FLASH radiotherapy (FLASH-RT) is a radiotherapy technique that achieves ultra-high dose rates in a fraction of a second. Based on data from experimental animal models, FLASH-RT appears to protect a number of normal tissues from radiation-induced damage, including the brain, gastrointestinal tract, and lung, while conventional radiotherapy (CONV-RT) causes radiation-induced toxicity in these tissues. In this review, we provide a brief summary of the history of radiation therapy and focus on some of the most recent FLASH-RT papers and findings. It is particularly noteworthy that pulmonary fibrosis represents a common complication of radiotherapy. New evidence indicates that FLASH-RT, unlike traditional radiotherapy methods, might help protect lung cancer patients from developing pulmonary fibrosis caused by radiation. FLASH-RT will advance more quickly than anticipated, although there are still a number of unresolved concerns. FLASH-RT will be a safer and more effective option for lung cancer treatment.

BACKGROUND:Berbamine (BBM) has been reported to play an important role in the anti-inflammatory and anti-neoplastic activities. However, whether BBM mediates the anti-tumor efficacy in renal cell carcinoma (RCC) cells and the potential molecular mechanisms remain unclear. METHODS:The effects of BBM on the proliferation, colony formation, cell cycle, cell migration and invasion abilities were performed in RCC cells 786-O and OSRC2, and the effect of BBM on tumor formation was further explored. Furthermore, the effects of BBM on the expression of fat mass and obesity associated gene (FTO) and its target genes were investigated. Finally, the effects of BBM on the proliferation, and invasion of RCC cells after knockdown of FTO were detected. RESULTS:BBM effectively inhibited the proliferation, migration and invasion of RCC cells in a dose-dependent manner, and BBM also significantly inhibited the growth of tumor in vivo, which has fewer toxic effects on the other organs. Molecular mechanistic studies showed that BBM significantly promoted the expression of FTO mRNA and protein in RCC cells, and knock-down of FTO by siRNA transfection reversed the inhibitory effect of BBM on the growth and invasion of RCC cells. CONCLUSION:Collectively, our findings revealed that targeting the tumor suppressive FTO by BBM is a new option to inhibit RCC cells growth and metastasis, providing a good drug candidate potential for development novel therapeutics against metastatic RCC.

目的 观察脉络膜黑色素瘤(CM)患者的临床及病理学特点.方法 回顾性病例研究.2011年至2021年于苏州大学附属第二医院病理科收检并经病理检查确诊的CM患者15例15只眼的石蜡标本纳入研究.通过医院信息系统回顾性收集患者年龄、性别、临床表现、治疗方案、病理检查结果等.分析其临床特点、免疫组织化学(免疫组化)染色、分子病理学特点.结果 15例患者中,男性8例,女性7例;平均年龄61岁;均为单眼发病.主述视力下降、视物模糊、眼前黑影遮挡感8例;眼红、流泪、脓性分泌物1例;视力丧失、无光感2例;伴视网膜脱离4例.肿瘤平均直径1.4 cm.肿瘤大体外观呈半球形、"蘑菇形"或扁平弥漫形.肿瘤细胞多呈实性、片状、交叉簇状排列,部分围绕血管呈假"菊形"团样排列伴坏死.15只眼中,梭形细胞型、上皮样型、混合细胞型分别为6、2、7只眼.胞质部分嗜双色或嗜酸性,部分透明,部分富含色素;细胞黏附性差,异形性显著,染色质粗糙,核分裂象多见,核仁明显.免疫组化染色结果显示,所有患眼肿瘤组织中HMB45、SOX10、S100、Melan-A均为阳性;上皮源性标记AE1/3、淋巴源性标记LCA以及神经内分泌标记CgA、Syn均为阴性.基因检测结果显示,所有患者均未发现C-KIT、BRAF、NRAS基因突变.随访时间为8～98个月.15例患者中,生存12例;肿瘤复发和(或)转移死亡3例.结论 CM临床无特异性表现,确诊依赖组织学形态及免疫组化染色.

