Src在口腔鳞状细胞癌侵袭和转移中的研究进展

口腔鳞状细胞癌（OSCC）是临床上较常见的头颈部恶性肿瘤之一,其高侵袭性和高转移性的特点使患者的生活质量和5年生存率均不理想。Src作为Src家族蛋白激酶的代表成员,是调控OSCC细胞侵袭和远处转移的关键介质,参与多种细胞的生物学行为,如各种细胞内外成分相互作用建立信号转导通路或产生级联反应。本文就近年来Src对OSCC侵袭、转移等生物学行为的影响及相关信号通路进行综述,以期进一步探索OSCC发生、发展机制,为肿瘤临床治疗与研究提供参考。     

上皮间充质转化对肺鳞状细胞癌侵袭和迁移能力的影响*

目的：研究肺鳞状细胞癌（lung squamous cell carcinoma ,LSCC）上皮间充质转化（epithelial-to-mesenchymal transition ,EMT ）的临床意义,并阐述EMT 对肺鳞癌侵袭转移能力的影响。方法：对79例肺鳞癌组织切片进行E-cadherin 、Vimentin 及TGF-β 1 的免疫组织化学染色,分析其临床意义。将肺鳞癌细胞系SK-MES-1 于含有不同浓度转化生长因子- β 1（transforming growth factor,TGF-β 1）的培养基中,分别诱导培养5、10d 后,利用Western blot、RT-PCR 检测E-cadherin 、Vimentin 的表达变化,以划痕、侵袭实验来判断不同浓度、诱导时间对SK-MES-1 细胞功能的影响。结果：肺鳞癌发生淋巴转移病例中E-cadherin 表达较未发生淋巴转移者低,而Vimentin 表达则高于未发生淋巴转移的病例,差异具有统计学意义（P < 0.05）。 TGF-β 1 阳性表达与淋巴结转移相关,差异具有统计学意义（P < 0.05）。 Western blot和RT-PCR 显示10ng/mL TGF-β 1 诱导培养的SK-MES-1 细胞中,Vi ?mentin 表达增强明显,E-cadherin 表达减弱。细胞划痕和侵袭实验结果表明SK-MES-1 经诱导后,迁移和体外侵袭能力增强。结论：肺鳞癌的淋巴转移与上皮间充质转化有关,TGF-β 1 可诱导肺鳞癌细胞发生EMT ,增强其侵袭和迁移的能力。     

长链非编码RNA STAG3L5P过表达对口腔鳞状细胞癌细胞增殖和迁移的影响

  目的  研究长链非编码RNA（long non-coding RNA,lncRNA）STAG3L5P在口腔鳞状细胞癌（oral squamous cell carcinoma,OSCC）细胞中的表达和定位及其对OSCC细胞增殖及迁移的影响。  方法  使用数据库GEPIA2（gene expression profiling interactive analysis 2）分析STAG3L5P在头颈部鳞状细胞癌（head and neck squamous cell carcinoma,HNSC）中的表达;利用数据库UCSC Xena（University of California Santa Cruz Xena）分析STAG3L5P在OSCC中的表达;实时荧光定量PCR（real-time fluorescence quantitative PCR,qPCR）检测STAG3L5P的表达水平;RNA核质分离实验检测其亚细胞定位;细胞计数试剂盒-8（cell counting kit-8,CCK-8）实验和Transwell迁移实验检测STAG3L5P过表达对OSCC细胞增殖和迁移能力的影响;qPCR和Western blot检测STAG3L5P过表达对上皮间充质转化（epithelial-mesenchymal transition,EMT）相关基因的影响;Western blot检测STAG3L5P过表达对PI3K/AKT通路的影响。  结果  STAG3L5P在OSCC组织中高表达,且其表达与组织学分级显著相关;STAG3L5P在OSCC细胞的表达水平显著升高,且在细胞质占比明显高于细胞核占比;STAG3L5P过表达组的细胞增殖和迁移能力均显著高于阴性对照组。STAG3L5P过表达导致N-cadherin和Vimentin的mRNA和蛋白表达均上调,E-cadherin蛋白表达下降。STAG3L5P过表达引起p-PI3K和p-AKT表达增多。  结论  STAG3L5P在OSCC组织和细胞中高表达,STAG3L5P过表达可以促进OSCC细胞的增殖及迁移能力,这可能与STAG3L5P激活PI3K/AKT通路促进EMT发生有关。     

