FAM64A promotes HNSCC tumorigenesis by mediating transcriptional autoregulation of FOXM1

Head and neck squamous cell carcinoma(HNSCC)still lacks effective targeted treatment.Therefore,exploring novel and robust molecular targets is critical for improving the clinical outcome of HNSCC.Here,we reported that the expression levels of family with sequence similarity 64,member A(FAM64A)were significantly higher in HNSCC tissues and cell lines.In addition,FAM64A overexpression was found to be strongly associated with an unfavorable prognosis of HNSCC.Both in vitro and in vivo evidence showed that FAM64A depletion suppressed the malignant activities of HNSCC cells,and vice versa.Moreover,we found that the FAM64A level was progressively increased from normal to dysplastic to cancerous tissues in a carcinogenic 4-nitroquinoline-1-oxide mouse model.Mechanistically,a physical interaction was found between FAM64A and forkhead box protein M1(FOXM1)in HNSCC cells.FAM64A promoted HNSCC tumorigenesis not only by enhancing the transcriptional activity of FOXM1,but also,more importantly,by modulating FOXM1 expression via the autoregulation loop.Furthermore,a positive correlation between FAM64A and FOXM1 was found in multiple independent cohorts.Taken together,our findings reveal a previously unknown mechanism behind the activation of FOXM1 in HNSCC,and FAM64A might be a promising molecular therapeutic target for treating HNSCC.

EpCAM表达水平与HNSCC放疗疗效的相关性

目的探讨上皮细胞黏附分子(epithelial cell adhesion molecule,EpCAM)表达水平与头颈部鳞癌(head and neck squamous cell carcinoma,HNSCC)放疗疗效的相关性。方法选择2015年8月-2017年10月内蒙古医科大学附属医院放疗科收治的NHSCC患者127例,应用免疫组化染色测定肿瘤组织中EpCAM的表达水平,据此分为低表达组和高表达组,分析两组患者临床资料,随访2年,比较两组患者2年无进展生存率(progression free survival,PFS);采用logistic回归方程分析影响NHSCC放疗后复发和死亡的独立相关因素。结果EpCAM高表达组在肿瘤直径、淋巴结转移、分化程度与低表达组比较差异有统计学意义(P<0.05);EpCAM高表达组2年PFS(42.55%vs 66.67%,Log-rankχ^2=10.662,P=0.001)低于EpCAM低表达组;进展病例在肿瘤直径、分化程度、临床分期、淋巴结转移情况及EpCAM表达与未进展病例比较差异有统计学意义(P<0.05);多因素分析显示,EpCAM高表达(OR=3.674)、临床分期高(OR=1.822)、肿瘤低分化(OR=4.005)、淋巴结N2转移(OR=3.508)是影响患者2年无进展生存率的独立相关因素(P<0.05)。结论EpCAM表达水平与NHSCC放疗预后相关,可作为评价NHSCC放疗预后的预测指标。

Extraordinary Potential of High Technologies Applications: A Literature Review and a Model of Assessment of Head and Neck Squamous Cell Carcinoma (HNSCC) Prognosis

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cause of cancer mortality in the world and the 5th most commonly occurring cancer (Siegel, R. 2014). In the last few decades a growing interest for the emerging data from both tumor biology and multimodality treatment in HNSCC has been developed. A huge number of new markers need to be managed with bio-informatics systems to elaborate and correlate clinical and molecular data. Data mining algorithms are a promising medical application. We used this technology to correlate blood samples with clinical outcome in 120 patients treated with chemoradiation for locally advanced HNSCC. Our results did not find a significant correlation because of the sample exiguity but they show the potential of this tool.

