastasis. TM4SF3 and ADAM12m might be potential targets of esophageal carcinoma for anti-metastasis therapy.     

Analysis of the disintegrin-metalloproteinases family reveals ADAM29 and ADAM7 are often mutated in melanoma

We performed a mutational analysis of the 19 disintegrin-metalloproteinases (ADAMs) genes in human cutaneous metastatic melanoma and identified eight to be somatically mutated in 79 samples, affecting 34% of the melanoma tumors analyzed. Functional analysis of the two frequently mutated ADAM genes, ADAM29 and ADAM7 demonstrated that the mutations affect adhesion of melanoma cells to specific extracellular matrix proteins and in some cases increase their migration ability. This suggests that mutated ADAM genes could play a role in melanoma progression.