P2X7受体在结肠癌进展中的作用

P2X7受体是以三磷酸腺苷(ATP)为配体的离子通道型受体,在多种免疫细胞和组织中广泛表达,其激活后可参与多种生理和病理过程。P2X7受体在结肠癌中异常表达,并在结肠癌的进展中发挥抑癌和促癌双重作用。P2X7受体被细胞外的ATP激活后,可通过多种机制有效抑制结肠癌细胞的增殖,并诱导细胞凋亡。另外,P2X7受体还能促进结...     

嘌呤受体P2Y2基因在恶性肿瘤中的研究进展

近年来恶性肿瘤的发病率逐年升高,严重影响了患者的生存质量及生存期.尽管随着放射治疗、化学治疗以及靶向治疗等治疗手段的不断发展,部分肿瘤患者获得了一定益处,但肿瘤细胞的远处转移以及肿瘤耐药的发生已经成为肿瘤患者转归过程中面临的巨大难题.因此,亟需寻找恶性肿瘤发生发展过程中相关靶向分子标志物,以阻断恶性肿瘤侵袭或耐药的发生...     

P2X家族受体在急性T淋巴细胞白血病小鼠中表达的特点

摘 要 目的：探讨不同P2X家族受体在小鼠急性T淋巴细胞白血病发展中的表达变化规律。方法：制备Notch1过表达小鼠GFP+T细胞急性淋巴细胞白血病移植模型,流式术分选CD45.2+GFP+白血病细胞,实时定量PCR检测P2X受体家族的表达变化,荧光分光光度计检测P2X7受体介导的钙离子浓度的变化。结果：对照组和白血病组小鼠骨髓细胞表达除P2X5外的其他6种P2X家族受体。Notch1过表达导致的小鼠白血病发展过程中,P2X7的表达水平逐渐升高,P2X1和P2X3的表达水平逐渐降低,而P2X2、P2X4和P2X6表达水平没有显著变化;分选后的CD45.2+GFP+白血病细胞中,P2X家族受体的表达呈现相同的规律。对照组和白血病组小鼠骨髓细胞中P2X7受体在激动剂苯甲酰-苯甲酸ATP（BzATP）的刺激下都能介导细胞内钙离子浓度升高,但白血病组小鼠骨髓细胞内钙离子处于持续高浓度状态,而对照组小鼠细胞内钙离子浓度短暂升高后逐渐下降;P2X7介导的这种钙离子反应可被其特异的拮抗剂KN62所阻断。结论：P2X受体家族中P2X1、P2X3和P2X7的表达变化与小鼠急性T淋巴细胞白血病的发展相关,提示其介导的细胞间通讯可能在白血病发展中发挥重要作用。     

P2X7受体与乳腺癌的发生和发展

 P2X7受体是腺甘三磷酸（ATP）门控的离子通道,对二价阳离子有较强的选择性,属于嘌呤能P2受体家族。P2X7受体参与细胞信号传导、细胞因子的分泌等多种生理功能。近几年研究发现P2X7受体通过增加氧化、磷酸化及细胞内ATP的储备,介导细胞的存活与生长。在乳腺癌中P2X7受体表达异常,活化的P2X7受体激活位于细胞质内的丝裂原活化蛋白激酶（MAPK）,后者受到刺激后磷酸化进入核内,引起细胞内一系列蛋白激酶的活化,进而影响乳腺癌的发生发展。     

白血病患者P2X7受体的功能性表达分析

目的研究P2X7受体在白血病患者中的功能性表达及与白血病治疗的关系。方法采用半定量RT-PCR、流式细胞术和细胞内钙离子测定的方法,从核酸、蛋白和功能水平研究白血病患者骨髓单个核细胞（BMMC）P2X7受体的表达和功能。结果白血病患者和正常人标本中可检出P2X7受体的表达,核酸、蛋白和功能水平结果一致。AML、ALL、CML患者P2X7受体表达阳性率高于正常人;但AML各亚型中P2X7受体阳性强度存在差异,M2组低于正常人,M5,M6组高于正常人;按照P2X7受体阳性强度分组,P2X7受体高表达患者诱导治疗后的完全缓解率显著低于P2X7受体阴性和P2X7受体低表达患者。结论P2X7受体在白血病患者BMMC中有功能性表达,其高表达与患者治疗不敏感相关。     