目的 探讨小檗碱(BER)对人肾癌细胞侵袭、迁移的抑制作用及可能机制.方法 以人肾癌OSRC-2细胞为对象进行实验.采用alamarBlue法测定0(对照组)、25、50、75、100、125、150、175、200 μmol/L BER作用24、48 h后对OSRC-2细胞增殖的抑制作用.用0(对照组)、50、100 μmol/L BER作用于细胞48 h后,通过流式细胞术分析BER对细胞周期的影响;通过细胞划痕实验观察24、36 h时各组细胞的迁移能力;通过Transwell实验观察作用24 h时各组细胞的侵袭能力;并通过Western blot法检测上述药物作用48 h后细胞中甲基转移酶样蛋白3(METTL3)的蛋白表达,通过RNA甲基化定量试剂盒检测各组细胞内RNA的N6-甲基腺嘌呤(m6A)水平.结果 与对照组比较,不同浓度BER均可显著升高OSRC-2细胞的增殖抑制率(P＜0.01),并呈时间和浓度依赖性趋势;50、100 μmol/L BER作用48 h后可将细胞周期阻滞在G0/G1期(P＜0.01);50、100 μmol/L BER组细胞的迁移、侵袭能力均显著降低(P＜0.05或P＜0.01),细胞中METTL3蛋白的表达水平和RNA的m6A水平均显著降低(P＜0.01).结论 BER可通过下调METTL3的表达,进而抑制m6A水平,从而抑制人肾癌细胞的侵袭、迁移.

Objective:To investigate the differences in small intestinal toxicity and taxonomic composition,diversity,and functional pathways of gut microbiome and metabolome after different radiotherapies in mouse colorectal cancer(CRC)model.Methods:Azoxymethane/dextran sodium sulfate(AOM/DSS)-induced mouse CRC model was treated with single pulse FLASH-RT(dose rate 100 Gy/s)or CONV-RT(dose rate 2 Gy/min)at whole abdomen.At 12 d after radiotherapy,sections of small intestinal tract tissue were dissected for hematoxylin and eosin(HE)staining and the fresh feces were collected for 16S ribosomal RNA(rRNA)microbiome sequencing and liquid chromatography and mass spectrometry(LC-MS)metabolomics sequencing to assess changes in the gut microbiota and metabo-lites.Microbial high-throughput 16S rRNA data was analyzed with QIIME2 and LEfSe softwares.ProteoWizard,XCMS and Ropls softwares were used for LC-MS analysis.Results:HE staining showed that FLASH-RT maintained small intestinal integrity and reduced the radiotherapy-induced injury.Sequencing analysis of gut fecal microbiome showed that phylum Bacteroidetes and genera Prevotella and Lactobacillus of microbial community were increased after FLASH-RT.Metabolomics sequencing analysis revealed that the metabolites after FLASH-RT were enriched in amino acid metabolism,while cholesterol metabolism was top enriched after CONV-RT.Conclusions:FLASH-RT significantly mitigates the small intestine tissue damage compared with CONV-RT.FLASH-RT and CONV-RT have different impact on gut microbiota and its metabolites.Our results provide a theoretical basis for the early evaluation,prediction and individualized treatment of the irradiation effect after novel FLASH-RT on tumors through the evaluation of intestinal microbiota and metabolites.

