mTOR信号通路与“炎-癌”转变

慢性炎症是指刺激因素持续作用或其他原因导致的难以消退的炎症反应.它与许多重大疾病的发生、发展密切相关.近年来,慢性炎症在癌症发生发展中的关键作用得到普遍认可,其促癌作用的机制已成为当前生命科学研究热点之一.哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin,mTOR)是接受细胞内外各种信号、调节细胞生长与代谢的关键分子,多数肿瘤存在mTOR通路的过度激活.最近,我们与其他实验室的研究发现mTOR通路在"炎-癌"转变中起重要作用.本综述将对慢性炎症与癌症的关系、慢性炎症的促癌作用机制做一概括介绍,重点讨论mTOR信号通路介导慢性炎症促癌效应的作用、机制及未来研究方向,为慢性炎症恶性转化分子机制研究提供新的观点.     

癌相关通路在肺腺癌中的共扰动机制

肺腺癌的发生涉及多个生物学功能通路的扰动,其遗传改变频繁地发生于MAPK信号、p53信号、Wnt信号、细胞周期和mTOR等通路的基因中。解析癌相关通路间的共扰动机制对我们理解癌机制以及寻找诊断标记具有重要意义。因此,本文基于肺腺癌突变谱数据,研究上述癌相关通路在肺腺癌中的共扰动机制。结果发现:在肺腺癌发生的过程中,MAPK信号、p53信号、Wnt信号、细胞周期和mTOR等通路同时被扰动。在不同的癌样本中,一对通路可能通过以下三种方式被共同扰动:(1)在两条通路中的不同基因间的共突变;(2)两条通路相互交叠基因的突变;(3)与两条通路同时具有频繁的互作关系的蛋白质的编码基因的突变。该结果提示,癌相关通路对在不同的样本中可能通过不同的方式被共扰动,这也可能是造成癌症异质性的重要原因之一。     

mTOR信号通路与衰老相关疾病

哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin,mTOR)是一种丝/苏氨酸蛋白激酶,在调节细胞的生长、增殖和存活中起着重要的作用。mTOR信号通路失调与许多衰老相关重大疾病如神经退行性病变、代谢综合征、肿瘤、心血管疾病等的发生发展密切相关,故对mTOR信号通路在衰老及衰老相关疾病中的作用机制的研究,对于揭示衰老及衰老相关疾病的发生机制具有重要意义,并为研发以mTOR信号通路为靶点的抗衰老及衰老相关疾病的治疗药物提供新策略。     

肝细胞癌中抑癌基因的发现与研究进展

肝细胞癌（HCC）的发病率高、治疗效果差。HCC的发病机制复杂,主要有2类：肝炎、酒精、黄曲霉素、代谢紊乱引起的肝损伤,进而导致的肝硬化;致癌基因和抑癌基因的突变或对应染色体区域的扩增或缺失。细胞内一些信号通路参与了HCC的发生发展,包括RAF／MEK／ERK、P13K／AKT／mTOR、WNT/β-catenin、胰岛素样生长因子、肝细胞生长因子／c-MET、生长因子调节的血管新生等6类信号通路。抑癌基因通过调节信号通路而调节细胞增殖、细胞周期、细胞凋亡等对肿瘤的发生、发展起重要作用的过程。我们简要概述HCC相关的肿瘤抑制分子及其所在的信号通路及作用的分子机制。     

Wnt/β-catenin信号通路与肝癌

肝细胞癌是常见的恶性肿瘤,其发病机制尚未完全明确。Wnt信号通路与人体内多种病理生理过程相关,其中肝癌的发生、发展可能与经典的Wnt/β-catenin信号通路密切相关。Wnt/β-catein信号通路通过表达癌症相关基因、激活肝星状细胞、调控肝干细胞行为、促进肝癌细胞侵袭转移等方式调控肝癌的发生、发展。Wnt/β-catein信号通路在肝癌发生、发展中的作用有望为肝癌研究提供新的思路。     

肿瘤坏死因子α通过激活NF-κB信号通路加快肝细胞周期进程

在慢性炎症部位有易发肿瘤的倾向,大约有20%的恶性肿瘤发生与慢性炎症相关,肝细胞癌是世界第三大癌症死亡病因,其患者多数有慢性炎症病史,当炎症慢性迁延,肝细胞癌发生率明显增加.但慢性炎症与肿瘤发生与发展的细胞和分子机制仍然不清楚.利用人肝细胞株L-02细胞,研究肿瘤坏死因子α(TNF-α)对细胞周期的影响及其机制,并探讨核因子κB(NF-κB)和ERK1/2活化对细胞周期的影响,以期能更确切地阐明炎症介质TNF-α在肝细胞癌发生发展中的作用.发现TNF-α能促进肝细胞从G0/G1期向S期转换.蛋白质印迹检测表明,TNF-α能以剂量依赖方式诱导cyclinD1表达,而对cyclinE的表达无明显影响.同时TNF-α能激活NF-κB,ERK1/2,抑制NF-κB活化降低了TNF-α诱导的cyclinD1表达,导致细胞周期阻滞于G0/G1期.抑制ERK1/2活化则对细胞周期和cyclinD1表达无显著影响.结果提示,TNF-α通过活化NF-κB信号通路,诱导cyclinD1表达,加快细胞周期进程,这可能是促进肿瘤的发生发展重要机制.针对TNF-α和NF-κB的治疗可能延长慢性炎症相关性肿瘤的潜伏期和抑制肿瘤的发展.     