P2X7受体在乳腺浸润性导管癌中的表达水平及临床意义

目的:检测P2X7受体(P2X7 purinergic receptor,P2X7R)在乳腺浸润性导管癌中的表达水平,并探讨其表达水平与乳腺浸润性导管癌患者临床病理参数及预后的关系。方法:采用免疫组织化学法检测P2X7R在170例乳腺浸润性导管癌、50例乳腺导管原位癌和34例乳腺癌旁正常组织中的表达水平。采用χ~2检验分析P2X7R表达与乳腺癌患者临床病理指参数的关系,并用Kaplan-Meier法和COX风险回归模型分析P2X7R表达水平与患者预后的相关性。结果:P2X7R在浸润性导管癌和导管原位癌组织中均高表达,且明显高于乳腺癌旁正常组织(P<0.01);P2X7R表达水平与患者淋巴结转移(P=0.039)、TNM分期(P=0.045)、雌激素受体(estrogen receptor,ER)(P=0.024)和孕激素受体(progesterone receptor,PR)(P=0.033)的表达水平存在相关性,且P2X7R在淋巴结转移患者、TNMⅢ期患者、ER阳性患者和PR阳性患者中高表达率更高。P2X7R与患者年龄、肿瘤大小、组织学分级、人类表皮生长因子受体2(human epidermal growth factor receptor-2,HER-2)、p53和Ki-67无相关性。P2X7R高表达乳腺浸润性导管癌患者的无病生存(disease-free survival,DFS)时间较低表达者短(P=0.013)。单因素分析结果显示,乳腺浸润性导管癌患者的DFS与肿瘤大小(P=0.002)、淋巴结转移(P=0.009)、TNM分期(P<0.001)、Ki-67(P=0.026)和P2X7R(P=0.013)相关;多因素分析结果显示,TNM分期(P=0.033)和P2X7R(P=0.043)是影响乳腺浸润性导管癌患者DFS的独立危险因素。结论:P2X7R在乳腺癌中高表达,并且P2X7R高表达的乳腺癌患者预后更差,提示其可以作为一种乳腺癌的潜在预后标志物。     

P2X7R激动剂BzATP对非小细胞肺癌A549细胞生长和凋亡的影响

目的 研究配体门控离子通道P2X7受体(P2X7R)在非小细胞肺癌A549细胞中的表达,观察P2X7R激动剂2'-3'-O-(4-苯甲酰-苯甲酰)腺苷三磷酸三乙烷胺盐(BzATP)对A549细胞生长及凋亡的影响,并探究相关作用机制.方法 采用免疫荧光法检测P2X7R在A549细胞中的表达.用不同浓度的BzATP(150、300、600 μmol/L)处理,未用BzATP干预的细胞作为对照组.采用四甲基偶氮唑蓝(MTT)和Hoest33342染色法分别检测细胞存活率与凋亡情况,酶联免疫吸附试验检测上清液中肿瘤坏死因子-α(TNF-α)的浓度,Western blotting检测核转录因子-κB(NF-κB) p65、NF-κB抑制因子α(IκBα)及磷酸化NF-κB抑制因子α(phospho-IκBα)蛋白的表达.结果 P2X7R在A549细胞膜上表达.在300、600 μmol/L BzATP作用下A549细胞存活率分别为(67.87±8.98)％、(44.73±6.92)％,较对照组(98.60±1.44)％明显下降,差异均具有统计学意义(=4.481,P=0.027;t =3.920,P=0.038).BzATP可促进细胞凋亡,并且300、600 μmol/L BzATP可上调细胞培养上清中TNF-α浓度,分别为(57.35±6.41)pg/ml、(78.63±11.33) pg/ml,与对照组(42.56±0.37) pg/ml比较差异具有统计学意义(t=6.410,P=0.035;t=11.330,P=0.005).此外,BzATP可下调NF-κB p65的表达,上调IκBα的表达,对phospho-IκBα的表达无明显作用.结论 P2X7R表达于A549细胞膜,BzATP能够抑制细胞增殖,促进细胞凋亡,其作用机制可能与促进细胞中TNF-α的释放,抑制NF-κB通路有关.     

大麻素受体2在胫骨癌痛大鼠脊髓背角细胞中的表达

目的：观察胫骨癌痛大鼠脊髓大麻素受体2（CB2）表达的变化,探讨CB2在骨癌痛中作用及其可能的脊髓机制。方法：雌性SD大鼠56只,体重160-180g,随机分为7组（n=8）：对照组、假手术组、骨癌痛组,假手术组和骨癌痛组又各分为3个亚组（术后7d、14d和21d组）,分别用免疫印迹法检测各组大鼠脊髓水平CB2表达的变化,激光共聚焦技术观察CB2的表达部位。结果：免疫印迹结果显示对照组基本没有CB2的表达,与对照组相比,假手术组及骨癌痛组脊髓CB2表达水平升高（P〈0.05）;与假手术组相比,骨癌痛7d组脊髓CB2蛋白表达明显上调（P〈0.05）。激光共聚焦技术显示CB2主要表达于脊髓小胶质细胞和星形胶质细胞。结论：胫骨癌痛大鼠脊髓背角有CB2表达,早期为其表达的高峰,且主要表达于小胶质细胞和星形胶质细胞。     