为揭示FLASH-RT的潜在作用机制,本文研究了超高剂量率放疗(FLASH-RT)和常规放疗(CONV-RT)对小鼠脾脏基因表达谱的影响.将11只C57BL/6J雄性小鼠按照随机数字法分为健康对照组(Ctrl组)、常规照射组(CONV-RT组)和超高剂量率照射组(FLASH-RT组).CONV-RT组和FLASH-RT组采用相应的方式对小鼠进行腹部照射,剂量均为12 Gy,照后将小鼠脱颈处死,收集脾脏组织,提取总RNA.通过转录组测序技术和生物信息学分析方法,探究小鼠受照后脾脏组织基因表达谱的变化.结果显示:FLASH-RT组与CONV-RT组之间共有936个差异表达基因(DEGs),其中上调基因321个、下调基因615个;FLASH-RT组与Ctrl组之间共有1 337个差异表达基因,其中上调基因322个、下调基因1 015个;CONV-RT组与Ctrl组之间共有1 082个差异表达基因,其中上调基因445个、下调基因637个.基因本体论(GO)分析显示,FLASH-RT组与CONV-RT组中的DEGs主要涉及对其他生物的防御反应及与其他生物细胞和双链RNA结合等功能,FLASH-RT组与Ctrl组中的DEGs主要涉及对其他生物的防御反应及与宿主细胞细胞质和双链RNA结合等功能.京都基因与基因组百科数据库(KEGG)分析显示,FLASH-RT组与CONV-RT组之间小鼠脾脏组织的差异基因涉及NOD样受体信号通路及抗原加工提呈等多种通路,FLASH-RT组与Ctrl组之间小鼠脾脏组织的差异基因涉及单纯疱疹感染及NOD样受体信号通路等多种KEGG通路.本研究展示了 FLASH-RT和CONV-RT可引起小鼠脾脏组织中基因表达谱的改变,这些DEGs涉及多种放射生物学相关的功能通路,FLASH-RT可以降低辐射引起的脾损伤,其机制可能与免疫应答引起的辐射抵抗有关.

目的 探讨成髓细胞瘤转录因子第2亚型(MYBL2)在前列腺癌组织中的表达及其临床意义.方法 收集2018年1月至2019年12月82例前列腺癌组织和29例良性前列腺组织.采用免疫组织化学法检测前列腺组织芯片中MY-BL2的蛋白表达水平,并分析其表达水平与临床病理特征的关系.采用实时荧光定量PCR(qPCR)法检测2019年20对前列腺癌组织及癌旁组织中MYBL2 mRNA的表达.采用GEPIA数据库分析MYBL2 mRNA在前列腺癌组织中的表达及与预后的关系.结果 MYBL2蛋白在前列腺癌组织中的高表达率为92.7％(76/82),显著高于良性前列腺组织的48.3％(14/29),差异有统计学意义(P<0.001);qPCR检测结果显示,在前列腺癌组织中MYBL2 mRNA的相对表达量为1.71±0.24,在癌旁组织中为1.0±0.21,差异有统计学意义(P=0.035).GEPIA数据库分析显示,MYBL2 mRNA在492例前列腺癌组织中的表达水平显著高于152例良性前列腺组织(P<0.05).MYBL2蛋白表达与前列腺癌临床分期、WHO/ISUP分级分组、Gleason分级评分、淋巴结转移和脉管侵犯有关(P<0.05),与年龄和神经侵犯无关(P>0.05).GEPIA数据库生存分析结果显示,MYBL2高表达前列腺癌患者的无病生存期明显缩短(P<0.001).结论 MYBL2在前列腺癌组织中表达显著上调,与肿瘤发生、进展、不良临床病理特征和预后有关.

Objective:To investigate the clinicopathological features, immunohistochemical phenotypes and molecular characteristics of adenosquamous carcinoma of the lung(ASC)in elderly patients.Methods:Clinical data of 72 ASC patients in the Department of Pathology, The Second Affiliated Hospital of Soochow University from January 2009 to December 2020 were retrospectively analyzed, and 48 patients aged ≥60 years were selected.Clinical manifestations, imaging findings, histopathological and immunohistochemical characteristics were collected, and gene mutations were detected by the amplification refractory mutation system(ARMS-PCR).Results:There were 48 patients including 32 males and 16 females with a mean age of 70 years(range: 60-84 years). The maximum diameters of the tumors ranged from 0.3 to 9.0 cm(mean: 2.8 cm). Microscopically, the tumors contained two components, squamous cell carcinoma and adenocarcinoma, with the squamous cell carcinoma tissue showing intercellular bridges and the adenocarcinoma tissue showing papillary, acinar or tubular structures.Immunohistochemistry assays detected varying expression levels of CK7(30/31), CK5/6(20/28), TTF1(12/31), P40(15/17), and P63(12/13). Molecular testing showed that the EGFR mutation rate was 58.8%(10/17)and the ALK fusion mutation rate was 5.9%(1/17), while ROS1 and MET mutations were not detected.All 48 patients underwent surgical resection.Conclusions:ASC cases are relatively rare and prone to misdiagnosis.The diagnosis requires the combination of HE morphology, immunohistochemistry and imaging examination, and surgery is the main treatment option.The mutation rate of the EGFR gene is relatively high in ASC patients.

