mTOR信号转导通路抑制剂及其与肿瘤耐药的研究进展

哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin, mTOR)是一种特异性的蛋白激酶,在调控细胞生长、增殖、代谢等多项生命活动中都具有重要意义。mTOR调控功能的失活与异常激活,会导致相关肿瘤和疾病的发生。近年来已有多种mTOR抑制剂用于治疗该信号转导通路异常引起的肿瘤。该文探究多种调控mTOR的信号通路和mTOR抑制剂用于肿瘤治疗的最新进展,还探讨肿瘤细胞对mTOR抑制剂产生耐药性的潜在机制和应对策略。因此,对mTOR信号通路及其调控机制的探索有助于研发全新的肿瘤治疗技术。     

mTOR 信号通路与自噬在肿瘤中的研究进展

自噬是以细胞内自噬体形成为特征,通过溶酶体吸收降解自身受损细胞器和大分子的一种自我消化过程,是细胞维持稳态的重要机制。自噬广泛参与多种重要的细胞功能,既能在代谢应激状态下保护受损细胞,又可能因为过度激活导致细胞发生II型程序性死亡,从而引发多种疾病,尤其对肿瘤的发生和发展更是发挥着"双刃剑"的作用。自噬通过多种分子信号机制调控肿瘤进程,包括mTOR依赖性和mTOR非依赖性途径。mTOR作为生长因子、能量和营养状态的感受器,可通过调节下游自噬复合物的形成,直接调控细胞自噬。阐明mTOR与细胞自噬的相互作用机制将有助于从分子水平上对各肿瘤病变进行分析和治疗。因此,本文就自噬与PI3K/Akt/mTOR通路在肿瘤中的研究进展作一综述。     

mTOR信号途径与肿瘤

mTOR信号途径是最近新出现的细胞内重要信号途径,该途径在进化上高度保守,主要通过控制蛋白合成来调节细胞生长。现发现人体某些错构瘤综合征和恶性肿瘤存在mTOR信号途径的异常激活,雷帕霉素及其衍生物是mTOR信号特异性的抑制荆。这些新发现对了解细胞的生长调控和肿瘤的靶向性治疗具有重要意义。     

靶向FGFR信号通路在肿瘤治疗中的进展

成纤维生长因子受体(FGFRs)是一类高度保守的跨膜受体酪氨酸激酶(RTKs),它调控着细胞的许多正常生理功能。大量的研究表明,异常激活的FGFR与肿瘤的发生和血管的生成密切相关。靶向FGFR的药物则可以通过抑制该信号通路从而达到抗癌的作用。目前,多款针对FGFR的小分子抑制剂、单抗类药物已经进入临床。本综述主要介绍紊乱的FGFR信号通路与肿瘤的关系和几款具有代表性的FGFR药物在临床测试阶段的情况。     

mTOR信号通路与癌症治疗

哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin,mTOR)是一种非典型的丝氨酸／苏氨酸蛋白激酶,在细胞的生长、分化、增殖、迁移和存活上扮演了重要的角色。由于mTOR信号转导通路在细胞周期进程中发挥了重要作用,而细胞周期进程调节异常与许多疾病尤其是癌症的发生、发展有关,因此mTOR信号通路的失调可引起多种癌症。mTOR的特异性抑制剂雷帕霉素及其衍生物CCI-779能抑制mTOR的功能,使细胞阻滞在G。期,并引起凋亡。CCI-779作为抗癌药物已分别进入Ⅱ期临床。通过临床实验CCI-779显示出较高的抗癌活性和相对较小的副作用。越来越多的实验证据显示,mTOR信号转导通路的抑制剂可开发成为潜在的肿瘤特异性治疗药物。     

间质表皮转化因子MET信号通路及其在肿瘤中的研究进展

间质表皮转化因子(Mesenchymal to epithelial transition factor,MET)蛋白作为一种受体酪氨酸激酶,通常存在于上皮细胞中,被HGF等配体激活后,能够参与调控细胞的增殖、凋亡、迁移侵袭和细胞形态等多种生物学功能。随着研究的深入,MET已被证实在多种恶性肿瘤中异常表达或基因扩增,其与肿瘤患者的预后有着密切的关系。因此,针对MET的抑制剂研究发展比较迅速,且其良好的抗肿瘤效果也得到了证实。本文结合目前本实验室的研究,对MET的结构、功能及其抑制剂研究的现状等进行了综述,为今后的研究者提供一个阶段性的数据资料。     