上皮间充质转化与肿瘤干细胞的研究进展

上皮细胞间充质转化(epithelial-mesenchymal transition, EMT) 在胚胎发育和肿瘤发生中具有重要作用, EMT可使上皮性肿瘤细胞获得间充质细胞表型, 在增强肿瘤细胞的侵袭和转移能力的同时, 也使得肿瘤细胞具有自我更新能力等干细胞样特性。多种转录因子、信号转导通路、microRNAs及细胞微环境等因素共同调控此过程。EMT与肿瘤干细胞之间有密不可分的联系, EMT可以促进肿瘤细胞获得干细胞特征, 具有干细胞特征的肿瘤细胞高表达EMT标记分子, microRNA可同时调控EMT和细胞干性。阐明EMT与肿瘤干细胞的相互关系及其调控机制, 有望为肿瘤转移与复发的靶向治疗开辟新思路。      

子宫内膜异位症相关卵巢癌患者上皮-间充质转化相关蛋白的表达及其影响因素

目的 探讨子宫内膜异位症相关卵巢癌(EAOC)患者上皮-间充质转化(EMT)相关蛋白的表达及其影响因素分析.方法 取60例EAOC患者及60例单纯子宫内膜异位症(EMS)患者的EAOC组织和EMS组织采用免疫组织化学法检测,比较各组织中EMT相关蛋白[上皮钙黏蛋白(E-cadherin)、神经钙黏蛋白(N-cadherin)及锌指转录因子Snail]的阳性表达情况,分析EAOC组织中EMT相关蛋白阳性表达的影响因素及其相关性.结果 EAOC组织中E-cadherin蛋白阳性表达率低于EMS组织(P﹤0.05),N-cadherin及Snail蛋白阳性表达率均高于EMS组织(P﹤0.05).临床分期为Ⅰ～Ⅱ期、无淋巴结转移的EAOC患者EAOC组织中E-cadherin蛋白阳性表达率均高于临床分期为Ⅲ～Ⅳ期、有淋巴结转移的患者(P﹤0.05);临床分期为Ⅰ～Ⅱ期、无淋巴结转移的EAOC患者EAOC组织中N-cadherin蛋白阳性表达率均低于Ⅲ～Ⅳ期、有淋巴结转移的患者(P﹤0.05);无淋巴结转移的EAOC患者EAOC组织中Snail蛋白阳性表达率低于有淋巴转移患者(P﹤0.05).多因素Logistic回归分析结果显示,临床分期为Ⅲ～Ⅳ期、有淋巴结转移均是E-cadherin蛋白阳性表达的独立危险因素(P﹤0.05),无淋巴结转移是N-cadherin、Snail蛋白阳性表达的独立危险因素(P﹤0.05).Spearman相关性分析显示,EAOC患者EAOC组织中E-cadherin蛋白阳性表达与其临床分期及淋巴转移情况呈负相关(r=-0.36、-0.44,P﹤0.05),而N-cadherin蛋白阳性表达与其临床分期及淋巴转移情况呈正相关(r=0.42、0.37,P﹤0.05),Snail蛋白阳性表达与其淋巴转移情况呈正相关(r=0.34,P﹤0.05).结论 EAOC患者临床分期及淋巴转移与其病灶组织中E-cadherin、N-cadherin及Snail蛋白阳性表达存在相关性,提示EAOC的进展可能与EMT相关蛋白间有密切联系.     

白细胞介素-8与肿瘤上皮-间充质转化的关系研究进展

上皮-间充质转化(EMT)在肿瘤细胞侵袭转移进程中十分关键.白细胞介素-8(IL-8)是由上皮细胞和巨噬细胞等分泌的一种细胞炎性因子.在食管癌、乳腺癌、肝癌、肠癌、卵巢癌、前列腺癌、口腔鳞状细胞癌、甲状腺癌、神经胶质瘤中均观察到IL-8可促进肿瘤EMT进程.IL-8不仅自身参与肿瘤EMT进程,同时还可以通过与受体结合诱...     