BACKGROUND:Clear cell renal cell carcinoma (ccRCC) is a urinary disease with high incidence. The high incidence of metastasis is the leading cause of death in patients with ccRCC. This study was aimed to identify the gene signatures during the metastasis of ccRCC.METHODS:Two datasets, including one gene expression profile dataset and one microRNA (miRNA) expression profile dataset, were downloaded from Gene Expression Omnibus (GEO) database. The integrated bioinformatics analysis was performed using the (limma) R package, miRWalk, DAVID, STRING, Kaplan-Meier plotter databases. Quantitative real-time polymerase chain reaction (qPCR) was conducted to validate the expression of differentially expressed genes (DEGs) and DE-miRNAs.RESULTS:In total, 84 DEGs (68 up-regulated and 16 down-regulated) and 41 DE-miRNAs (24 up-regulated and 17 down-regulated) were screened from GSE22541 and GSE37989 datasets, respectively. Furthermore, 11 hub genes and 3 key miRNAs were identified from the PPI network, including FBLN1, THBS2, SCGB1A1, NKX2-1, COL11A1, DCN, LUM, COL1A1, COL6A3, SFTPC, SFTPB, miR-328, miR-502, and miR-504. The qPCR data showed that most of the selected genes and miRNAs were consistent with that in our integrated analysis. A novel mRNA-miRNA network, SFTPB-miR-328-miR-502-miR-504-NKX2-1 was found in metastatic ccRCC after the combination of data from expression, survival analysis, and experiment validation.CONCLUSION:In conclusion, key candidate genes and miRNAs were identified and a novel mRNA-miRNA network was constructed in ccRCC metastasis using integrated bioinformatics analysis and qPCR validation, which might be utilized as diagnostic biomarkers and molecular targets of metastatic ccRCC.

肾细胞癌是发生于肾小管上皮的恶性肿瘤,它被分为不同的亚型.透明细胞肾细胞癌(clear cell renal cell carcinoma,CCRCC)是肾脏恶性肿瘤中最常见的亚型,约占80％.转移作为肿瘤发展进程中的关键事件,是影响CCRCC预后的重要因素.肾细胞癌最常转移的部位是肺和骨,而转移到软组织的病例比较罕见.CCRCC患者未发生转移和晚期转移的5年生存率为70％～90％,而原发转移患者5年生存率仅为10％,因此需引起重视.本研究收集1例CCRCC腕部转移患者临床病理资料并随访,观察和分析其临床和病理组织学特征,与软组织疾病进行鉴别,并进行文献复习,旨在提高对该病的认识,帮助临床病理医师准确诊断疾病.

