PI3K/Akt/mTOR通路在头颈部鳞状细胞癌中的靶向治疗研究进展

头颈部鳞状细胞癌（HNSCC）在全球最常见的恶性肿瘤中位居第六,晚期患者转移并复发率高,预后较差,为患者家庭和社会经济带来严重损失。靶向药物结合经典放化疗的个性化方案有望提高治疗功效并延长生存期。磷脂酰肌醇3-激酶/蛋白激酶B/哺乳动物雷帕霉素靶蛋白（PI3K/Akt/mTOR）在HNSCC中普遍存在过度激活,是控制肿瘤发生、发展及研发靶向药物的重要通路。本文就PI3K/Akt/mTOR通路应用于HNSCC靶向治疗的个体性差异发生的潜在机制,以及临床试验取得的进展与目前所面临的困境进行探讨,拟为HNSCC的临床靶向治疗提供参考思路,从而提高患者的生存质量。     

The role of NEFL in cell growth and invasion in head and neck squamous cell carcinoma cell lines

The neurofilament light polypeptide (NEFL) gene located on chromosome 8q21 is associated with the cancer of several organs and is regarded as a potential tumor suppressor gene. However, the role of the NEFL protein has not yet been studied in cancer cells. Although evidence suggests that there is a correlation between NEFL expression and cancer, studies regarding the role of the NEFL protein have been mostly limited to neurological diseases, such as Charcot–Marie–Tooth's disease (CMT). Most of these studies have not explored the role of NEFL in cancer cell apoptosis and/or invasion. In this study, NEFL expression was manipulated, and apoptosis and invasion were compared in head and neck squamous cell carcinoma cell lines. The results show that the expression of NEFL induces cancer cell apoptosis and inhibits invasion in these cell lines, suggesting that NEFL may play a role in cancer cell apoptosis and invasion.     

Angiogenin expression in head and neck basaloid and conventional squamous cell carcinoma: a site‐ and stage‐matched comparison

J Oral Pathol Med (2011) 40 : 55–60 Background: Basaloid squamous cell carcinoma is an uncommon variant of squamous cell carcinoma (SCC). Angiogenin (ANG), a member of the ribonuclease super‐family, is essential to tumor angiogenesis, but has also been implicated in tumor consolidation and proliferation. Methods: ANG expression was first investigated in 12 head and neck basaloid squamous cell carcinomas (HNBSCCs) and compared with a control group of 24 site‐ and stage‐matched conventional SCCs to establish whether the supposedly more aggressive biological behavior of HNBSCCs might be ANG‐related. Results: No significant differences were found between HNBSCCs, and SCCs in terms of recurrence, disease‐free survival (DFS), or overall survival rates. In HNBSCC, we identified a trend toward a significant inverse correlation between endothelial ANG expression and DFS (statistical trend, P = 0.08). Endothelial ANG expression did not differ significantly in HNBSCCs and SCCs. A high ANG expression in carcinoma cells was directly associated with pT in both the HNBSCC (P = 0.04) and the SCC (statistical trend, P = 0.07) groups. ANG expression in carcinoma cells was significantly lower in HNBSCCs than in SCCs (P = 0.005). Conclusions: All the biological mechanisms investigated to date, including ANG‐mediated angiogenesis or cell proliferation, have failed to confirm that HNBSCCs have a more aggressive behavior than matched SCC.     

甘草苷调控PI3K/Akt/m-TOR信号通路对口腔鳞状细胞癌细胞及裸鼠移植瘤小鼠的作用研究

目的:目的探讨甘草苷(Liquiritin,LIQ)对人口腔鳞状细胞癌细胞(OSCCs)的增殖抑制、凋亡诱导作用和分子机制并通过裸鼠模型进行验证。方法:CCK-8检测LIQ对口腔鳞状细胞癌细胞的增殖抑制作用;流式细胞术及TUNEL实验检测凋亡情况;Western blot检测蛋白表达变化;构建裸鼠瘤模型,连续给药20 d,绘制肿瘤生长曲线,并计算抑瘤率。结果:LIQ可以抑制口腔鳞状细胞癌细胞增殖及裸鼠瘤体积增长,并诱导细胞凋亡;LIQ抑制PI3K/Akt/m-TOR信号通路的过度激活。结论:LIQ能够在体内外对口腔鳞状细胞癌产生抗癌效果,其机制可能是通过抑制PI3K/AKT/m-TOR信号通路的过度激活。     