HNSCC和癌前白斑病人中常见血浆叶酸降低

研究结果支持叶酸缺乏是头、颈癌形成的风险因素，并提示增补叶酸可能对有癌前期喉白斑的病人有化学预防作用。

Implantable versatile oxidized bacterial cellulose membrane for postoperative HNSCC treatment via photothermal-boosted immunotherapy

The recurrence of head and neck squamous cell carcinoma(HNSCC)after surgical resection continues to pose a major challenge to cancer treatment.Advanced HNSCC exhibits a low response rate to immune checkpoint blockade(ICB),while photothermal therapy(PTT)can increase the infiltration of immune cells to make tumors more susceptible to cancer immunotherapy.In this regard,we designed and constructed a novel multifunctional nanocomposite comprised of oxidized bacterial cellulose(OBC),thrombin(TB),and gold nanocages(AuNCs)containing anti-programmed death 1(PD-1)antibody(αPD-1@AuNCs),which allows the combination of therapies with remarkable postoperative antitumor immunity to control local tumor recurrence.TheαPD-1@AuNCs displayed high light-to-heat conversion efficiency and induced pyroptosis under near infrared(NIR)irradiation,which activated a potent antitumor immune response.More importantly,the therapeutic system could induce tumor pyroptosis and enhance antitumor immune response by increasing T-cell infiltration and reducing the immune suppressive cells,when combined with local ICB therapy,which effectively avoided the tumor recurrence in a HNSCC postoperative mice model.Overall,the newly developed multifunctional nanocomposites could be a promising candidate for the treatment of postoperative HNSCC.

Inhibitory effect of saffron on head and neck squamous cell carcinoma via targeting of ESR1 and CCND1 by its active compound crocetin

Background:Traditional Chinese medicine is promising for managing challenging and complex disorders,including cancer,and in particular,saffron is applied in treating various cancer types.However,its potential therapeutic efficacy and active components in managing squamous cell carcinoma of the head and neck(HNSCC)remain unclear yet.Methods:Using network pharmacology approaches,active ingredients of saffron,their target genes,and HNSCC-related genes were identified.Enrichment analyses were conducted for determining molecular functions and pathways enriched by genes that overlapped between the saffron target gene set and the HNSCC gene set.Among the four known active ingredients of saffron,crocetin was found to have the strongest inhibitory impact on HNSCC,based on the findings of cell viability and migration assays.Therefore,the potential target genes of crocetin in HNSCC cells were examined using molecular docking experiments and were confirmed by qPCR.Result s:Four active ingredients of saffron and 184 of their target genes were identified.Further,a total of 34 overlapping saffron-/HNSCC-associated targets related to the four active ingredients were screened,and crocetin was chosen for further investigation because it had the strongest inhibitory effect on HNSCC cells.Molecular docking experiments indicated that ESR1 and CCND1 were the target genes of crocetin.These results were confirmed through qPCR analysis,in which crocetin was found to lower the expression of the ESR1 and CCND1 genes in AMC-HN-8 and FaDu cells.Conclusion:According to our results,crocetin is a primary active anti-cancer component of saffron that may have potential in the development of novel HNSCC-treating medications.However,more thorough molecular research is necessary for confirming these results and elucidating the anti-cancer mechanism underlying saffron.

头颈部鳞状细胞癌巨噬细胞关键基因的筛选分析

目的 应用生物信息学的方法分析筛选头颈部鳞状细胞癌(HNSCC)巨噬细胞中的潜在关键基因,为HNSCC的预后提供靶点。方法 基于在线数据库,利用一致流形近似与投影(UMAP)降维,捕获巨噬细胞群;进一步通过t-分布随机近邻嵌入(tSNE)聚类降维分析肿瘤组织与正常组织细胞群分布的变化并筛选差异基因的表达;运用Monocle包对关键风险基因在不同发育阶段细胞中的表达情况进行分析;利用Kaplan-Meier Plotter在线数据平台分析生存曲线;运用空间转录组技术验证关键基因在组织中的表达映射;多色荧光免疫组化进行临床样本的验证。结果 捕获得到7个巨噬细胞亚群,其中第1亚群仅存在于肿瘤组织中且分泌型磷蛋白1(SPP1)基因高富集。SPP1高表达趋向巨噬细胞M2型极化并处于细胞分化的终末阶段。SPP1+巨噬细胞糖酵解、缺氧、上皮间质化、血管生成等功能活跃,与HNSCC患者的预后呈负相关。结论 SPP1可能成为HNSCC中有价值的预后生物标志物。