目的 探讨Semaphorin4D(Sema4D)在透明细胞肾细胞癌(clear cell renal cell carcinoma,ccRCC)中的表达及其与ccRCC临床病理特征、预后的相关性.方法 收集2009年10月～2019年7月苏州大学附属第二医院存档的ccRCC组织标本285例及癌旁正常肾脏组织标本253例,采用免疫组化EnVision法检测ccRCC及相应癌旁正常组织中Sema4D蛋白的表达,分析Se-ma4D表达与ccRCC临床病理特征的关系.利用qRT-PCR检测20对新鲜冷冻ccRCC组织和癌旁正常组织中Sema4D mRNA的表达.利用GEPIA在线数据库分析Sema4D mRNA表达与ccRCC患者预后的关联性.结果 Sema4D蛋白在ccRCC组织中的阳性率(31.2％)低于癌旁正常组织(86.6％)(χ2=167.664,P<0.001).Sema4D蛋白表达与ccRCC的ISUP/WHO分级(χ2=7.262,P=0.007)和脉管转移(χ2=4.066,P=0.044)有关联.qRT-PCR检测显示,Sema4D mRNA在ccRCC组织中表达下调(t=3.807,P=0.001).Kaplan-Meier生存分析显示,ccRCC中Sema4D蛋白高表达组患者的生存时间高于低表达组(χ2=3.868,P=0.049).GEPIA分析进一步表明:Sema4D高表达ccRCC患者的总生存时间和无瘤生存时间均高于Sema4D低表达者(P=0.0016,P=0.00052).结论 Sema4D蛋白在ccRCC中低表达,其可能成为ccRCC潜在的治疗靶点,并为ccRCC患者的预后评估提供重要的指标.

目的:观察肾上腺转移性肺腺癌的临床病理学特征，并了解其驱动基因的变化。方法:收集苏州大学附属第二医院病理科2015年12月至2018年9月诊断的4例肾上腺转移性肺腺癌临床病理学资料，采用HE染色、免疫组织化学及二代测序等方法观察组织学、免疫表型及分子病理学特征，并结合文献进行总结。结果:4例患者男性3例，女性 1例，年龄51~62岁（平均年龄58岁）。镜下观察：肿瘤细胞排列呈筛状、腺泡状、巢状及实性片状分布，细胞异型性显著，肿瘤组织坏死明显。免疫组织化学结果表明4例均不同程度表达肺组织标志物。二代测序检测结果示，有3例患者的原发肺癌和肾上腺转移癌之间的驱动基因变异存在差异。4例患者随访时间21~73个月（平均40个月），3例存活，1例死亡。结论:肺癌转移至肾上腺的病例相对少见，易造成漏诊，确诊依赖HE形态及免疫组织化学诊断，并需与其他肾上腺肿瘤进行鉴别，原发肺癌和肾上腺转移癌的驱动基因变异存在差异，患者预后较差。

目的 探讨骨髓母细胞增生症病毒癌基因同源物样2(MYB proto-oncogene like 2,MYBL2)在透明细胞性肾细胞癌(clear cell renal cell carcinoma,ccRCC)中的表达及其与临床病理特征的相关性.方法 应用qRT-PCR法检测ccRCC及癌旁正常肾组织中MYBL2 mRNA的表达水平;运用免疫组化法观察MYBL2蛋白表达,分析其表达与临床病理特征及预后的关系;利用TCGA数据库进一步验证MYBL2 mRNA的表达及其与患者预后的关系.通过计算Pearson相关系数获得与MYBL2表达显著相关的基因,且对这些基因进行GO分析.结果 与正常肾组织相比,MYBL2 mRNA在ccRCC组织中高表达(P=0.020),MYBL2蛋白在ccRCC组织中高表达(P=0.004),且其表达与远处转移相关(P=0.025).MYBL2蛋白高表达是ccRCC患者的不良预后因素.TCGA数据库分析结果进一步证实,MYBL2 mRNA在ccRCC中的表达高于正常肾组织(P<0.001),且MY-BL2基因高表达ccRCC患者的生存时间显著缩短(P<0.001).相关系数及GO分析显示,ccRCC组织中,MYBL2相关基因明显富集在ATP酶活性、丝氨酸/苏氨酸激酶活性、有丝分裂细胞周期转变的调控等功能簇.结论 MYBL2在ccRCC中高表达,可能参与了ccRCC的发生、发展和转归.