大麻素受体2在胫骨癌痛大鼠脊髓背角细胞中的表达

目的:观察胫骨癌痛大鼠脊髓大麻素受体2(CB2)表达的变化,探讨CB2在骨癌痛中作用及其可能的脊髓机制。方法:雌性SD大鼠56只,体重160-180g,随机分为7组(n=8):对照组、假手术组、骨癌痛组,假手术组和骨癌痛组又各分为3个亚组(术后7d、14d和21d组),分别用免疫印迹法检测各组大鼠脊髓水平CB2表达的变化,激光共聚焦技术观察CB2的表达部位。结果:免疫印迹结果显示对照组基本没有CB2的表达,与对照组相比,假手术组及骨癌痛组脊髓CB2表达水平升高(P<0.05);与假手术组相比,骨癌痛7d组脊髓CB2蛋白表达明显上调(P<0.05)。激光共聚焦技术显示CB2主要表达于脊髓小胶质细胞和星形胶质细胞。结论:胫骨癌痛大鼠脊髓背角有CB2表达,早期为其表达的高峰,且主要表达于小胶质细胞和星形胶质细胞。     

规范化癌痛护理在晚期癌痛患者中的临床体会

目的:采用规范化癌痛护理晚期癌痛患者可提高并改善患者生活质量及延长生存期。方法:选取2015年3月至2017年3月收治的240例晚期癌痛患者,随机数字表法分成观察组和对照组,各组120例,对照组以常规止痛护理,观察组以规范化癌痛护理。比较两种不同护理方式对患者生活质量及疼痛评分的影响。结果:观察组患者SDS、SAS、疼痛评分、患者社会/家庭状况、生理状况、功能状况、情感状况评分均明显优于对照组(P<0.01)。结论:规范化癌痛护理有利于改善并提高晚期癌痛患者生活质量,同时可延长生存时间。     

P2X7受体激活乳腺癌JNK/SAPK信号通路的研究进展

P2X7受体是ATP门控的离子通道,对二价阳离子有较强的选择性,属于嘌呤受体P2X家族。P2X7受体参与细胞信号转导、细胞因子的分泌等多种生理功能。近年研究发现P2X7受体通过增加氧化磷酸化及细胞内ATP的储备,介导细胞的存活与生长。在乳腺癌中P2X7受体表达异常,并能激活JNK/SAPK途径,诱导乳腺癌细胞凋亡。本文综述了P2X7受体与乳腺癌发生发展分子机制的相关研究。     

Targeting of the P2X7 receptor in pancreatic cancer and stellate cells

The ATP‐gated receptor P2X7 (P2X7R) is involved in regulation of cell survival and has been of interest in cancer field. Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer and new markers and therapeutic targets are needed. PDAC is characterized by a complex tumour microenvironment, which includes cancer and pancreatic stellate cells (PSCs), and potentially high nucleotide/side turnover. Our aim was to determine P2X7R expression and function in human pancreatic cancer cells in vitro as well as to perform in vivo efficacy study applying P2X7R inhibitor in an orthotopic xenograft mouse model of PDAC. In the in vitro studies we show that human PDAC cells with luciferase gene (PancTu‐1 Luc cells) express high levels of P2X7R protein. Allosteric P2X7R antagonist AZ10606120 inhibited cell proliferation in basal conditions, indicating that P2X7R was tonically active. Extracellular ATP and BzATP, to which the P2X7R is more sensitive, further affected cell survival and confirmed complex functionality of P2X7R. PancTu‐1 Luc migration and invasion was reduced by AZ10606120, and it was stimulated by PSCs, but not by PSCs from P2X7^‐/‐ animals. PancTu‐1 Luc cells were orthotopically transplanted into nude mice and tumour growth was followed noninvasively by bioluminescence imaging. AZ10606120‐treated mice showed reduced bioluminescence compared to saline‐treated mice. Immunohistochemical analysis confirmed P2X7R expression in cancer and PSC cells, and in metaplastic/neoplastic acinar and duct structures. PSCs number/activity and collagen deposition was reduced in AZ10606120‐treated tumours.     

