过表达SOCS5对非小细胞肺癌增殖、迁移和侵袭的作用及机制研究

摘要：目的?分析细胞因子信号传导抑制因子5(SOCS5)对非小细胞肺癌(NSCLC)细胞增殖、迁移和侵袭能力的影响，并探讨其可能的作用机制。方法?应用癌症基因组图谱(TCGA)数据库分析SOCS5在肺癌组织中的表达情况； western blot检测SOCS5在NSCLC细胞系PC-9、A549和SPC-A-1及正常支气管上皮细胞系16HBE中的表达水平；选择SOCS5表达水平最低的NSCLC细胞系进行SOCS5过表达质粒转染，实验设对照(NC)组和SOCS5过表达质粒转染(oe-SOCS5)组。采用MTS试验检测各组细胞增殖能力；划痕试验检测各组细胞迁移能力；Boyden试验检测各组细胞侵袭能力；western blot检测各组细胞中PI3K/Akt/mTOR信号通路活性。结果?TCGA数据库分析结果显示，SOCS5?mRNA在肺腺癌和肺鳞癌组织中的表达水平显著低于正常肺组织(P<0.05)。western blot结果显示，SOCS5蛋白在PC-9、A549和SPC-A-1细胞中的表达水平均低于其在16HBE细胞中的表达水平(P<0.05)；选择表达水平最低的PC-9细胞进行SOCS5过表达质粒转染，结果发现与NC组相比，oe-SOCS5组PC-9细胞增殖、迁移和侵袭能力均降低(P<0.05)；western blot结果显示，与NC组相比，oe-SOCS5组细胞pPI3K、pAkt和pmTOR蛋白的表达水平均降低(P<0.05)。结论?SOSC5在NSCLC中呈异常低表达，过表达SOCS5可抑制NSCLC细胞的增殖、迁移和侵袭能力，抑制PI3K/Akt/mTOR信号通路的激活可能是作用机制之一。     

miR-124a和miR-449a对非小细胞肺癌的诊断价值

目的 探讨微小RNA-124a(miR-124a)和微小RNA-449a(miR-449a)对非小细胞肺癌(NSCLC)的诊断价值.方法 选取行手术切除肿瘤的NSCLC患者90例(NSCLC组),出院随访36个月,根据术后复发情况分为复发组(56例)和未复发组(34例).另选取肺部良性结节患者60例(良性结节组)、健康...     

Pembrolizumab for the treatment of non-small cell lung cancer

ABSTRACT

Introduction: Immune checkpoint inhibitors targeting programmed death protein 1 (PD-1) receptor and its ligand, PD-L1, have recently led to significant and durable improvements in the clinical outcomes of some types of cancers including lung cancer.

Areas covered: Pembrolizumab was approved by the US FDA for the treatment of advanced or metastatic NSCLC whose disease has progressed after other treatments and with tumors that express PD-L1. In the phase I KEYNOTE-001 trial, the overall response rate (ORR) was 19.4%, the median progression-free survival (PFS) and overall survival (OS) were 3.7 months and 12.0 months for 495 unselected NSCLC patients. Strong PD-L1 expression (≥ 50%) was associated with higher ORR, longer PFS, and longer OS. The phase II/III randomized KEYNOTE-010 trial demonstrated that pembrolizumab improved OS versus docetaxel in patients with previously treated NSCLC.

Expert opinion: Pembrolizumab, demonstrated durable response and prolonged OS especially in NSCLC patients with high expression of PD-1, thereby suggests a new treatment paradigm. However, many issues remain to be explored, including the identification of other robust biomarkers that can accurately predict the immune-responsiveness of tumors. Along with the identification of predictive biomarkers, further understanding of the tumor microenvironment is necessary to improve treatment outcomes through combinations of immunotherapy or combined with other targeted therapies.     

血清miR-6801在非小细胞肺癌辅助诊断中的临床意义

目的探讨血清miR-6801在非小细胞肺癌(NSCLC)患者中的表达水平及其在NSCLC辅助诊断中的临床意义。方法采用实时荧光定量聚合酶链反应(PCR)检测40例健康人和78例NSCLC患者血清中miR-6801的表达量,并构建受试者操作特征(ROC)曲线计算血清miR-6801的灵敏度和特异度。结果 NSCLC患者血清中miR-6801的表达水平显著低于健康者,差异有统计学意义(P0.05);血清miR-6801在Ⅲ期+Ⅳ期中的表达水平显著低于Ⅰ期+Ⅱ期(P0.05);血清miR-6801对NSCLC检测的灵敏度为51.9%;miR-6801对Ⅰ期、Ⅱ期NSCLC检测的灵敏度为40.6%。结论 NSCLC患者miR-6801的检测对于NSCLC的辅助诊断和早期诊断有一定的临床应用价值。     