目的 探讨GRP78在胰腺癌组织中的表达及临床意义.方法 采用免疫组化EnVision法检测胰腺癌组织及相应癌旁正常导管上皮中GRP78蛋白的表达,分析GRP78表达与胰腺癌临床病理特征的关系.利用GEPIA在线数据库(包括TCGA和GTEx RNA测序表达数据)分析胰腺癌中GRP78 mRNA的表达.利用qRT-PCR检测20对新鲜冷冻胰腺癌组织和癌旁正常组织中GRP78 mRNA的表达.结果 GRP78蛋白在胰腺癌组织中的阳性率显著高于癌旁正常导管上皮(P=0.007).胰腺癌中GRP78蛋白表达水平与肿瘤大小(P=0.036)、分化程度(P=0.019)、T分期(P=0.017)显著相关.GRP78蛋白高表达是胰腺癌患者的不良预后因素(P=0.010).GEPIA分析结果 表明,胰腺癌组织中GRP78 mRNA表达水平显著高于癌旁正常组织(P<0.05).qRT-PCR实验证实GRP78 mRNA在胰腺癌组织中高表达(P<0.05).结论 GRP78蛋白在胰腺癌组织中高表达,且与肿瘤进展密切相关,可能成为胰腺癌治疗的潜在靶点.

Aberrant CTNNB1 signaling is one of the fundamental processes in cancers, especially colorectal cancer (CRC). Here, we reported that TRAF6, an E3 ubiquitin ligase important for inflammatory signaling, inhibited epithelial-mesenchymal transition (EMT) and CRC metastasis through driving a selective autophagic CTNNB1 degradation machinery. Mechanistically, TRAF6 interacted with MAP1LC3B/LC3B through its LC3-interacting region 'YxxL' and catalyzed K63-linked polyubiquitination of LC3B. The K63-linked ubiquitination of LC3B promoted the formation of the LC3B-ATG7 complex and was critical to the subsequent recognition of CTNNB1 by LC3B for the selective autophagic degradation. However, TRAF6 was phosphorylated at Thr266 by GSK3B in most clinical CRC, which triggered K48-linked polyubiquitination and degradation of TRAF6 and thereby attenuated its inhibitory activity towards the autophagy-dependent CTNNB1 signaling. Clinically, decreased expression of TRAF6 was associated with elevated GSK3B protein levels and activity and reduced overall survival in CRC patients. Pharmacological inhibition of GSK3B activity stabilized the TRAF6 protein, promoted CTNNB1 degradation, and effectively suppressed EMT and CRC metastasis. Thus, targeting TRAF6 and its pathway may be meaningful for treating advanced CRC. Abbreviations: AMBRA1: autophagy and beclin 1 regulator 1; AOM: azoxymethane; ATG5: autophagy related 5; ATG7: autophagy related 7; Baf A1: bafilomycin A1; BECN1: beclin 1; CoIP: co-immunoprecipitation; CQ: chloroquine; CRC: colorectal cancer; CTNNB1/β-catenin: catenin beta 1; DSS: dextran sodium sulfate; EMT: epithelial-mesenchymal transition; FBS: fetal bovine serum; GFP: green fluorescent protein; GSK3B/GSK3β: glycogen synthase kinase 3 beta; IgG: Immunoglobulin G; IHC: immunohistochemistry; LIR: LC3-interacting region; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; RFP: red fluorescent protein; RT: room temperature; shRNA: short hairpin RNA; siRNA: small interfering RNA; TRAF6: TNF receptor-associated factor 6; WT: wild-type; ZEB1: zinc finger E-box binding homeobox 1.