对mTOR信号通路干扰导致基因差异翻译分析

mTOR(mammalian target of rapamycin)是丝氨酸/苏氨酸蛋白激酶,其在细胞生长中处于核心地位,并参与很多的病理学过程,例如癌症的发生发展,但mTOR下游的大量过程和临床表现的异质性都阻碍我们对疾病机制的深入了解和治疗方案的最佳选择。本研究采用最新的研究方法 Xtail,对建立在TSC2(tuberous sclerosis complex2)缺失的细胞模型及两种mTOR抑制剂雷帕霉素和AZD-8055(ATP-competitive mTOR kinase inhibitor)处理的条件下的核糖体分析数据做研究,我们发现了大量翻译水平异常表达的基因,并对这些基因做功能和信号通路的富集,发现TSC2(结节性脑硬化复合物2)是mTOR活性调节中的关键抑制因子,其突变会使mTOR和它的下游效应分子的激活和不受调控,为mTOR信号通路的研究提供了新的信息。     

吸烟与癌症相关性的研究进展

研究肿瘤的易感性对理解认识肿瘤发生发展及诊断治疗都有重要意义,遗传危险因素与环境危险因素的相互作用决定了人体部分器官癌症的易感性。研究表明吸烟与肿瘤的发生发展密切相关。本文综述了基因多态性和吸烟协同促癌作用和机制,吸烟通过激活自噬等信号通路促进癌症发生、侵袭和转移及与癌症预后相关性的研究进展。     

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。     

慢性炎症与甲状腺癌关系的研究进展

甲状腺癌是内分泌系统恶性肿瘤中最为常见的类型,其发病率约占90％,且仍有上升趋势。近年来,随着免疫学技术及分子生物学技术的快速发展和人类对甲状腺癌发病机制认识的不断深入,慢性炎症与甲状腺癌的相关性引起了大家的广泛关注。因此,本文就慢性炎症与甲状腺癌的最新研究进展进行综述。     

阴道炎症与宫颈癌发生的相关性研究进展

阴道炎症是妇科疾病中发病率最高的疾病,不同年龄和种族的妇女均可患病。近年来,阴道炎症与妇科肿瘤的相关性日益受到关注。而在妇科恶性肿瘤中,宫颈癌的发病率高居第一。虽然高危型HPV感染很常见,但是宫颈癌的发病率却并不高,这是因为若缺乏协同因素作用就不会有宫颈癌的发生。目前认为阴道炎症除了与阴道黏膜被破坏、免疫功能受到抑制有关外,还与HPV感染、宫颈癌前病变和宫颈癌的发生发展密切相关。因此,阴道炎症与宫颈癌的相关性研究已成为人们关注的热点,本文就阴道炎症及其与宫颈癌的关系的研究进展作一综述。     

白介素17 与结直肠癌

结直肠癌是世界范围内的高发癌症,其发病机理尚不明确。大量研究数据表明,基因突变、表观遗传学的改变、饮食习惯以及生活方式等均是结直肠癌发生发展的高危因素。目前,普遍认为慢性炎症在肿瘤的发生发展中起重要作用。白介素17主要由T细胞的亚型Th17细胞分泌产生,能够促进肿瘤相关性炎症,使肿瘤细胞逃避免疫监控。已在胃癌、宫颈癌、食管癌、非小细胞肺癌、肝细胞肝癌、卵巢癌、黑色素瘤、淋巴瘤、乳腺癌、前列腺癌、结直肠癌等多种恶性肿瘤中发现白介素17呈高表达。现有研究表明,白介素17与肠炎和结直肠癌的发生发展密切相关。尽管尚存在争议,多数学者认为白介素17在结直肠癌的发生发展中起促进作用。本文将近年来关于IL-17在结直肠癌的发生发展中的作用以及其与结直肠癌的预后的研究成果进行总结。     

Cancer and diet: How are they related?

Extensive research in the past decade has revealed cancer to be a multigenic disease caused by perturbation of multiple cell signalling pathways and dysregulation of numerous gene products, all of which have been linked to inflammation. It is also becoming evident that various lifestyle factors, such as tobacco and alcohol use, diet, environmental pollution, radiation and infections, can cause chronic inflammation and lead to tumourigenesis. Chronic diseases caused by ongoing inflammation therefore require chronic, not acute, treatment. Nutraceuticals, compounds derived from fruits, vegetables, spices and cereals, can be used chronically. This study discusses the molecular targets of some nutraceuticals that happen to be markers of chronic inflammation and how they can prevent or treat cancer. These naturally-occurring agents in the diet have great potential as anti-cancer drugs, thus proving Hippocrates, who proclaimed 25 centuries ago, 'Let food be thy medicine and medicine be thy food'.     

