癌基因与肺癌对EGFR抑制剂的抵抗相关联

吉非替尼和埃罗替尼通过激活表皮生长因子受体基因突变治疗非小细胞肺癌。不幸的是，大多数肿瘤最终对这些药物产生抵抗。半数病例的这种抵抗是由于表皮生长因子受体二次突变所致。其余半数的抵抗原因还不清楚。     

荧光原位杂交技术检测非小细胞肺癌EGFR基因扩增

目的探讨荧光原位杂交(FISH)技术检测非小细胞肺癌(non-small cell lung cancer,NSCLC)表皮生长因子受体(epider-mal growth factor receptor,EGFR)基因扩增的临床应用价值。方法采用FISH技术检测57例人NSCLC石蜡组织标本中EG-FR基因扩增水平。对于EGFR基因扩增阳性的患者采用酪氨酸激酶抑制剂(tyrosine kinase inhibitors,TKIs)药物进行治疗,其余患者采用传统化疗进行治疗。结果 57例NSCLC患者中有18例EGFR基因扩增阳性(31.58%),其中12例为高多体性扩增(66.67%),5例为成簇扩增(27.78%),以肺腺癌为主(72.22%)。TKIs靶向药物治疗有效率(RR)、中位生存时间(MST)和1年生存率分别为61.11%1、3.5个月和55.56%,对照组分别为35.89%、7.6个月和33.33%,差异均有显著性(P<0.05),前者的疾病控制率(DCR)高于后者,但差异无统计学意义(P>0.05)。结论使用FISH技术检测NSCLC患者EG-FR基因扩增水平可以为临床采用TKIs药物治疗提...     

肾癌中细胞自噬的作用及自噬调节剂在肾癌治疗中的研究进展

细胞自噬是细胞体内的一种“自我吞噬”的分解代谢过程,通过将细胞内衰老的细胞器、受损蛋白和其他细胞成分包裹于自噬溶酶体中,从而实现能量供应和物质的循环利用。研究表明,细胞自噬与肾癌的发生、发展和转归密切相关,其不仅参与肾癌的发生,而且在肾癌发展的不同阶段分别起促进或抑制的双重作用。有针对性地靶向调节不同阶段肾癌的自噬水平可能是治疗肾癌的新策略。该文对细胞自噬的发生过程及其在肾癌发展进程中的作用进行综述,并探讨自噬调节剂(自噬抑制剂/诱导剂)在肾癌治疗中的潜在作用。     

表皮生长因子受体在靶向治疗非小细胞肺癌中的研究进展

肺癌是最常见的恶性肿瘤之一,其发病率和死亡率呈逐年上升趋势,在全世界癌症死亡中占第一位[1]。按照临床和组织病理学特征,肺癌分为非小细胞肺癌(non-small cell lung cancers,NSCLC)和小细胞肺癌(small cell lung cancers,SCLC);其中,NSCLC约占80%,SCLC约占20%[2]。目前,NSCLC的治疗仍以化疗为主,常用的化疗药物为含     

细胞自噬与凋亡相互作用分子机制的研究进展

细胞自噬与细胞凋亡是两个不同的生理现象,但其在功能上有着密切的联系.本文主要介绍细胞自噬和凋亡的分类及发生过程,并就自噬体形成过程中的一些关键调节蛋白以及凋亡和抗凋亡蛋白的双重作用对自噬和凋亡的影响进行论述,从而探讨细胞自噬与凋亡之间的关系,以期为进一步研究自噬与凋亡相关疾病提供理论基础.     

厄罗替尼联合塞来昔布阻断EGFR和COX-2抑制肺癌A549细胞增殖

目的探讨厄罗替尼联合塞来昔布对肺腺癌A549细胞系凋亡、表皮生长因子受体(EGFR)和环氧合酶-2(COX-2)表达的影响。方法厄罗替尼、塞来昔布单独或联合干预细胞48 h后,倒置相差显微镜观察细胞形态;四甲基偶氮唑盐(MTT)法测定细胞抑制率;Hoechst33258法和TUNEL法检测细胞凋亡和流式细胞术检测细胞周期;免疫荧光检测EGFR和COX-2蛋白表达。结果厄罗替尼联合塞来昔布组相比单药组A549细胞明显出现大量颗粒和空泡,细胞变圆开始脱落;二者联合作用时抑制作用更强(P<0.05),厄罗替尼与塞来昔布均能诱导细胞凋亡,联合作用后细胞凋亡率更高(P<0.05),并使细胞发生明显的G1期阻滞(P<0.05),进一步下调了EGFR和COX-2蛋白的表达(P<0.05)。结论厄罗替尼与塞来昔布联合应用可协同介导细胞凋亡,阻滞细胞周期于G0/G1期及阻滞EGFR和COX-2信号途径。     