敲减TULP3对头颈鳞癌细胞生物学行为的影响

目的 探讨敲减TULP3对头颈鳞状细胞癌(HNSCC)细胞生物学行为的影响。方法 应用TCGA数据比较头颈鳞癌组织与癌旁组织中TULP3表达水平;体外培养人HNSCC细胞系HN4、HN6、CAL27、HSC3、SCC4及正常口腔上皮角质细胞HOK并应用Western Blot比较TULP3蛋白表达水平,免疫组化分析TULP3在HNSCC组织中表达情况。构建RNA干扰寡核苷酸si-TULP3及si-NC转染HN4、HN6,应用CCK-8实验、平板克隆形成实验、划痕愈合实验、Transwell侵袭实验检测敲减TULP3对HNSCC细胞增殖、侵袭、迁移能力的影响。实时定量逆转录PCR及Western Blot检测细胞周期及上皮间质转化(EMT)相关指标变化。构建HN6-shTULP3及HN6-shNC细胞株接种于裸鼠皮下,分析裸鼠移植瘤体积差异。结果 TCGA数据显示头颈鳞癌组织TULP3表达量显著高于癌旁组织(P<0.000 1);HN4、HN6、CAL27、HSC3细胞中TULP3蛋白表达量均高于HOK细胞,TULP3在HNSCC组织中呈阳性表达。HN4、HN6细胞转染si-TUL...     

Co‐inhibitory immune checkpoints in head and neck squamous cell carcinoma

The upregulation of co‐inhibitory immune checkpoints hampers the immune response toward tumor cells and facilitates the tumor cells ability to evade immunosurveillance. Specific inhibitory immune checkpoint delivers inhibitory signals to T cells using multiple mechanisms. More in‐depth understanding of the co‐inhibitory immune checkpoints could be exploited for head and neck squamous cell carcinoma (HNSCC) treatment. In this review, we summarize the expression and the mechanism of partial co‐inhibitory immune checkpoint signals and discuss targeting co‐inhibitory immune checkpoints as an immunotherapeutic target for cancer therapy. This review may provide a better understanding of the co‐inhibitory immune checkpoints and could promote applications of immunotherapy.     

头颈部鳞状细胞癌侵袭与转移的分子水平研究进展

近年来，在头颈鳞状细胞癌侵袭和转移方面的分子水平研究成为头颈鳞癌研究的重点和热点之一。本文就目前在头颈鳞癌侵袭与转移相关的动物模型、相关基因与临床预后、生物治疗相关分子靶点等实验和临床研究作一综述。     

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目的 探讨人头颈鳞癌中CCR7与磷酸化mTOR表达的关系,以及二者与肿瘤生物学行为之间的联系.方法 收集中国医科大学附属口腔医院口腔颌面外科2008-2009年收治的78例头颈鳞癌患者术后标本及临床详细资料,行免疫组化染色检测肿瘤原发灶CCR7和磷酸化mTOR表达情况,分析其表达的相关性及其与临床病理学因素间的关系.结果 78例头颈鳞癌原发灶中,CCR7阳性表达48例,磷酸化mTOR阳性表达40例;而10例正常口腔黏膜仅有1例CCR7阳性表达,无一例为磷酸化mTOR阳性表达.CCR7及磷酸化mTOR在头颈鳞癌原发灶与正常口腔黏膜中的表达差异均有统计学意义（均P＜ 0.05）.CCR7及磷酸化mTOR在不同临床分期和有无淋巴结转移患者的表达差异均有统计学意义（均P＜ 0.05）,而在不同年龄和性别患者的表达差异均无统计学意义(均P＞ 0.05).CCR7表达与磷酸化mTOR表达具有相关性(r=0.479,P＜0.05).结论 人头颈鳞癌组织中CCR7和磷酸化mTOR蛋白的高表达均与淋巴结转移和临床TNM分期相关,CCR7表达与磷酸化mTOR表达正相关.     

Stem cells in head and neck squamous cell carcinoma

The existence of a small subpopulation of tumourigenic cancer stem cells in the bulk of human head and neck squamous cancers (SCC) has been recognised in recent reports. This subpopulation has self-renewal properties and is responsible for the production of differentiated daughter cells that form the bulk of the tumour. Stem cells in head and neck SCC can be identified functionally using their self-renewal properties, or by their characteristic surface markers. As their resistance to contemporary cancer treatments may eventually lead to the failure of treatment there is an urgent need to better understand their biology with the ultimate goal of developing new diagnostic markers and curative cancer treatments.     