Molecular approach for development of new medicaments for chronic infections treatment

Owing to the progress in cellular microbiology it has been evidently proved that inflammation induced by infectious agents forms the basis of many chronic conditions. Therefore a microbial infection can be considered as a triggering factor of such widespread and significant diseases as infertility, arthritis, atherosclerosis, asthma, gastritis, stomach ulcer and cancer, neurological syndromes and some oncological formations. Practically all pathogenic and conditionally pathogenic bacteria can induce chronic infections of different organs and tissues. It has been revealed that in spite of differences of clinical syndromes and participation of different bacteria in their induction the several general mechanisms of chronic infections are detected. Failure in chronic infections therapy is due to the absence of medicaments to eradicate persistent forms of pathogens. The development of new medicaments for chronic infections treatment should be based on the selection of new specific targets, influence on which would to inhibit the mechanism of chronic infections induction.     

Interplay between inflammation and cancer

Tumor-promoting inflammation is one of the hallmarks of cancer. It has been shown that cancer development is strongly influenced by both chronic and acute inflammation process. Progress in research on inflammation revealed a connection between inflammatory processes and neoplastic transformation, the progression of tumour, and the development of metastases and recurrences. Moreover, the tumour invasive procedures (both surgery and biopsy) affect the remaining tumour cells by increasing their survival, proliferation and migration. One of the concepts explaining this phenomena is an induction of a wound healing response. While in normal tissue it is necessary for tissue repair, in tumour tissue, induction of adaptive and innate immune response related to wound healing, stimulates tumour cell survival, angiogenesis and extravasation of circulating tumour cells. It has become evident that certain types of immune response and immune cells can promote tumour progression more than others. In this review, we focus on current knowledge on carcinogenesis and promotion of cancer growth induced by inflammatory processes.     

非可控性炎症与头颈恶性肿瘤的关系

"癌症源于慢性炎症"之说越来越被人们关注与认可,已成为近年肿瘤领域研究的热点。与肿瘤密切相关的炎症实质为非可控性炎症,触发并参与肿瘤的发生、发展、浸润转移等各个病理过程;而在肿瘤发生发展过程中,肿瘤细胞同样可通过自分泌或其他方式调控非可控性炎症反应,以利于自身生长。非可控性炎症在头颈恶性肿瘤发生、进展过程中均扮演着十分重要的角色,在此过程中涉及众多分子和信号通路的参与。本文就非可控性炎症与头颈恶性肿瘤(鼻咽癌、喉癌、口腔癌、甲状腺肿瘤及皮肤肿瘤)的相互关系进行简要综述。     

The interplay between innate and adaptive immunity regulates cancer development

There is increasing clinical and experimental evidence that inflammation and cancer are causally linked. Much progress has been made in understanding how inflammatory cells contribute to cancer development; however, it is still largely unknown which molecular mechanisms are responsible for initiation and maintenance of chronic inflammation associated with developing neoplasms. This review will discuss how the adaptive and innate immune systems interact during physiological and chronic inflammation, with a focus on studies revealing new insights into the role of adaptive immune cells as important regulators of chronic inflammation-associated carcinogenesis. We will speculate on whether current knowledge about the dysregulated interplay between adaptive and innate immunity during chronic inflammatory disorders might be useful in understanding and targeting the underlying mechanisms of chronic inflammation-associated neoplastic progression.This article is a symposium paper from the conference Tumor Escape and its Determinants, held in Salzburg, Austria, on 10–13 October 2004     

食品中的免疫调节功能因子研究进展

经过自然进化,人类免疫系统与各种天然食品资源相适应。利用天然资源中的功能因子调节人体免疫系统成为一项重要的研究内容。调节免疫功能是我国保健食品可以申报的27项功能之一,在伤病员康复、预防炎症和慢性疾病、增强体质等方面具有重要作用。本文综述了氨基酸、维生素、ω-3多不饱和脂肪酸、黄酮和异黄酮类、多酚类、类胡萝卜素等免疫调节功能因子及其调节机理的研究进展。     

Versatile role of heparanase in inflammation

Heparanase is the only known mammalian endoglycosidase capable of degrading heparan sulfate glycosaminoglycan, both in extracellular space and within the cells. It is tightly implicated in cancer progression and over the past few decades significant progress has been made in elucidating the multiple functions of heparanase in malignant tumor development, neovascularization and aggressive behavior. Notably, current data show that in addition to its well characterized role in cancer, heparanase activity may represent an important determinant in the pathogenesis of several inflammatory disorders, such as inflammatory lung injury, rheumatoid arthritis and chronic colitis. Nevertheless, the precise mode of heparanase action in inflammatory reactions remains largely unclear and recent observations suggest that heparanase can either facilitate or limit inflammatory responses, when tissue/cell-specific contextual cues may dictate an outcome of heparanase action in inflammation. In this review the involvement of heparanase in modulation of inflammatory reactions is discussed through a few illustrative examples, including neuroinflammation, sepsis-associated lung injury and inflammatory bowel disease. We also discuss possible action of the enzyme in coupling inflammation and tumorigenesis in the setting of inflammation-triggered cancer.