CAV1和CAV2在头颈部鳞状细胞癌组织中的表达及其对生存、免疫的影响

目的:基于生物信息学方法筛选出头颈部鳞状细胞癌(head and neck squamous cell carcinoma,HNSCC)的关键生物标记物CAV1和CAV2,并探究其在HNSCC中的表达情况以及临床预后价值。方法:本研究中,我们首先基于GEPIA数据库比较了caveolins及cavins在HNSCC的差异表达情况,随后同时在Ualcan平台分析了caveolins及cavins家族中差异基因与临床表型的关系;比较与临床表型相关的差异基因与HNSCC生存的关系;此外还进行了CAV1与CAV2的富集分析及免疫浸润分析。结果:GEPIA数据库分析显示CAV1、CAV2、CAVIN2、CAVIN3等存在显著相关性,其中CAV1、CAV2与临床表型显著相关且能显著影响HNSCC患者生存预后。GSEA富集分析显示CAV1主要上调IL-17 signaling pathway、PI3K-Akt signaling pathway、NOD-like receptor signaling pathway;CAV2主要上调NOD-like receptor signaling pathway、PI3K-Akt signaling pathway。免疫浸润分析表明CAV1及CAV2能显著改变HNSCC肿瘤免疫微环境,与多种免疫细胞浸润存在相关性。结论:CAV1与CAV2在HNSCC中高表达,是与免疫侵袭相关的独立预后因素,可作为确定HNSCC患者的免疫侵袭相关预后的候选预后标志物。

尿激酶型纤溶酶原激活因子调控人头颈部鳞状细胞癌转移的功能与机制研究

目的 探究尿激酶型纤溶酶原激活因子(urokinase-type plasminogen activator,PLAU)在头颈部鳞状细胞癌中的表达以及转移中的作用,并对其相关分子机制进行研究。方法 实验室培养人咽鳞癌细胞株FaDu细胞与人喉癌细胞株TU686细胞;使用siRNA靶向敲减/过表达PLAU基因后,利用qRT-PCR和Western Blot实验验证转染效率;Transwell与细胞划痕实验检测肿瘤细胞的侵袭、迁移能力变化情况;检测N-钙黏蛋白、锌指转录蛋白、波形蛋白在HNSCC细胞中表达的情况,分析其表达与PLAU对肿瘤远处转移的相关性。结果 PLAU在HNSCC中高表达,组间差异有统计学意义(P<0.05),且晚期或复发转移性HNSCC中的PLAU明显高表达于早期或原位癌。过表达PLAU有促进喉癌细胞转移的能力,PLAU可能调控N-钙黏蛋白、锌指转录蛋白、波形蛋白等诱导头颈部肿瘤的转移组间差异有统计学意义(P<0.05)。结论 PLAU可能是通过细胞-间充质转化过程促进HNSCC的迁移和侵袭。

TRMT61A的表达在头颈部鳞状细胞癌中的作用及临床价值

目的:探究tRNA甲基转移酶61A(tRNA methyltransferase 61A,TRMT61A)表达在头颈部鳞状细胞癌(head and neck squamous cell carcinoma,HNSCC)中的作用及其临床价值。方法:利用TCGA数据库对TRMT61A在泛癌中的表达水平进行分析,并对HNSCC组织及正常头颈组织中TRMT61A的mRNA表达水平及预后特征进行分析。采用Western blot实验、CCK-8实验、平板克隆实验检测敲低TRMT61A后对HNSCC细胞系的细胞增殖、克隆形成能力。结果:TRMT61A在HNSCC组织中高表达,且高表达使患者的总生存期(overall survival,OS)、无进展生存期(progression-free survival,PFS)、疾病特异性生存期(disease-specific survival,DSS)显著降低。体外实验表明敲低TRMT61A能够抑制HNSCC细胞的细胞增殖与克隆形成能力。结论:TRMT61A在HNSCC的肿瘤进展中具有重要作用,TRMT61A的表达是影响HNSCC细胞增殖的重要途径,有望成为预测HNSCC患者预后的有效指标之一,可能成为HNSCC潜在的治疗靶点。