热疗联合Id-1基因沉默对舌鳞癌CAL-27细胞增殖及侵袭的影响

目的: 探讨热疗联合Id-1基因沉默对舌鳞癌细胞增殖及侵袭的影响及其机制。方法: 将培养的舌鳞癌细胞株CAL-27分为4组。①沉默Id-1组（Id-1-siRNA）—用siRNA基因转染法沉默舌鳞癌CAL-27细胞中Id-1的表达,RT-PCR法检测其Id-1的mRNA表达变化;②热疗组（HT）—细胞置于42.5℃恒温培养箱内40min;③联合组（HT+ Id-1-siRNA）—siRNA基因转染法沉默细胞内Id-1的表达后进行42.5℃、40 min的热疗处理;④空白对照组—常规培养细胞。通过CCK8和Transwell侵袭实验,分别检测CAL-27细胞的增殖能力和侵袭能力变化; Western免疫印迹法检测CAL-27细胞中PI3K、磷酸化Akt（p-Akt）蛋白表达变化。采用SPSS19.0软件包对数据进行统计学分析。结果: siRNA能成功沉默CAL-27细胞内Id-1的表达,沉默Id-1组与空白对照组相比,Id-1的mRNA表达水平下降81.6%。沉默Id-1和热疗均可抑制CAL-27细胞的增殖和侵袭能力,下调PI3K、p-Akt蛋白表达（P<0.05）,热疗联合沉默Id-1作用于CAL-27细胞后的结果更为显著（P<0.01）。结论: 热疗协同沉默Id-1可显著抑制人舌鳞癌细胞的增殖及侵袭能力,其作用是通过PI3K/Akt信号通路来实现。     

Cyclooxygenase‐2 expression in oral tongue squamous cell carcinoma

J Oral Pathol Med (2010) 40 : 385–389 Background: Cyclooxygenase‐2 expression is associated with unfavorable outcome in various cancers, and evidence is accumulating that carcinogenesis possibly evolves from intracellular changes in response to induction of this enzyme. Today selective cyclooxygenase‐2 inhibitors are being studied and used as complement in cancer treatment. This study examined the prognostic value of cyclooxygenase‐2 expression in oral tongue squamous cell carcinoma (OTSCC). Methods: Expression of cyclooxygenase‐2 was determined in biopsies from 76 stage matched patients with OTSCC by immunohistochemistry between January 2000 and December 2004 in Stockholm, Sweden. Additionally, twelve samples taken after pre‐operative radiotherapy were investigated. Results: All OTSCC specimen expressed cyclooxygenase‐2 by immunostaining. The cyclooxygenase‐2 staining intensity increased significantly with more advanced stage (P = 0.020). Fifty percent of the surgical specimen showed a decrease in immunostaining post‐radiation (P = 0.031). No association was found with survival. Conclusion: Cyclooxygenase‐2 expression has limited prognostic value in OTSCC.     

PI3K与PTEN蛋白在口腔鳞癌中的表达及相关性研究

目的：探讨口腔鳞癌中PTEN、PI3K的表达情况,并对其表达水平与临床特征之间的关系进行相关性分析,探讨其与口腔鳞癌发生、发展和转移的关系。方法采用免疫组化SP法对52例口腔鳞癌石蜡标本及20例癌旁正常组织中PTEN、PI3K蛋白的表达情况进行研究,分析其与临床病理特征的关系。结果 PTEN在口腔鳞癌中表达明显低于癌旁正常组织。PI3K表达明显高于癌旁正常组织。PTEN与PI3K表达与细胞分化、临床分期、淋巴结转移相关。PTEN与PI3K阳性表达之间呈负相关。结论 PI3K在口腔鳞癌中的表达上调, PTEN在口腔鳞癌中的表达下调。PTEN与PI3K蛋白表达呈负相关。     

Expression of insulin‐like growth factor II mRNA‐binding protein 3 in squamous cell carcinomas of the head and neck

J Oral Pathol Med (2013) 42 : 125–132 Background: Insulin‐like growth factor II mRNA‐binding protein 3 (IMP3) was found overexpressed in various cancer types suggesting its possible role in carcinogenesis. Analysis of IMP3 expression in head and neck squamous cell carcinomas (HNSCC) is rare so that we evaluated it using tissue microarray method. Method: Immunohistochemical analysis of IMP3 was performed on samples from over 400 patients. The expression was measured semiquantitative, subsequently divided into four categories (negative, weak, medium, or strong) and correlated with several available clinicopathologic parameters. Results: For HNSCC, positive IMP3 expression was observed in patients with all tumor stages (pT1–4) and nodal stages (pN0–3), showing also significant statistical correlation (P = 0.023 and P = 0.0013, respectively). No further correlations were found. Separate analysis according to tumor localization (oral cavity, oropharyngeal, and laryngeal) showed a significant correlation of positive IMP3 expression and overall survival (P = 0.038) only in patients with tumors of the oral cavity. Multivariate analysis showed IMP3 as an independent predictive marker for oral squamous cell carcinomas (OSCC). Conclusion: Insulin‐like growth factor II mRNA‐binding protein 3 (IMP3) expression might be used as an independent prognostic factor in the subgroup of OSCC.