自噬在非小细胞肺癌EGFR-TKIs治疗中的作用

自噬是一种应激细胞反应,其与耐药的产生密切相关。表皮生长因子受体酪氨酸激酶抑制剂(epidermal growth factor receptor-tyrosine kinase inhibitors,EGFR-TKIs)对EGFR突变的非小细胞肺癌(non-small cell lung cancer,NSCLC)患者有效;然而NSCLC的EGFR突变患者最终对EGFR-TKIs产生了耐药性。目前,自噬在EGFR-TKIs治疗中的作用尚存在争议,一方面,自噬抑制剂克服EGFR-TKIs的耐药性,增强了药物疗效;另一方面,自噬激活剂的使用促进了凋亡,从而增加药物疗效。该文着重对自噬在NSCLC的EGFR-TKIs治疗中的作用进行综述。     

EGFR-TKI治疗EGFR敏感突变的晚期NSCLC一线与二线疗效对比的研究进展

本文对近年来关于表皮生长因子络氨酸激酶抑制剂(EGFR-TKI)的多项研究进行分析：EGFR-TKI与传统化疗相比,无论一线还是二线治疗表皮生长因子(EGFR)突变的非小细胞肺癌(non-small cell lung cancer,NSCLC)患者均能够提高客观缓解率(objective response rate,ORR),延长无进展生存期(progression free survival,PFS),改善生活质量;应尽早明确患者基因突变状态,二线治疗进行基因检测也是十分必要的;对于EGFR敏感突变的患者,有研究显示EGFR-TKI一线治疗与二线治疗相比,能提高有效率及疾病控制率,但并未见PFS及总生存期(overall survival,OS)的延长。     

细胞自噬在血管新生中作用的研究进展

自噬(autophagy)是细胞利用溶酶体降解自身受损的细胞器和大分子物质的过程,在稳定细胞内环境中发挥着重要作用。在血管新生的病理生理过程中,细胞自噬作用持续存在。从自噬的角度探索血管新生的发生发展进程,能够为临床治疗血管相关疾病提供新的思路。     

EGFR inhibitors identified as a potential treatment for chordoma in a focused compound screen

Chordoma is a rare malignant bone tumour with a poor prognosis and limited therapeutic options. We undertook a focused compound screen (FCS) against 1097 compounds on three well‐characterized chordoma cell lines; 154 compounds were selected from the single concentration screen (1 µm ), based on their growth‐inhibitory effect. Their half‐maximal effective concentration (EC₅₀) values were determined in chordoma cells and normal fibroblasts. Twenty‐seven of these compounds displayed chordoma selective cell kill and 21/27 (78%) were found to be EGFR/ERBB family inhibitors. EGFR inhibitors in clinical development were then studied on an extended cell line panel of seven chordoma cell lines, four of which were sensitive to EGFR inhibition. Sapitinib (AstraZeneca) emerged as the lead compound, followed by gefitinib (AstraZeneca) and erlotinib (Roche/Genentech). The compounds were shown to induce apoptosis in the sensitive cell lines and suppressed phospho‐EGFR and its downstream pathways in a dose‐dependent manner. Analysis of substituent patterns suggested that EGFR‐inhibitors with small aniline substituents in the 4‐position of the quinazoline ring were more effective than inhibitors with large substituents in that position. Sapitinib showed significantly reduced tumour growth in two xenograft mouse models (U‐CH1 xenograft and a patient‐derived xenograft, SF8894). One of the resistant cell lines (U‐CH2) was shown to express high levels of phospho‐MET, a known bypass signalling pathway to EGFR. Neither amplifications (EGFR, ERBB2, MET) nor mutations in EGFR, ERBB2, ERBB4, PIK3CA, BRAF, NRAS, KRAS, PTEN, MET or other cancer gene hotspots were detected in the cell lines. Our findings are consistent with the reported (p‐)EGFR expression in the majority of clinical samples, and provide evidence for exploring the efficacy of EGFR inhibitors in the treatment of patients with chordoma and studying possible resistance mechanisms to these compounds in vitro and in vivo. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.     

自噬与炎性反应之间分子联系的研究进展

自噬是机体重要的代谢过程,参与细胞的多种应激反应如炎性反应。自噬与炎性反应之间具有密切的分子联系。一方面,多种炎性反应介质可调控自噬发生及自噬基因的转录;另一方面,自噬通过多种方式可抑制机体过激的炎性反应。因此,机体的多种炎性反应疾病包括克罗恩病(CD)可能与自噬缺陷相关。     

自噬在肠黏膜屏障功能作用机制的研究进展

自噬是细胞通过膜囊泡结构降解胞质内大分子物质和受损细胞器维持机体稳态的生物学过程。在肠黏膜屏障功能发生障碍过程中,自噬对于维持肠上皮细胞的存活起关键性作用。负调控自噬可导致肠道炎性反应和肿瘤的发生。     