Identification of anthelmintic parbendazole as a therapeutic molecule for HNSCC through connectivity map-based drug repositioning

Head and neck squamous cell carcinoma(HNSCC) is one of the most common human cancers;however, its outcome of pharmacotherapy is always very limited. Herein, we performed a batch query in the connectivity map(cMap) based on bioinformatics, queried out 35 compounds with therapeutic potential, and screened out parbendazole as a most promising compound, which had an excellent inhibitory effect on the proliferation of HNSCC cell lines. In addition, tubulin was identified as a primary target of parbendazole, and the direct binding between them was further verified. Parbendazole was further proved as an effective tubulin polymerization inhibitor, which can block the cell cycle, cause apoptosis and prevent cell migration, and it exhibited reasonable therapeutic effect and low toxicity in the in vivo and in vitro anti-tumor evaluation. Our study repositioned an anthelmintic parbendazole to treat HNSCC, which revealed a therapeutic utility and provided a new treatment option for human cancers.

整合素αvβ6在头颈部鳞状细胞癌中的作用研究

头颈部鳞状细胞癌(head and neck squamous cell carcinoma, HNSCC)起源于口腔、鼻腔、鼻窦和咽的黏膜上皮,为头颈部常见恶性肿瘤。许多患者以局部晚期病变为特征,经过手术联合放化疗后生存率仍然较低。局部复发、颈淋巴结转移、远处转移是影响HNSCC患者预后的重要因素。识别与复发和转移相关的肿瘤标志物,对预测肿瘤生物学行为和治疗策略的方向具有重要意义。大量研究证实整合素αvβ6在HNSCC中表达显著上调,而且能通过多种机制介导HNSCC肿瘤细胞的侵袭与转移。其表达的增加与HNSCC的疾病进展和较差的预后有关。因此,整合素αvβ6有望成为HNSCC预后的预测指标和治疗靶点。

PLEK2通过c-Myc介导的正反馈回路促进头颈鳞状细胞癌发生发展及干性形成

背景与目的头颈部鳞状细胞癌(head and neck squamous cell carcinoma,HNSCC)是全球高发的恶性肿瘤之一,具有预后不良、淋巴结转移率高以及早期复发的特点。然而,调控HNSCC发生发展的分子机制尚未明确。因此,揭示其潜在机制以寻找有治疗前景的新靶点具有重要意义。本研究主要探讨PLEK2(pleckstrin-2)在调控HNSCC发生发展中的作用。方法通过分析独立公共数据集以及内部队列,确定PLEK2在HNSCC表达情况及其临床意义。同时,使用体内外实验,包括细胞增殖、集落形成、Matrigel侵袭、肿瘤球形成、ALDEFLUOR检测、蛋白印迹分析,以及异种移植小鼠模型等方法,明确PLEK2在调控HNSCC细胞恶性生物学行为中的作用。另外,通过免疫共沉淀、环己酮霉素追踪分析、泛素化实验、染色质免疫沉淀–定量聚合酶链反应、荧光素酶报告基因实验和挽救实验等方法,阐明PLEK2在促进肿瘤发展中的潜在分子机制。结果在HNSCC组织中,PLEK2 mRNA和蛋白质表达水平较正常组织明显增加;PLEK2的过度表达与不良预后和治疗抗性显著关联。此外,PLEK2在维持HNSCC细胞的增殖、侵袭、上皮间质转换、癌症干细胞特征和肿瘤形成中发挥重要作用,并能改变癌细胞的代谢。在分子机制方面,PLEK2能与c-Myc结合,降低FBXW7(F-Box And WD Repeat Domain Containing 7)与c-Myc的相互作用,避免了c-Myc的泛素化和随后的蛋白酶体介导的降解。更进一步,PLEK2激活的c-Myc信号对于维持HNSCC细胞的恶性生物学行为至关重要。此外,c-Myc可结合到PLEK2启动子并促进其转录,形成了正反馈循环。结论我们揭示了PLEK2通过调控c-Myc促进HNSCC发生发展的分子机理,表明PLEK2可能成为HNSCC的潜在治疗靶点。