The expression of P2X7 receptors in EPCs and their potential role in the targeting of EPCs to brain gliomas

In order to use endothelial progenitor cells (EPCs) as a therapeutic and imaging probe to overcome antiangiogenic resistance for gliomas, how to enhance proliferation and targeting ability of transplanted EPCs is a high priority. Here, we confirmed, for the first time, the expression of P2X₇ receptors in rat spleen-derived EPCs. Activation of P2X₇ receptors in EPCs by BzATP promoted cells proliferation and migration, rather than apoptosis. In vivo, the homing of transplanted EPCs after long-term suppression of P2X₇ receptors by persistent BBG stimulation was evaluated by MRI, immunohistochemistry and flow cytometry. Compared to the group without BBG treatment, less transplanted EPCs homed to gliomas in the group with BBG treatment, especially integrated into the vessels containing tumor-derived endothelial cells in gliomas. Moreover, western blot showed that CXCL1 expression was downregulated in gliomas with BBG treatment, which meant P2X₇ receptors suppression inhibited the homing of EPCs to gliomas through down-regulation of CXCLl expression. Further, effects of P2X₇ receptors on C6 glioma cells or gliomas were evaluated at the same dose of BzATP or BBG used in EPCs experiments in vitro and in vivo. MTT assay and MRI revealed that P2X₇ receptors exerted no significant promoting effect on C6 glioma cells proliferation, gliomas growth and angiogenesis. Taken together, our findings imply the possibility of promoting proliferation and targeting ability of transplanted EPCs to brain gliomas in vivo through P2X₇ receptors, which may provide new perspectives on application of EPCs as a therapeutic and imaging probe to overcome antiangiogenic resistance for gliomas.     

The evolving role of receptors as predictive biomarkers for metastatic breast cancer

Introduction: In breast cancer, estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) are essential biomarkers to predict response to endocrine and anti-HER2 therapies, respectively. In metastatic breast cancer, the use of these receptors and targeted therapies present additional challenges: temporal heterogeneity, together with limited sampling methodologies, hinders receptor status assessment, and the constant evolution of the disease invariably leads to resistance to treatment.

Areas covered: This review summarizes the genomic abnormalities in ER and HER2, such as mutations, amplifications, translocations, and alternative splicing, emerging as novel biomarkers that provide an insight into underlying mechanisms of resistance and hold potential predictive value to inform treatment selection. We also describe how liquid biopsies for sampling of circulating markers and ultrasensitive detection technologies have emerged which complement ongoing efforts for biomarker discovery and analysis.

Expert commentary: While evidence suggests that genomic aberrations in ER and HER2 could contribute to meeting the pressing need for better predictive biomarkers, efforts need to be made to standardize assessment methods and better understand the resistance mechanisms these markers denote. Taking advantage of emerging technologies, research in upcoming years should include prospective trials incorporating these predictors into the study design to validate their potential clinical value.     

P2X7受体与肿瘤发生发展关系的研究进展

P2X7受体作为嘌呤类受体家族中的一个重要成员,能够被细胞外ATP激活,从而参与细胞信号转导、细胞因子的分泌,介导细胞的生长与凋亡等细胞生物学功能的调控。近些年研究表明,P2X7受体的异常表达与多种肿瘤的发生发展密切相关,有望成为肿瘤靶向治疗的新型生物学标志物。本文结合国内外最新报导,对P2X7受体在肿瘤中的异常表达及相关致癌机制研究作一综述。     

The role of Eph receptors and ephrin ligands in colorectal cancer

Eph receptors and their ephrin ligands constitute the largest subfamily of receptor tyrosine kinases and are components of the cell signaling pathways involved during development. Eph and ephrin overexpression have been documented in a variety of human cancers including gastrointestinal malignancies and in particular colorectal malignancies. EphB and ephrin B proteins have been implicated in the homeostasis of the gastrointestinal tract where EphB2‐ and EphB3‐ephrin B signaling regulates cell sorting in the mature epithelium. These proteins are also reported to be upregulated in colon carcinomas. The EphA/ephrin A system has also been implicated in epithelial tissue structure and function. More recently, EphA receptors and their corresponding ligands have been implicated in numerous malignancies. Of these, EphA2 in particular has been intensively investigated and has been proposed as a therapeutic target. An interesting observation emerging from these studies is the role for Ephs and ephrins in critical aspects of cell adhesion, migration and positioning, and a crucial role in tumor progression and metastasis. However, the underlying role of Ephs and ephrins in these processes has generally been studied on individual Eph or ephrin genes. Given the multiplicity of Eph expression on gut epithelial cells, a more global approach is needed to define the precise role of Eph–ephrin interaction in malignant transformation. Here, we will review the recent advances on the role of Eph–ephrin signaling in colorectal malignancies.