肿瘤相关巨噬细胞促进非小细胞肺癌细胞增殖和侵袭的研究

目的研究肿瘤相关巨噬细胞(TAMs)对非小细胞肺癌增殖、转移的影响。方法免疫组化方法分析肺癌组织中巨噬细胞浸润情况。CCK-8法和Transwell法分别检测单核巨噬细胞系THP-1(构建为M2型TAMs后)对肺癌细胞系A549细胞增殖和侵袭能力的影响。结果免疫组化结果显示,TAMs浸润数在肺癌组织中显著多于癌旁组织。激活诱导的TAMs细胞促进A549细胞的增殖和侵袭。结论巨噬细胞浸润增加造成的肿瘤周围炎症微环境可能是肺癌发展的机制之一。     

同步放化疗治疗非小细胞肺癌的临床研究

目的观察同步放化疗治疗非小细胞肺癌的疗效及毒性反应。方法 32例Ⅱ~Ⅲb期非小细胞肺癌患者接受同步放化疗。6MVX线加速器常规分割放射治疗,2 Gy/次,5次/周,总计量为60~66 Gy(6~7周)。放疗开始后同步进行EP方案:VP-16 100 mg/m2,第1~3天;DDP 30 mg/m2,第1~3天,3周为1个周期,共化疗4个周期。结果近期有效率为84.38%,1年生存率为68.75%。主要的毒副反应为骨髓抑制(71.88%),胃肠道反应(75.00%),放射性食管炎(56.25%)和放射性肺炎(21.88%)。结论 EP方案同步放疗治疗非小细胞肺癌疗效确切,毒副反应可耐受,值得在临床上进一步推广。     

多西他赛单药一线治疗晚期非小细胞肺癌临床研究

目的探讨多西他赛单药一线治疗晚期非小细胞肺癌临床疗效及不良反应。方法48例晚期非小细胞肺癌患者,多西他赛75m4g／lm2静脉滴注,第1天。21d为1个周期,治疗2～4个周期后评价临床疗效及不良反应。结果48例患者共化疗140个周期,中位化疗2．9个周期。RR为25．O％,DCR为56．3％,中位无进展生存期5．3个月,中位生存期8．6个月,1年生存率35．4％。不良反应以粒细胞减少、贫血、腹泻、脱发为主。结论多西他赛单药一线治疗晚期非小细胞肺癌临床疗效良好,患者耐受性较好。     

CIMAvax-EGF,a therapeutic non-small cell lung cancer vaccine

Introduction: Lung cancer represents the most common cause of cancer death worldwide. While the prognosis remains poor, immunotherapy is giving a positive impact on survival. Cancer vaccines represent a form of active immunotherapy that historically has given modest results in terms of efficacy.

The overexpression of the EGFR by tumor cells was reported in more than half of cases of lung cancer, representing a mechanism of cancerogenesis. CIMAvax-EGF, a therapeutic vaccine for non-small cell lung cancer (NSCLC) developed in Cuba, consists of a human recombinant EGF able to induce antibodies against the autologous EGF, resulting in serum EGF withdrawal and lower EGF-EGFR interaction.

Area covered: We critically reviewed the existing literature about CIMAvax-EGF, from the Pilot studies to the efficacy controlled studies. We also overviewed the ongoing trials.

Expert opinion: CIMAvax-EGF demonstrated to be safe and immunogenic. In a phase III randomized study CIMAvax-EGF, used as a switch maintenance treatment after platinum-based chemotherapy, did not significantly improve survival. Current data are not sufficient to recommend CIMAvax-EGF as a treatment option for advanced stage NSCLC. Further studies, conducted in a context of worldwide standardized clinical practice, are needed to better define if a subpopulation of patients can benefit from the vaccination.     

MicroRNA-4521基因在非小细胞肺癌中的表达分析研究

目的:初步探索非小细胞肺癌中差异表达microRNA,并对其靶基因进行预测及相关生物信息学分析。方法:通过mirExtra2.0数据库筛选非小细胞肺癌中差异表达microRNA,采用miRDB、miRWalk和TargetScan7三个数据库预测候选分子靶基因,并利用Metascapes数据库对预测靶基因进行功能注释、KEGG通路富集以及蛋白质网络互作分析。结果:非小细胞肺癌组织及对照组织表达谱中共筛选出634个差异microRNA,依据fold change比值及文献筛选microRNA-4521为候选基因。通过靶基因预测软件共获得235个潜在靶基因,其功能主要富集在细胞增殖和分裂及中心碳代谢信号通路等方面;蛋白质网络互作分析显示主要集中在非小细胞肺癌及中心碳代谢过程中。结论:筛选目标microRNA-4521在非小细胞肺癌中显著高表达,并可能通过参与中心碳代谢信号通路的调控从而影响非小细胞肺癌的发生发展。     