慢性牙周炎与口腔鳞状细胞癌关系的研究进展

口腔鳞状细胞癌(oral squamous cell carcinoma,OSCC)的发病率和死亡率呈年轻化趋势上升,已成为世界范围内的主要公共卫生问题.近年来,慢性牙周炎(chronic periodontitis,CP)与口腔鳞癌之间的关系越来越受到重视,一些研究发现,以慢性炎症和微生物失调为特征的牙周病是口腔肿瘤...     

口腔菌群与口腔鳞状细胞癌的相关性研究进展

目的 总结口腔菌群在口腔鳞状细胞癌(OSCC)发生及发展中的作用及其在OSCC诊断、治疗及预后中的潜在价值,以期为后续的研究提供方向。方法 以“口腔微生物群、口腔鳞状细胞癌、标志物、诊断、预后”等为中文关键词检索中国知网数据库,以“oral microbiota、oral squamous cell carcinoma、biomarker、diagnosis、prognosis”为英文关键词检索PubMed数据库,查阅2000-01-01-2023-02-01发表的相关中英文文献。纳入标准：(1)口腔菌群参与OSCC发生和发展的机制研究;(2)口腔菌群作为OSCC诊断或预后标志物的相关研究;(3)口腔菌群在OSCC治疗中的应用。排除标准：(1)个案报道;(2)研究机制不明文献;(3)内容相似的文献。根据标准纳入64篇文献。结果 口腔菌群可以通过诱导肿瘤增殖、血管新生、抑制凋亡等多种途径参与OSCC的发生发展,并有巨大潜力成为OSCC的诊断和预后标志物,此外,OSCC的治疗可能会使口腔菌群发生变化,部分菌群与治疗耐药相关,调节菌群或可改善疗效。结论 口腔菌群在OSCC中起重要作用,针对口...     

PKMYT1 regulates the proliferation and epithelial-mesenchymal transition of oral squamous cell carcinoma cells by targeting CCNA2

Oral squamous cell carcinoma (OSCC) has gradually become a global public health issue in recent years. Therefore, the current study aimed to explore the mechanism of OSCC development and to identify a potential target that may be used in its treatment. The expression of protein kinase, membrane-associated tyrosine/threonine 1 (PKMYT1) and cyclin A2 (CCNA2) in SCC-9 cells was determined prior to and following transfection with short hairpin RNA targeting PKMYT1. Cell proliferation, colony-forming ability, migration and invasion were determined using Cell Counting Kit-8, colony formation, wound healing and Transwell assays, respectively. Furthermore, the expression of epithelial-mesenchymal transition (EMT)- and migration-related proteins were evaluated using western blot analysis. Additionally, co-immunoprecipitation was used to verify the binding of PKMYT1 and CCNA2. The results revealed that PKMYT1 was highly expressed in OSCC cells and that PKMYT1 knockdown could inhibit proliferation, colony formation, migration, invasion, EMT and CCNA2 expression in SCC-9 cells. In addition, PKMYT1 was demonstrated to bind to CCNA2, and knocking down PKMYT1 resulted in inhibitory effects on cell proliferation, colony formation ability, migration, invasion and EMT by downregulating CCNA2 expression. PKMYT1 was observed to regulate the proliferation, migration and EMT of OSCC cells by targeting CCNA2, which may be used in the future to improve OSCC treatment.     