靶向Ras信号通路抑制剂在肿瘤治疗中的研究进展

Ras信号通路在肿瘤的发生发展中有着重要作用,该通路与肿瘤细胞的增殖、转移、凋亡等关系密切,但目前没有确定的靶向药物在临床上使用。近年来,靶向Ras信号通路的抑制剂研究火热,并且在临床试验中取得了很好疗效。该文围绕着Ras信号通路,重点介绍了Ras信号通路与肿瘤的关系、靶向Ras信号上下游的抑制剂、针对Ras蛋白的共价抑制剂研发进展以及联合用药策略,总结了相关抑制剂的最新进展。该文指出了靶向Ras信号通路面临的诸多挑战,改进抑制剂的结构、明确具体机制以及联合治疗策略将是未来研究大方向。     

mTOR信号通路及其与阿尔茨海默病的关系

哺乳动物雷帕霉素靶蛋白mTOR是一个进化上十分保守的蛋白激酶,属于PIKK超家族。在细胞内mTOR存在两种功能不同的复合体mTORC1和mTORC2。mTOR主要通过接受上游信号分子Rheb、TSC1/TSC2的调控来整合细胞内外信号,其下游效应器是4E-BP和p70S6K,通过影响特定mRNA的翻译调节细胞的生长和增殖。在神经系统方面,神经元的发育、突触可塑性的调节、学习和记忆的形成都依赖于适当的mTOR通路的活化。新近的研究显示,神经退行性疾病阿尔茨海默病患者表现mTOR通路的异常,在双转基因鼠中,APP和PS1表达与mTOR/P70S6K下调关联,并影响精神状态评分。mTOR信号通路生理功能和调节机制的研究对了解AD的发病机理和寻找药物靶点具有重要意义。     

PI3K/AKT/mTOR信号通路及其在卵巢癌治疗中的应用

卵巢癌是女性生殖系统常见的恶性肿瘤,发病率居于妇科恶性肿瘤第三位,死亡率居于妇科恶性肿瘤之首。目前对卵巢癌的标准治疗包括肿瘤细胞减灭术及卡铂和紫杉醇的联合化疗。PI3K/AKT/mTOR信号通路在卵巢癌的细胞增殖、侵袭、细胞周期进展、血管生成及耐药中发挥重要作用,是卵巢癌中最常发生改变的细胞内途径。本文对PI3K/AKT/mTOR信号通路及其在卵巢癌增殖和进展中的影响、PI3K/AKT/mTOR信号通路抑制剂在卵巢癌中的治疗应用做简要综述。     

AMPK/mTOR信号通路的研究进展

mTOR是细胞生长和增殖的中枢调控因子。mTOR形成2个不同的复合物mTORC1和mTORC2。mTORC1受多种信号调节,如生长因子、氨基酸和细胞能量,同时,mTORC1调节许多重要的细胞过程,包括翻译、转录和自噬。AMPK作为一种关键的生理能量传感器,是细胞和有机体能量平衡的主要调节因子,协调多种代谢途径,平衡能量的供应和需求,最终调节细胞和器官的生长。能量代谢平衡调控是由多个与之相关的信号通路所介导,其中AMPK/mTOR信号通路在细胞内共同构成一个合成代谢和分解代谢过程的开关。此外,AMPK/mTOR信号通路还是一个自噬的重要调控途径。本文着重于目前对AMPK和mTOR信号传导之间关系的了解,讨论了AMPK/mTOR在细胞和有机体能量稳态中的作用。     

Therapeutic strategies of different HPV status in Head and Neck Squamous Cell Carcinoma

Head and neck squamous cell carcinoma (HNSCC) is the 9^th most common malignant tumor in the world. Based on the etiology, HNSCC has two main subtypes: human papillomavirus (HPV) -related and HPV-unrelated. HPV-positive HNSCC is more sensitive to treatment with favorable survival. Due to the different biological behaviors, individual therapy is necessary and urgently required to deduce the therapeutic intensity of HPV-positive disease and look for a more effective and toxicity-acceptable regimen for HPV-negative disease. EGFR amplification and PI3K/AKT/mTOR pathway aberrant activation are quite common in HPV-positive HNSCC. Besides, HPV infection alters immune cell infiltrating in HNSCC and encompasses a diverse and heterogeneous landscape with more immune infiltration. On the other hand, the chance of HPV-negative cancers harboring mutation on the P53 gene is significantly higher than that of HPV-positive disease. This review focuses on the updated preclinical and clinical data of HPV-positive and HPV-negative HNSCC and discusses the therapeutic strategies of different HPV status in HNSCC.     