TKI药物对非小细胞肺腺癌的临床效果观察

目的：探讨T K I药物对非小细胞肺腺癌的临床治疗效果。方法选取非小细胞肺腺癌患者100例,分为两组,使其有可比性。对其临床资料进行回顾分析。观察组患者采取吉非替尼治疗,对照组除不使用吉非替尼外所有治疗均同观察组。对两组患者治疗前后肿瘤大小进行比较,对观察组患者的临床效果进行统计,并记录不良反应发生情况。结果经过治疗,两组患者肿瘤均缩小,其中观察组缩小更为明显。观察组患者随访40个月,死亡31例,中位生存期16．73个月;生存期超过1年者28例（56．00％）,35例（70．00％）患者疾病进展或者出现死亡,中位无疾病进展时间12．63个月;16例（32．00％）患者达到部分缓解,中位缓解期11．37个月;20例（40．00％）患者稳定,10例（20．00％）患者进展,还有4例（8．00％）患者疗效未能作出评价。除4例疗效未能作出评价的患者外其余46例患者在接受吉非替尼治疗过程中,其临床疗效受患者年龄、是否吸烟、有无皮疹以及呼吸困难是否加重等因素影响。皮疹是吉非替尼治疗后最常见的不良反应,其次是腹泻,各种不良反应均以Ⅰ度为主,Ⅱ度和Ⅲ度很少。结论吉非替尼作为TKI的代表性药物,在治疗非小细胞肺腺癌方面有确切效果,可以延长患者的生存期,而且不良反应少,容易在临床进行推广。     

紫杉醇联合奈达铂治疗晚期非小细胞肺癌的临床观察

目的观察紫杉醇（PTX）联合奈达铂（NDP）治疗晚期非小细胞肺癌的疗效及不良反应。方法 48例晚期非小细胞肺癌患者应用紫杉醇（PTX）联合奈达铂（NDP）方案化疗：PTX 135~175 mg/m2,静脉滴注,第1天;NDP 80~100 mg/m2,静脉滴注,第2天,21 d为1个周期。结果全组48例患者中,完全缓解率（CR）3例（6.3%）,部分缓解率（PR）16例（33.3%）,稳定（SD）22例（45.8%）,病情进展（PD）7例（14.6%）。有效率（RR）为39.6%,疾病控制率（DCR）为85.4%。主要不良反应为骨髓抑制及胃肠道反应,肝、肾毒性较轻。结论紫杉醇联合奈达铂治疗晚期非小细胞肺癌不良反应轻,疗效较好,值得临床推广。     

非小细胞肺癌患者血浆纤维蛋白原检测的临床意义

目的探讨非小细胞肺癌（NSCLC）患者血浆纤维蛋白原水平与肺癌临床病理特征关系及预后的相关性。方法对55例NSCLC患者及20例健康人的血浆纤维蛋白原分别进行测定。结果NSCLC患者血浆纤维蛋白原水平显著高于健康对照组（P〈0．01）,肺癌患者血浆纤维蛋白原水平与患者的病理类型、TNM分期之间无明显关系。NSCLC患者血浆纤维蛋白原水平与其生存期之间有显著的负相关（r=-0．37,P〈0．01）。结论NSCLC患者存在血浆纤维蛋白原水平增高,血液存在高凝状态;血浆纤维蛋白原水平与患者的生存期呈负相关,血浆纤维蛋白原是反映NSCLC患者预后的重要指标。     

非小细胞肺癌患者血浆纤维蛋白原检测的临床意义

目的探讨非小细胞肺癌(NSCLC)患者血浆纤维蛋白原水平与肺癌临床病理特征关系及预后的相关性。方法对55例NSCLC患者及20例健康人的血浆纤维蛋白原分别进行测定。结果NSCLC患者血浆纤维蛋白原水平显著高于健康对照组(P<0.01),肺癌患者血浆纤维蛋白原水平与患者的病理类型、TNM分期之间无明显关系。NSCLC患者血浆纤维蛋白原水平与其生存期之间有显著的负相关(r=-0.37,P<0.01)。结论NSCLC患者存在血浆纤维蛋白原水平增高,血液存在高凝状态;血浆纤维蛋白原水平与患者的生存期呈负相关,血浆纤维蛋白原是反映NSCLC患者预后的重要指标。     

Necitumumab for non-small cell lung cancer

Introduction: Targeting the EGFR pathway is a rational approach to treat patients with advanced NSCLC. Necitumumab, a second-generation recombinant fully human immunoglobulin G1 monoclonal antibody directed against EGFR, has recently been assessed in combination with first-line cisplatin-based chemotherapy.