HSP90AA1 promotes lymphatic metastasis of hypopharyngeal squamous cell carcinoma by regulating epithelial-mesenchymal transition

Lymphatic metastasis(LM)emerges as an independent prognostic marker for hypopharyngeal squamous cell carcinoma(HSPSCC),chiefly contributing to treatment inefficacy.This study aimed to scrutinize the prognostic relevance of HSP90AA1 and its potential regulatory mechanism of concerning LM in HPSCC.Methods:In a preceding investigation,HSP90AA1,a differential gene,was discovered through transcriptome sequencing of HPSCC tissues,considering both the presence and absence of LM.Validation of HSP90AA1 expression was accomplished via qRT-PCR,western-blotting(WB),and immunohistochemistry(IHC),while its prognostic significance was assessed employing Kaplan–Meier survival analysis(KMSA),log-rank test(LR),and Cox’s regression analysis(CRA).Bioinformatics techniques facilitated the prediction and analysis of its plausible mechanisms in LM,further substantiated by in vitro and in vivo experiments utilizing FaDu cell lines.Results:HSP90AA1 is substantially upregulated in HPSCC with LM and is identified as an independent prognostic risk determinant.The down-regulation of HSP90AA1 can achieve inhibition of tumor cell proliferation,migration and invasion.Both in vivo experiments and Bioinformatics exploration hint at promoting LM by Epithelial-mesenchymal transition(EMT),regulated by HSP90AA1.Conclusions:HSP90AA1,by controlling EMT,can foster LM in HPSCC.This finding sets the foundation for delving into new therapeutic targets for HPSCC.

Identification and verification of aging-related lncRNAs for prognosis prediction and immune microenvironment in patients with head and neck squamous carcinoma

Aging is highly associated with tumor formation and progression.However,little research has explored the association of aging-related lncRNAs(ARLs)with the prognosis and tumor immune microenvironment(TIME)of head and neck squamous cell carcinoma(HNSCC).RNA sequences and clinicopathological data of HNSCC patients and normal subjects were downloaded from The Cancer Genome Atlas.In the training group,we used Pearson correlation,univariate Cox regression,least absolute shrinkage/selection operator regression analyses,and multivariate Cox regression to build a prognostic model.In the test group,we evaluated the model.Multivariate Cox regression was done to screen out independent prognostic factors,with which we constructed a nomogram.Afterward,we demonstrated the predictive value of the risk scores based on the model and the nomogram using time-dependent receiver operating characteristics.Gene set enrichment analysis,immune correlation analysis,and half-maximal inhibitory concentration were also performed to reveal the different landscapes of TIME between risk groups and to predict immuno-and chemo-therapeutic responses.The most important LINC00861 in the model was examined in HNE1,CNE1,and CNE2 nasopharyngeal carcinoma cell lines and transfected into the cell lines CNE1 and CNE2 using the LINC00861-pcDNA3.1 construct plasmid.In addition,CCK-8,Edu,and SA-β-gal staining assays were conducted to test the biofunction of LINC00861 in the CNE1 and CNE2 cells.The signature based on nine ARLs has a good predictive value in survival time,immune infiltration,immune checkpoint expression,and sensitivity to multiple drugs.LINC00861 expression in CNE2 was significantly lower than in the HNE1 and CNE1 cells,and LINC00861 overexpression significantly inhibited the proliferation and increased the senescence of nasopharyngeal carcinoma cell lines.This work built and verified a new prognostic model for HNSCC based on ARLs and mapped the immune landscape in HNSCC.LINC00861 is a protective factor for the development of HNSCC.