Loss of CPAP causes sustained EGFR signaling and epithelial-mesenchymal transition in oral cancer

Higher epidermal growth factor receptor (EGFR) signaling can contribute to tumor metastasis and resistance to therapies in oral squamous cell carcinoma (OSCC). EGFR signaling can promote epithelial-mesenchymal transition (EMT) in OSCC. EMT is a process by which epithelial cells acquire invasive properties and it can contribute to tumor metastasis. Not only do the abnormal functions of microtubule and microtubule-organizing centers (MTOC) such as centrosomes lead to cancers, but also the malignant tissues are characterized by aberrant centriolar features and amplified centrosomes. Microtubule inhibition therapies increase the sensitivity to EGFR targeting drugs in various cancers. In this study, we show that the loss of expression of a microtubule/tubulin binding protein, centrosomal protein 4.1-associated protein (CPAP), which is critical for centriole biogenesis and normal functioning of the centrosome, caused an increase in the EGFR levels and its signaling and, enhanced the EMT features and invasiveness of OSCC cells. Further, depletion of CPAP enhanced the tumorigenicity of these cells in a xeno-transplant model. Importantly, CPAP loss-associated EMT features and invasiveness of multiple OSCC cells were attenuated upon depletion of EGFR in them. On the other hand, we found that CPAP protein levels were higher in EGF treated OSCC cells as well as in oral cancer tissues, suggesting that the frequently reported aberrant centriolar features of tumors are potentially a consequence, but not the cause, of tumor progression. Overall, our novel observations show that, in addition to its known indispensable role in centrosome biogenesis, CPAP also plays a vital role in suppressing tumorigenesis in OSCC by facilitating EGFR homeostasis.     

RACK1 predicts poor prognosis and regulates progression of esophageal squamous cell carcinoma through its epithelial-mesenchymal transition

Background. RACK1 is known to be involved in tumor progression, and its prognostic value on many kinds of tumors has been identified. However, there are limited studies about the functional role of RACK1 in esophageal squamous cell carcinoma (ESCC). Patients and methods. RACK1 expression was examined in 100 ESCC tissue samples using immunohistochemistry staining. RACK1 was knocked-down in ESCC cell lines by shRNA. The effects on cell proliferation, invasion and migration were examined in ESCC cell lines and nude mouse model. Vimentin and E-cadherin were introduced to further study the association between RACK1 and EMT. Results. RACK1 expression was significantly associated with the tumor length (P = 0.012), diameter<3 cm (P = 0.047), T stage (P = 0.032), and lymph node metastasis (P = 0.038), respectively. Kaplan-Meier survival analysis and Cox analyses revealed RACK1 expression was an independent predictor for OS (P = 0.030) and DFS (P = 0.027) in ESCC. Down-regulation of RACK1 inhibited cell proliferation, along with invasion and migration in vitro and in vivo. A significant positive correlation between RACK1 expression and vimentin (P = 0.0190) and an inverse correlation between RACK1 expression and E-cadherin (P = 0.0047) were found. Conclusions. RACK1 predicted poor prognosis in ESCC, promoted tumor progression, and was involved in EMT of ESCC.     

EGFR inhibitors prevent induction of cancer stem-like cells in esophageal squamous cell carcinoma by suppressing epithelial-mesenchymal transition

There exists a highly tumorigenic subset of esophageal squamous cell carcinoma (ESCC) cells defined by high expression of CD44. A novel therapy targeting these cancer stem-like cells (CSCs) is needed to improve prognosis of ESCC. CSCs of ESCC have a mesenchymal phenotype and epithelial-mesenchymal transition (EMT) is critical to enrich and maintain CSCs. EGFR, frequently overexpressed in ESCC, has pivotal roles in EMT induced by TGF-β in invasive fronts. Thus, EMT in invasive fronts of ESCC might be important for CSCs and EGFR could be a target of a novel therapy eliminating CSCs. However, effects of EGFR inhibitors on CSCs in ESCC have not been fully examined. EGFR inhibitors, erlotinib and cetuximab, significantly suppressed enrichment of CSCs via TGF-β1-mediated EMT. Importantly, EGFR inhibitors sharply suppressed ZEB1 that is essential for EMT in ESCC. Further, EGFR inhibitors activated Notch1 and Notch3, leading to squamous cell differentiation. EGFR inhibition may suppress expression of ZEB1 and induce differentiation, thereby blocking EMT-mediated enrichment of CSCs. In organotypic 3D culture, a form of human tissue engineering, tumor cells in invasive nests showed high expression of CD44. Erlotinib significantly blocked invasion into the matrix and CD44 high expressing CSCs were markedly suppressed by erlotinib in organotypic 3D culture. In conclusion, EMT is a critical process for generation of CSCs and the invasive front of ESCC, where EMT occurs, might form a CSC niche in ESCC. EGFR inhibitors could suppress EMT in invasive fronts and be one therapeutic option targeting against generation of CSCs in ESCC.     