Upregulation of SQLE Contributes to Poor Survival in Head and Neck Squamous Cell Carcinoma

Recently, increasing attention has been paid to the role of Squalene epoxidase (SQLE) in several types of cancers. However, its functional role in tumor progression of head and neck squamous cell carcinoma (HNSCC) is still unclear. We performed bioinformatic analyses and relative experiments to assess the potential mechanism of SQLE-mediated HNSCC malignancy. And the results showed that SQLE was significantly upregulated in tumor samples compared with peritumor samples. Mechanistically, miR-584-5p downregulation may lead to the upregulation of SQLE in HNSCC. Moreover, high SQLE expression in HNSCC was associated with TNM stage, distant metastasis, and poor survival, indicating that SQLE be involved in the progression of HNSCC. Furtherly, SQLE boosted proliferation, migration, invasion of HNSCC cells in vitro and in vivo. Bioinformatic studies showed that PI3K/Akt signaling participated in HNSCC progression mediated by SQLE overexpression, which is confirmed by in vitro and in vivo analysis. Particularly, treatment with terbinafine, an inhibitor of SQLE widely used in the treatment of fungal infections, showed a therapeutic influence on HNSCC. Our findings demonstrate that SQLE plays a vital role in HNSCC progression, providing research evidence for SQLE as a prospective HNSCC therapeutic target and for terbinafine as a candidate drug of HNSCC treatment in the future     

Alpha-2 Heremans Schmid Glycoprotein (AHSG) Modulates Signaling Pathways in Head and Neck Squamous Cell Carcinoma Cell Line SQ20B

This study was performed to identify the potential role of Alpha-2 Heremans Schmid Glycoprotein (AHSG) in Head and Neck Squamous Cell Carcinoma (HNSCC) tumorigenesis using an HNSCC cell line model. HNSCC cell lines are unique among cancer cell lines, in that they produce endogenous AHSG and do not rely, solely, on AHSG derived from serum. To produce our model, we performed a stable transfection to down-regulate AHSG in the HNSCC cell line SQ20B, resulting in three SQ20B sublines, AH50 with 50% AHSG production, AH20 with 20% AHSG production and EV which is the empty vector control expressing wild-type levels of AHSG. Utilizing these sublines, we examined the effect of AHSG depletion on cellular adhesion, proliferation, migration and invasion in a serum-free environment. We demonstrated that sublines EV and AH50 adhered to plastic and laminin significantly faster than the AH20 cell line, supporting the previously reported role of exogenous AHSG in cell adhesion. As for proliferative potential, EV had the greatest amount of proliferation with AH50 proliferation significantly diminished. AH20 cells did not proliferate at all. Depletion of AHSG also diminished cellular migration and invasion. TGF-β was examined to determine whether levels of the TGF-β binding AHSG influenced the effect of TGF-β on cell signaling and proliferation. Whereas higher levels of AHSG blunted TGF-β influenced SMAD and ERK signaling, it did not clearly affect proliferation, suggesting that AHSG influences on adhesion, proliferation, invasion and migration are primarily due to its role in adhesion and cell spreading. The previously reported role of AHSG in potentiating metastasis via protecting MMP-9 from autolysis was also supported in this cell line based model system of endogenous AHSG production in HNSCC. Together, these data show that endogenously produced AHSG in an HNSCC cell line, promotes in vitro cellular properties identified as having a role in tumorigenesis.     

头颈部鳞状细胞癌相关肿瘤标志物的研究进展

头颈部鳞状细胞癌(head and neck squamous cell carcinoma,HNSCC)是头颈部恶性肿瘤的主要病理类型,约占所有头颈部肿瘤的90%。而据我们临床所见,大约有70%~80%的患者就诊时已为局部晚期,其治疗效果欠佳,预后差。肿瘤标志物又叫做肿瘤标记物,是指特征性存在于恶性肿瘤细胞,或是由恶性肿瘤细胞异常而产生的物质,或是宿主对于肿瘤的刺激反应而产生的物质,并且能够反映肿瘤发生、发展,以及监测肿瘤对治疗反应的一类物质。作为近年来研究热点的肿瘤标志物,具有简便、经济、快速、无创的特点,更重要的是一些标志物在组织器官发生形态学变化之前就有表达。因此,肿瘤标志物的研究对头颈部鳞状细胞癌的早期诊断以及判断预后都具有十分重要的意义。本文综述近几年来发现的可能与头颈部鳞状细胞癌的发生发展或者预后相关的肿瘤标志物。     

Bitter Melon Reduces Head and Neck Squamous Cell Carcinoma Growth by Targeting c-Met Signaling