The oncogene c-Myc is aberrantly expressed and plays a key role in malignant transformation and progression of hepatocellular carcinoma (HCC). Here, we report that c-Myc is significantly up-regulated by tumor necrosis factor receptor-associated factor 6 (TRAF6), an E3 ubiquitin ligase, in hepatocarcinogenesis. High TRAF6 expression in clinical HCC samples correlates with poor prognosis, and the loss of one copy of the Traf6 gene in Traf6+/- mice significantly impairs liver tumorigenesis. Mechanistically, TRAF6 first interacts with and ubiquitinates histone deacetylase 3 (HDAC3) with K63-linked ubiquitin chains, which leads to the dissociation of HDAC3 from the c-Myc promoter and subsequent acetylation of histone H3 at K9, thereby epigenetically enhancing the mRNA expression of c-Myc. Second, the K63-linked ubiquitination of HDAC3 impairs the HDAC3 interaction with c-Myc and promotes c-Myc protein acetylation, which thereby enhances c-Myc protein stability by inhibiting carboxyl terminus of heat shock cognate 70-kDa-interacting protein-mediated c-Myc ubiquitination and degradation. Importantly, TRAF6/HDAC3/c-Myc signaling is also primed in hepatitis B virus-transgenic mice, unveiling a critical role for a mechanism in inflammation-cancer transition. In clinical specimens, TRAF6 positively correlates with c-Myc at both the mRNA and protein levels, and high TRAF6 and c-Myc expression is associated with an unfavorable prognosis, suggesting that TRAF6 collaborates with c-Myc to promote human hepatocarcinogenesis. Consistently, curbing c-Myc expression by inhibition of TRAF6 activity with a TRAF6 inhibitor peptide or the silencing of c-Myc by small interfering RNA significantly suppressed tumor growth in mice. Conclusion: These findings demonstrate the oncogenic potential of TRAF6 during hepatocarcinogenesis by modulating TRAF6/HDAC3/c-Myc signaling, with potential implications for HCC therapy.

[This corrects the article DOI: 10.1371/journal.pone.0171347.].

Inflammation is a key contributor to various types of acute and chronic liver disease. We recently reported that lack of Nur77, an orphan nuclear receptor, contributes to the pathogenesis of inflammatory diseases including inflammatory bowel disease and sepsis. However, whether Nur77 plays a critical role in liver inflammation remains to be fully understood. Employing in vivo acute liver inflammation model in wild-type (Nur77+/+) and Nur77-/- mice, we here found that Nur77 deficiency dramatically increased the production of pro-inflammatory cytokines and accelerated liver injury induced by poly (I:C)/D-GalN in Nur77-/- mice. Mechanistically, Nur77 acts as a negative regulator of NF-κB signaling by inducing the expression of ubiquitin-editing enzyme A20, a novel target gene of Nur77. Notably, in inflammatory cells, overexpression of A20 enhanced, whereas knockdown of A20 by siRNA approach impaired, the inhibitory effect of Nur77 on poly (I:C)-triggered inflammation. Collectively, our data suggest that the orphan nuclear receptor Nur77 plays a protective role in poly (I:C)-triggered liver inflammation by inducing A20, thus making it a promising target for the prevention and treatment of liver inflammation.

Nur77, an orphan member of the nuclear receptor superfamily, plays critical roles in inflammation and immunity. However, the role of Nur77 in tumor microenvironment remains elusive. Results showed that deletion of Nur77 strikingly enhanced tumor metastasis compared to WT mice. Additionally, compared to the conditioned media derived from Nur77+/+ peritoneal macrophages (CM1), the conditioned media derived from Nur77-/- peritoneal macrophages (CM2) significantly promoted the EMT of cancer cells, and greatly enhanced the migratory and invasive abilities of cancer cells. Moreover, studies using TNF-α blocking antibody demonstrated that pro-inflammatory cytokine TNF-α was indispensable in supporting CM2-induced EMT to drive cancer cells migration and invasion. Furthermore, we found that Nur77 promoted the expression of CSF-1R, a novel downstream target gene of Nur77, and subsequently enhanced the migration of inflammatory cells. Notably, infiltration of inflammatory cells in the tumors of Nur77-/- mice was markedly abrogated compared to Nur77+/+ mice. Collectively, these results revealed that host Nur77 expression was pivotal in antitumor immune response, and in inhibiting tumor metastasis.