磷酸化EZH2在头颈部鳞癌中的表达特征及对化疗敏感性的影响

目的:探究头颈部鳞状细胞癌(head and neck squamous cell carcinoma,HNSCC)中磷酸化Zeste同源增强子(enhancer of Zeste homolog 2,EZH2)的表达特征及对化疗敏感性的影响。方法:选取2018年1月至2021年3月天津医科大学肿瘤医院HNSCC患者组织标本及临床资料53例。免疫组织化学染色分析HNSCC组织标本中p-EZH2^(S21)、p-STAT3^(Y705)、HIF-1α和Ki-67的表达水平。Western blot检测HNSCC组织和细胞株中p-EZH2^(S21)的表达情况。在HNSCC细胞中构建EZH2野生型(EZH2-WT)和EZH2^(S21)位点突变(EZH2-^(S21)A)的稳转细胞,CCK8实验和平板克隆实验检测EZH2以及^(S21)位点磷酸化对HNSCC细胞增殖能力及其对顺铂(cisplatin,DDP)和5-氟尿嘧啶(5-fluorouracil,5-FU)敏感性的影响。结果:HNSCC中p-EZH2^(S21)表达升高,并且与p-STAT3^(Y705)(P<0.05),HIF-1α(P<0.01)表达呈正相关。临床特征相关性分析发现HNSCC中p-EZH2^(S21)表达与淋巴结转移(P<0.0005)、T分期(P<0.05)、N分期(P<0.0001)和AJCC分期(P<0.05)呈正相关。体外实验证实EZH2表达促进HNSCC细胞增殖能力并且抑制其对化疗的敏感性,抑制EZH2^(S21)磷酸化可以恢复肿瘤细胞对DDP和5-FU的敏感性。结论:p-EZH2^(S21)在HNSCC肿瘤进展中具有重要作用,^(S21)位点磷酸化是EZH2影响HNSCC细胞增殖及其对化疗敏感性的重要途径。

头颈部鳞癌抑癌基因nm23-H_1的表达、DNA倍体与淋巴结转移的关系

目的 :研究头颈部鳞状细胞癌 (HNSCC)nm2 3 H1基因的表达、DNA含量与淋巴结转移的关系。方法 :选择 3 0例未经治疗的HNSCC患者术后新鲜肿瘤标本 ,应用免疫组化ABC技术和流式细胞术 (FCM )检测瘤细胞nm 2 3 -H1基因表达、异倍体 (aneuploid)和S期细胞比例 (S phasefraction ,SPF) ,探索这 3个参数与淋巴结转移之间的关系。结果 :nm 2 3 H1的阳性率为 60 % ,异倍体检出率为 66.7%。nm 2 3 H1表达、DNA倍体和SPF与淋巴结转移有关 (均为P <0 .0 1)。nm 2 3 H1表达与DNA倍体无关 (P >0 .0 5 ) ,nm 2 3 H1表达与SPF有关 (P <0 .0 5 )。结论 :对nm2 3 H1表达、DNA倍体和SPF的检测可预测HNSCC淋巴结转移趋势和预后 。

头颈部鳞癌的微卫星不稳定性和杂合性丢失的初步研究

目的 :探讨头颈部鳞癌的微卫星不稳定性 (MSI)及杂合性丢失 (LOH)。方法 :选择来自 3、5、6、8、9、13、17和 18号染色体的 15个微卫星标志对 36例头颈部鳞癌标本和相应的外周血进行微卫星分析。结果 :36例头颈部鳞癌中 ,2 7.8% (10 / 36 )分别有 1- 8个位点存在MSI,MSI发生率较高的位点为 :D17S5 2 0 (2 2 9% )、D6S10 5 (16 7% )和D8S2 6 4(13 9% )。在 9p2 1-p2 2和 3p14等处存在一定的LOH。微卫星异常的检出率与肿瘤分期、分级无相关性。结论 :提示MSI是头颈部鳞癌中较为常见的遗传学变化 ,染色体 9p2 1-p2 2和 3p14区域可能存在与头颈部鳞癌有关的抑癌基因。