Areas covered: This article reviews literature on necitumumab development, from preclinical data to results of Phase III clinical trials, either published or presented in international scientific conferences. Ongoing clinical trials were searched with the clinical-trials.gov website.

Expert opinion: During the last decade, advances in treatment of metastatic NSCLC have been exclusively achieved in patients with non-squamous histology. In this context, any treatment improvement, even modest, was eagerly awaited for patients with squamous NSCLC. In this patient’s population, the SQUIRE Phase III study demonstrated a relatively small, but statistically significant survival benefit in patients treated with necitumumab in combination with standard chemotherapy (cisplatin and gemcitabin) compared with those treated with chemotherapy alone. However, the identification of predictive biomarker for treatment outcome is still needed to select the patients who will experience a large benefit from the targeted treatment.     

多西他赛单药一线治疗晚期非小细胞肺癌疗效观察

目的探讨多西他赛单药一线治疗晚期非小细胞肺癌（NSCLC）的疗效及安全性。方法将60例老年晚期NSCLC初治患者作为治疗组,另选同期初治拒绝接受化疗患者30例作为对照组。治疗组予多西他赛单药治疗,对照组予最佳支持治疗。比较2组近期疗效、远期疗效、生活质量及毒性反应。结果治疗组有效率、临床受益率显著高于对照组,中位TTP（5.8个月）、中位OS（11.2个月）较对照组（2.6个月、4.6个月）显著延长;治疗组1年生存率（40.0%）显著高于对照组（10.0%）;治疗组药物毒性反应较轻。结论多西他赛单药一线治疗晚期NSCLC患者安全有效,值得临床推广应用。     

Ipilimumab (MDX-010) in the treatment of non-small cell lung cancer

Respiratory syncytial virus (RSV) is a major cause of bronchiolitis and pneumonia in young children and the elderly. Despite its clinical importance, there is no licensed vaccine available at present. Vaccine development has been hampered by observations of increased pathology after RSV infection in infants vaccinated with formalin-inactivated RSV; incomplete immunity following natural infection; and the need to be effective during the neonatal period when levels of maternal antibody are high. Four categories of RSV vaccine carriers – live-attenuated RSVs, recombinant vectors expressing the protective antigens of RSV, DNA vaccines and subunit vaccines – have been evaluated in animal models and/or clinical trials. So far, studies with live-attenuated virus vaccines highlight the need to improve immunogenicity whilst maintaining a suitable level of attenuation. Studies with recombinant vectors, DNA and subunit vaccines illustrate the pivotal nature of the vaccine carrier in determining the balance between immune-mediated protection against infection and the induction of immune-mediated pulmonary pathology.     

复方乌骨藤汤治疗晚期非小细胞肺癌的临床研究

目的观察和评价复方乌骨藤汤治疗晚期非小细胞肺癌的临床疗效和毒副作用。方法84例晚期非小细胞肺癌患者均经病理组织学检查确诊。复方乌骨藤汤每日3次,口服,4周为1个周期,共治疗2个周期。结果84例患者均可评价,完全缓解(CR)16例,部分缓解(PR)31例,稳定(SD)24例,恶化(PD)13例,患者的近期有效率56.0%,疾病进展时间(TTP)5.4个月,中位生存期11.2个月,1年生存率71.4%。主要毒副作用为个别患者血红蛋白减少,血小板减少和心电图异常,但均可以耐受。结论复方乌骨藤汤治疗晚期非小细胞肺癌有较好的临床疗效,毒副作用比较轻,患者均可以耐受,可改善患者的生存质量,延长生存时间。     

吉西他滨联合紫杉醇治疗晚期非小细胞肺癌的临床研究

目的探讨紫杉醇联合吉西他滨治疗晚期非小细胞肺癌(NSCLC)的近期疗效和安全性。方法老年晚期非小细胞肺癌92例,随机分为2组:吉西他滨1 000 mg联合紫杉醇120 mg方案(TG组)45例,吉西他滨联合卡铂方案(GC组)47例,每3~4周为l周期,连续用药3周期。结果近期疗效:2组组间总有效率(RR)及疾病控制率(DCR)经比较,差异无统计学意义;TG组中位生存期为8.6个月,3年生存率约6.6%;GC组中位生存期为9个月,3年生存率约6.4%;主要不良反应是Ⅲ~Ⅳ度骨髓抑制、血液学毒性、肝功能损害等,TG组血小板减少、白细胞减少以及贫血(Ⅲ~Ⅳ度)发生率明显少于GC组。结论吉西他滨联合紫杉醇治疗老年晚期NSCLC疗效较好,毒性反应较轻。