Carvacrol抑制ADAM9在口腔鳞状细胞癌中的表达

目的:探讨carvacrol对口腔鳞状细胞癌中ADAM9表达的影响。方法:蛋白印记法分析carvacrol处理的口腔鳞状细胞癌中的去整合素金属蛋白酶9（ADAM9）蛋白表达。另外,提取40 μmol/L carvacrol处理24小时的UM-SCC-23细胞系和Tca8113细胞系中总RNA进行反转录,利用实时定量PCR（real-time PCR）扩增检测ADAM9基因表达。结果:Carvacrol明显降低UM-SCC-23细胞系和Tca8113细胞系ADAM9的蛋白和基因表达。结论:研究揭示了carvacrol的重要机制,可能为口腔鳞状细胞癌治疗提供新的理论依据。     

钆血卟啉单甲醚介导的光动力疗法治疗口腔舌鳞状细胞癌移植瘤的实验研究

目的:探讨钆血卟啉单甲醚（gadolinium coordinated hemetoporphyrin monomethyl ether,Gd-HMME）介导的光动力疗法（photodynamic therapy,PDT）对裸鼠口腔舌鳞状细胞癌（oral tongue squamous cell carcinoma,OTSCC）移植瘤的治疗效果,为今后的临床治疗提供理论依据。方法:选取36只BALB/c-nu裸鼠随机分为4组,分别为对照组、PDT组、Gd-HMME组和Gd-HMME-PDT组,每组9只。治疗后定期测量裸鼠体重以及肿瘤体积,14 d后各组随机处死裸鼠6只,计算抑瘤率和生命延长率,行苏木精-伊红（hematoxylin-eosin staining,HE）染色后病理形态学观察,评估Gd-HMME-PDT对移植瘤的治疗效果。结果:实验结果显示,各处理组的肿瘤体积均小于对照组,Gd-HMME-PDT组肿瘤体积减小最明显（P＜0.01）;PDT组、Gd-HMME组、Gd-HMME-PDT组的抑瘤率分别为3.17%、6.13%、59.62%。HE染色可见Gd-HMME-PDT组肿瘤细胞坏死和空泡性变,对照组及PDT组、Gd-HMME组均未见明显改变;PDT组、Gd-HMME组、Gd-HMME-PDT组的生命延长率分别为2.82%、7.04%、73.24%。结论:Gd-HMME-PDT对口腔舌鳞状细胞癌移植瘤的生长具有抑制作用,并且可以延长裸鼠的生存时间。     

HPV感染在口腔鳞癌中的研究进展

口腔鳞状细胞癌(OSCC)是头颈部最常见的恶性肿瘤,预后较差,整体5年生存率较低,世界卫生组织预计在未来十几年中OSCC的发病率将持续上升。除了烟草、槟榔、饮酒等因素,人乳头瘤病毒(HPV)感染也被确定为危险因素,HPV的感染与OSCC的发生及预后有着密切的关系,目前研究表明,HPV感染逐渐成为OSCC的主要致病因素。HPV感染引起的OSCC可能会成为OSCC中一种发病机制、肿瘤微环境、生物学行为和预后都相对独特的一种类型。笔者通过广泛查阅文献,围绕HPV在OSCC中作用机制、HPV阳性OSCC的特征及HPV与OSCC治疗和预防的相关性的研究进展进行总结。     