Head and neck squamous cell carcinoma (HNSCC) remains difficult to treat, and despite of advances in treatment, the overall survival rate has only modestly improved over the past several years. Thus, there is an urgent need for additional therapeutic modalities. We hypothesized that treatment of HNSCC cells with a dietary product such as bitter melon extract (BME) modulates multiple signaling pathways and regresses HNSCC tumor growth in a preclinical model. We observed a reduced cell proliferation in HNSCC cell lines. The mechanistic studies reveal that treatment of BME in HNSCC cells inhibited c-Met signaling pathway. We also observed that BME treatment in HNSCC reduced phosphoStat3, c-myc and Mcl-1 expression, downstream signaling molecules of c-Met. Furthermore, BME treatment in HNSCC cells modulated the expression of key cell cycle progression molecules leading to halted cell growth. Finally, BME feeding in mice bearing HNSCC xenograft tumor resulted in an inhibition of tumor growth and c-Met expression. Together, our results suggested that BME treatment in HNSCC cells modulates multiple signaling pathways and may have therapeutic potential for treating HNSCC.     

Challenges in EGFRvIII Detection in Head and Neck Squamous Cell Carcinoma

ObjectiveHead and neck squamous cell carcinoma (HNSCC) accounts for more than 5% of all cancers worldwide. The mortality rate of HNSCC has remained unchanged (approximately 50%) over the last few decades. Ubiquitous overexpression of wild type EGFR in many solid tumors has led to the development of EGFR targeted therapies. EGFR can be constitutively activated via several mechanisms including the truncated, EGFR variant III isoform (EGFRvIII). EGFRvIII lacks exons 2–7 and has been reported to be present in up to 20–40% of HNSCC. EGFRvIII has been shown to contribute to cetuximab resistance. The mechanisms leading to EGFRvIII expression in HNSCC are unknown. The present investigation was undertaken to determine the etiology of EGFRvIII in HNSCC.ResultsUnlike glioma, EGFRvIII expression in HNSCC did not correlate with EGFR amplification. We found evidence of genomic deletion of the exon 2–7 in 6 of 7 HNSCC cases examined, however, the presence of genomic deletion did not always result in mRNA expression of EGFRvIII. RNA sequencing with automated alignment did not identify EGFRvIII due to microhomology between intron 1 and exon 8. RNA sequencing analyzed by manual alignment methods did not correlate well with RT-PCR and PCR findings.ConclusionThese findings suggest that genomic deletion as well as additional regulatory mechanisms may contribute to EGFRvIII expression in HNSCC. Further, large scale automated alignment of sequencing are unlikely to identify EGFRvIII and an assay specifically designed to detect EGFRvIII may be necessary to detect this altered form of EGFR in HNSCC tumors.     

Decitabine Rescues Cisplatin Resistance in Head and Neck Squamous Cell Carcinoma

Cisplatin resistance in head and neck squamous cell carcinoma (HNSCC) reduces survival. In this study we hypothesized that methylation of key genes mediates cisplatin resistance. We determined whether a demethylating drug, decitabine, could augment the anti-proliferative and apoptotic effects of cisplatin on SCC-25/CP, a cisplatin-resistant tongue SCC cell line. We showed that decitabine treatment restored cisplatin sensitivity in SCC-25/CP and significantly reduced the cisplatin dose required to induce apoptosis. We then created a xenograft model with SCC-25/CP and determined that decitabine and cisplatin combination treatment resulted in significantly reduced tumor growth and mechanical allodynia compared to control. To establish a gene classifier we quantified methylation in cancer tissue of cisplatin-sensitive and cisplatin-resistant HNSCC patients. Cisplatin-sensitive and cisplatin-resistant patient tumors had distinct methylation profiles. When we quantified methylation and expression of genes in the classifier in HNSCC cells in vitro, we showed that decitabine treatment of cisplatin-resistant HNSCC cells reversed methylation and gene expression toward a cisplatin-sensitive profile. The study provides direct evidence that decitabine restores cisplatin sensitivity in in vitro and in vivo models of HNSCC. Combination treatment of cisplatin and decitabine significantly reduces HNSCC growth and HNSCC pain. Furthermore, gene methylation could be used as a biomarker of cisplatin-resistance.     

Head and Neck Squamous Cell Carcinoma: Prognosis using molecular approach

Head and neck squamous cell carcinoma (HNSCC) is the fifth most prevalent cancer worldwide. Apart from various known clinicopathogical factors, it is still a major concern as many genetic and epigenetic alterations bring about the possibility of this deadly disease. The aim of this review is to explore the possible role of DNA repair pathways and the polymorphic status of DNA repair genes (XPA, XPC, XPD, XRCC1 and XRCC3) in the onset of HNSCC, along with sequence variations in genes such as Glutathione S-transferases (GSTT1, M1 and P1) that are significantly associated with HNSCC risk. We also focus on the p53 gene mutation induced by various etiological agents and threat factors with its implications towards HNSCC, and emphasise the current therapeutic interventions in treating HNSCC.