Purpose: Breast cancer is one of the most common tumors with high malignancy and metastatic rate. DNAJA1 is closely related to tumor progress in several tumors. However, the role and mechanisms of DNAJA1 in the metastasis and proliferation of breast cancer are unknown. Methods: Immunohistochemistry and western blot were used to detect the protein expression genes. In vivo and vitro experiments were performed to evaluate the proliferation, invasive and metastatic abilities of breast cancer cells. Results: DNAJA1 was high expressed in 234 cases of breast cancer tissues and associated with metastasis, p53 expression and poor survival for patients. Knock down of DNAJA1 decreased the number of plate clone formation and the OD value of CCK8 assays in breast cancer cells. Depletion of DNAJA1 also in decreased the invasive abilities of breast cancer cells. In vivo, knock down DNAJA1 decreased the growth of subcutaneous tumor and lung metastatic nodes. Mechanically, DNAJA1 could bind with P53-(R175H) and reduced its degradation. Up regulation of DNAJA1 in mutant P53-(R175H) breast cancer cell promoted the nuclear translocation of p65, activated NF-kappa B pathway and enhanced the transcription of its downstream genes such as MMP9, CXCL10 et al. Blockade of NF-kappa B pathway effectively rescued the effects of DNAJA1 on proliferation and metastasis in breast cancer. Conclusion: Our study reveals that DNAJA1 is up regulated in breast cancer and promotes breast cancer cells proliferation and metastasis via P53-(R175H)/NF-kappa B pathway. It might be a potential prognosis marker for the breast cancer patients.

目的 探讨DNAJ热休克蛋白40 家族成员A1(DNAJA1)在胃癌中的表达、临床病理特征及其对胃癌细胞生物学行为的影响.方法 采用免疫组化PV两步法检测 160 例胃癌石蜡组织中DNAJA1 的表达;应用Western blot及RT-PCR检测胃癌细胞中DNAJA1 表达水平;运用MTT、Transwell侵袭实验检测DNAJA1 对胃癌细胞增殖和侵袭能力的影响.结果 DNAJA1 在胃癌组织中高表达率为69.37％,高于癌旁正常胃组织(44.37％,P＜0.001).临床病理特征分析发现,DNAJA1 高表达与淋巴结转移(P=0.019)、p53 状态(P=0.003)、HER-2 状态(P =0.001)、浸润深度(P =0.035)及WHO分型(P =0.008)相关.体外实验证实,过表达DNAJA1 促进胃癌细胞增殖和侵袭(MTT MOCK组:0.45±0.02,DNAJA1 组:0.74±0,P＜0.05;Tran-swell MOCK组:48.00±7.54,DNAJA1 组:144.33±9.50,P＜0.01);干扰DNAJA1 抑制胃癌细胞增殖和侵袭(MTTNC组:0.92±0.02,siRNA1 组:0.69±0.08,siRNA2 组:0.74±0.03,P＜0.05;Transwell NC 组:132.66±4.16,siRNA1 组:26.00±3.60,siRNA2 组:38.00±5.29,P＜0.01).结论 DNAJA1 促进胃癌细胞增殖和侵袭,其在胃癌中高表达与肿瘤TNM分期、预后有关,可作为预测胃癌患者肿瘤分期及预后的生物学标志物.

目的:分析DNAJ热休克蛋白40家族成员A1[DNAJ heat shock protein 40 family(Hsp40)member A1,DNAJA1]在人乳腺癌组织中的表达及其与患者临床病理特征的关系,探讨DNAJA1对乳腺癌细胞增殖及侵袭的影响,揭示其与乳腺癌患者预后及化疗抵抗的关系.方法:免疫组织化学检测169例乳腺癌患者配对石蜡组织及120例接受新辅助化疗前穿刺活检石蜡组织中DNAJA1的表达情况.CCK-8、平板克隆、Transwell侵袭及细胞划痕实验检测DNAJA1对乳腺癌细胞增殖和侵袭的影响.结果:DNAJA1在原发灶及转移灶的乳腺癌组织中的表达明显高于癌旁组织(P＜0.001,P＜0.001).临床病理分析发现,DNAJA1的高表达与分子分型、p53的突变和肿瘤复发密切相关.DNAJA1高表达还与患者的较短生存时间相关(P=0.023).另外,DNAJA1在接受新辅助化疗的Miller-Payne(MP)5级组患者的癌组织中表达明显低于其他组(P=0.000 4).体外实验证实,敲低DNAJA1能明显抑制乳腺癌细胞的增殖和侵袭.结论:DNAJA1能促进乳腺癌细胞的增殖和侵袭,且DNAJA1在乳腺癌组织中高表达与患者不良预后及化疗抵抗相关,可作为预测患者预后及新辅助化疗效果的一个新靶点.

OBJECTIVES:Use of immune checkpoint inhibitors as first-line treatment for advanced (stage IIIB/IV) non-small cell lung cancer (NSCLC) remains controversial. Clinical trials comparing single-drug immunotherapy (IO) with immunotherapy plus chemotherapy (IC) are lacking. We aimed to compare the efficacy of IO alone with that of IC as first-line treatment for advanced NSCLC.DESIGN:Systematic review.DATA SOURCES:PubMed, the Cochrane Library and Embase for related studies on NSCLC; ClinicalTrials.gov, American Society of Clinical Oncology Meeting Library and World Conference on Lung Cancer for relevant conference abstracts (to July 2019).ELIGIBILITY CRITERIA:Articles meeting the following criteria were selected: (1) randomised controlled trials on NSCLC treatment, (2) all individuals in the studies had not received treatment previously and (3) research on IO monotherapy using programmed death-1/programmed death ligand-1 (PD-L1) inhibitors or IC.DATA EXTRACTION AND SYNTHESIS:After reading the original literature, two reviewers independently extracted the relevant information. The primary outcomes were progression-free survival (PFS), overall survival (OS) and objective response rate (ORR). We also extracted data on treatment-related adverse events and immune-related adverse events (irAEs).RESULTS:Overall, 10 randomised controlled clinical trials (n=5765) were included. As first-line treatment for advanced NSCLC, IC tended to yield better PFS, OS and ORR than did IO. Furthermore, IC yielded significantly better PFS than IO when tumour PD-L1 expression was at least 50% (HR: 1.81, 95% CI: 1.18 to 2.78) and yielded a better OS and PFS when tumour PD-L1 expression was at least 1%; IO resulted in fewer adverse events than did IC. However, the incidence of irAEs was higher for IO than for IC.CONCLUSIONS:The findings of the indirect comparison indicate that IC as first-line treatment for advanced NSCLC is significantly more effective than IO in patients with PD-L1 expression in at least 50% of tumour cells.TRIAL REGISTRATION NUMBER:CRD 42018116589.