5种肿瘤标志物联合检测在口腔鳞状细胞癌中的诊断价值

目的:通过检测血清肿瘤标志物（SCC-Ag、CYFRA21-1、CEA、CA125、NSE）探讨联合检测对口腔鳞状细胞癌(oral squamous cell carcinoma,OSCC)的临床诊断意义及诊断效能。方法:收集2015年1月至2018年1月就诊于新疆维吾尔自治区人民医院口腔颌面外科的OSCC患者60例,非OSCC恶性肿瘤患者60例,同期健康体检者60例作为正常组,均抽取空腹外周血2 ml,检测SCC-Ag、CYFRA21-1、CEA、CA125、NSE浓度。结果:OSCC患者的5种血清肿瘤标志物水平与非OSCC恶性肿瘤组、正常组比较差异具有统计学意义(P<0.05)。将CEA、CA125、SCC-Ag、CYFRA21-1、NSE联合检测后敏感性、特异性、准确性、阳性预测值均显著提高。结论:SCC-Ag、CYFRA21-1、CEA、CA125、NSE 5种肿瘤标志物在OSCC中联合检测可以显著提高诊断效能;5种肿瘤标志物的血清表达量在OSCC的临床诊断中具有一定的价值。     

LGR5与肝癌上皮间质转化的关系

目的:研究LGR5与原发性肝癌侵袭转移过程中上皮间质转化(epithelial-mesenchymal transition,EMT)间的关系。方法:采用免疫组织化学的方法(SP法),分别检测20例原发性肝癌组织、20例癌旁组织及14例正常肝组织中LGR5、E-钙黏蛋白(E-CAD)及N-钙黏蛋白(N-CAD)的表达情况。并分析它们与原发性肝癌临床病理参数的关系。结果:LGR5、E-CAD、N-CAD的表达:在20例肝癌组织中,LGR5、E-CAD、N-CAD的阳性表达分别为15例（75%）、7例（35%）及16例（80%）。在20例癌旁组织中,阳性表达分别为11例（55%）、11例（55%）及11例（55%）。在14例正常肝组织中,阳性表达分别为4例（29%）、11例（79%）及4例（29%）。统计分析表明,LGR5在肝癌中的阳性表达率均明显高于癌旁及正常组织（P<0.05）。而E-CAD在肝癌中的阳性表达率则明显低于癌旁及正常组织中的阳性表达（P<0.05）。同时,N-CAD在肝癌中的阳性表达率明显高于癌旁及正常组织（P<0.05）。LGR5、E-CAD、N-CAD在原发性肝癌中的表达与临床病理参数的关系:LGR5的表达与患者术前肝功能有关（P<0.05）,而与患者的年龄、性别、肿瘤大小、肿瘤TNM分期、分级、HBV、肝硬化、甲胎蛋白(AFP)等差异无统计学意义;而E-CAD、N-CAD的表达与术前肝功能、年龄、性别、肿瘤大小、肿瘤TNM分期、HBV、肝硬化、甲胎蛋白差异均无统计学意义（P>0.05）。相关性分析结果:E-CAD、N-CAD表达呈负相关（r=-0.999,P<0.05）。而LGR5与E-CAD表达呈负相关（r=-1.00,P<0.05）,与N-CAD的表达呈正相关（r=0.998,P<0.05）。结论:原发性肝癌中存在明显的上皮间质转化现象。LGR5与原发性肝癌侵袭转移过程中上皮间质转化有关。     

Survivin expression in oral squamous cell carcinoma

A series of 110 cases of oral squamous cell carcinoma (SCC) together with six lymph node and one distant metastatic lesions was analysed for expression of survivin, a recent apoptosis inhibitor, by immunohistochemistry and Western blotting. In total, 91 cases (82.7%) of carcinoma and all metastasis (seven cases, 100%) were positive for survivin expression, with weighted survivin scores ranging from 1 to 4. In contrast, normal oral epithelium did not express survivin. There was no significant correlation between survivin expression and age, sex, tumour size, the presence of lymph node and distant metastases. Survivin expression was increased in poorly differentiated tumours, even if differences were not statistically significant. In contrast, when analysed for prognostic significance, patients with low survivin expression had statistically significant better survival rates than the group with high survivin expression (P<0.05). These data suggest that survivin expression may identify cases of oral SCC with more aggressive and invasive phenotype.