细胞自噬在宫颈癌中的相关研究进展

细胞自噬指细胞利用溶酶体降解细胞质中错误折叠的蛋白质及受损细胞器等,重新利用降解物质及胞内有害物质的过程,以维持细胞内环境稳定。正常状态下细胞的自噬维持在低水平,当细胞处在不利因素条件下,自噬也会被激活应对不利因素。自噬在肿瘤发生、发展、转移、复发、药物抵抗等方面有着重要作用,但自噬在这些方面的详细机制仍不清楚。我们在文中对宫颈癌细胞中自噬相关基因的表达情况进行了阐述,自噬治疗在宫颈癌中具有重要的应用前景。     

细胞自噬在骨肉瘤中的作用机制

文题释义：自噬(autophagy)：是由Ashford和Porter在1962年发现细胞内有“自己吃自己”的现象后提出的,是指从粗面内质网的无核糖体附着区脱落的双层膜包裹部分胞质和细胞内需降解的细胞器、蛋白质等成分形成自噬体,并与溶酶体融合形成自噬溶酶体,降解其所包裹的内容物,以实现细胞本身的代谢需要和某些细胞器的更新。哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin,mTOR)信号通路：mTOR是一种蛋白激酶,其催化亚单位是两种生化上截然不同的复合物：mTORC1和mTORC2,在控制翻译和细胞周期进程以及自噬的负调节中非常重要。近来发现mTOR通路的抑制有助于自噬的启动,AKT抑制剂及其下游靶点mTOR信号具有抗癌作用。背景：自噬似乎在癌症形成的早期阶段充当肿瘤抑制因子,然而在后期阶段,自噬可能支持或促进肿瘤生长、扩散,并可能增加治疗耐药性。                                                                                      目的：综述国内外相关文献,总结自噬与骨肉瘤的关系,探讨细胞自噬在骨肉瘤中的作用机制及治疗前景。方法：中文以“自噬,化学治疗,自噬相关因子,骨肉瘤,细胞凋亡,耐药”检索 CNKI、万方、维普数据库;英文以“Autophagy,Chemotherapy,Autophagy related factors,Osteosarcoma,Apoptosis,Drug resistance”检索 PubMed数据库,收录与自噬在骨肿瘤中的作用机制相关的文献报道,按照选文标准对文献进行筛选,并排除重复性研究及年代久远的文献。共纳入52篇文章进行综述分析。结果与结论：①自噬可能是促进和预防癌症的重要因素,其作用随着肿瘤发生发展而表现出不同;②对自噬途径的充分了解和调节可能提高肿瘤治疗的潜力;③考虑到自噬在肿瘤生物学中的重要性,研究自噬调节miRNA将有助于更好地了解恶性肿瘤,并可能会发现新的疾病标志物和治疗策略;④上述结论仍需要大量更科学的研究及合理的实验予以证实。ORCID:0000-0003-1255-5479(李时斌)中国组织工程研究杂志出版内容重点：人工关节;骨植入物;脊柱;骨折;内固定;数字化骨科;组织工程     

UCH-L1 involved in regulating the degradation of EGFR and promoting malignant properties in drug-resistant breast cancer

Ubiquitin carboxy terminal hydrolase-L1 (UCHL1) belongs to the UCH proteases family that deubiquitinates ubiquitin-protein conjugates in the ubiquitin-proteasome system. Our previous research showed that UCH-L1 and EGFR could regulate the expression of P-gp, CD147 and MMPs in multi-drug resistance (MDR) breast cancer cells, respectively. But it is still unclear whether direct regulation exists between the UCH-L1 and EGFR in MDR breast cancer. In order to clarify this, MDR human breast carcinoma cell line MCF7/Adr, that expresses relatively high UCH-L1, and its parental cell line MCF7, that expresses relatively low UCH-L1, were chosen for this study. We added ubiquitin proteasome inhibitor MG-132 into the culture of MCF7/Adr cells and transfected pIRES2-UCH-L1-EGFP plasmid into MCF7 cells, respectively. Using quantitative real-time polymerase chain reaction and western blot analyses, we found accompanying over-expression of UCH-L1, EGFR was up-regulated in both MCF7/ADR and MCF7 cells. Preliminary results indicated the degradation of EGFR might be regulated by ubiquitin level. So we speculated that up-regulated UCH-L1 could promote expression level of EGFR, thereby enhance the invasion and metastasis abilities of tumor cells. Moreover, to further explore the role of UCH-L1 and EGFR, we investigated the expression of UCH-L1, EGFR and P-gp in 65 local advanced breast cancer cases by immunohistochemistry assay. The result showed that the patients not responding to chemotherapy had higher UCH-L1, EGFR and P-gp expression levels and more lymph nodes metastasis. The Kaplan-Meier survival analysis showed that the patients with elevated UCH-L1 expression after chemotherapy presented shorter overall survival and disease free survival times than those with down-regulated or unchanged expression of UCH-L1. Our findings suggest that UCH-L1 may be an indicator of chemotherapy-response and poor-survival in breast cancer. UCH-L1 might be an appropriate target for improving chemo-resistant breast cancer therapy.