容积敏感性外向整流氯离子通道对容积调节和细胞凋亡影响研究的现状

目的：对容积敏感性外向整流（volumesensitive outwardly rectifying，VSOR）氯通道在细胞容积调节和细胞凋亡中的作用，以及细胞容积调节与凋亡性细胞皱缩（apoptotic volume decrease，AVD）之间的关系进行分析。方法：以“氯通道、调节性容积回缩（regulatory volume decrease，RVD）、调节性容积增大（regulatory volume increase，RVI）和AVD”为关键词，计算机检索Pubmed（2002～2007年）和CNKI（2002～2007年），筛选出符合VSOR氯通道在RVD、RVI和AVD中所起作用的文献，而其他类型氯通道在其中所起作用的文献则予以淘汰。共检索符合文献54篇。结果：Cl^-是RVD的关键性离子；VSOR Cl^-通道参与了RVI的发生；VSOR Cl^-通道在细胞凋亡早期事件AVD中发挥了重要的作用。结论：RVD、RVI和AVD的发生均与VSOR氯通道的激活密切相关，且RVD与AVD、RVI与AVD之间存在着关联。     

氯离子通道在胃癌中的研究进展

胃癌是一种具有高度侵袭性和致命性的恶性肿瘤,其发病率及死亡率呈逐年增高,好发年龄在50岁以上,男女比例约为2∶1。因此明确胃癌的病因与发病机制、寻找早期诊断方法及有效药物靶点显得尤为重要。近年的研究表明,氯离子通道蛋白的异常表达与肿瘤的发生发展密切相关,氯离子通道的主要功能是调节跨上皮转运、膜电位和细胞免疫应答。氯离子通道异常与胃癌的增殖、凋亡、迁移、侵袭密切相关。本文就氯离子通道蛋白CLIC1、 TMEM16A和SLC26A9与胃癌的关系进行一综述。     

容积激活性氯通道在神经胶质瘤细胞迁移中的作用

容积激活性氯通道(volume-activated chloride channels,VACC)是广泛存在于脊椎动物细胞膜上的一种阴离子通道,参与维持细胞容积、细胞迁移等各种功能。神经胶质瘤的一个主要的生物学特性是侵袭性,VACC在神经胶质瘤的侵袭转移方面发挥着重要作用。笔者综合近年有关文献对VACC及其在神经胶质瘤细胞迁移中的作用的研究做一综述。     

细胞内氯离子通道蛋白4与恶性肿瘤发生发展的研究进展

细胞内氯离子通道蛋白4(chloride intracellular channel 4,CLIC4)是细胞内氯离子通道家族成员之一,广泛分布于细胞内,定位于多种细胞器如线粒体、内质网及细胞核和细胞质中,在多种肿瘤组织中表达异常,与肿瘤细胞的黏附、分化、凋亡等生物学行为密切相关,研究其在肿瘤发生、发展过程中的具体作用,将为多种肿瘤的诊断、治疗及预后提供新的依据。     

Hippo-YAP/TAZ信号通路调控铁死亡对肿瘤影响的研究进展

铁死亡是一种新型的铁依赖的程序性细胞死亡，常伴随脂质过氧化物的异常累积。Hippo 通路是一种高度进化保守的蛋白激酶信号通路，通过调节下游效应蛋白YAP/TAZ的亚细胞定位和蛋白稳定性，参与调节细胞的多种生命活动，包括组织生长、干细胞分化、肿瘤的发生发展等。近年来的研究发现，Hippo-YAP/TAZ信号通路通过细胞密度、细胞接触、细胞代谢、机械信号等多种细胞外途径影响肿瘤细胞对铁死亡的敏感性，在不同类型的肿瘤组织中通过特定的刺激条件、铁死亡靶向蛋白及其分子机制，影响泌尿、生殖、消化、呼吸和内分泌系统等肿瘤的发生和发展。Hippo-YAP/TAZ信号通路作为铁死亡新的调节机制，其激活为转移性及耐药性肿瘤的治疗提供了新的思路和方向。     

恶性脑胶质瘤分子靶向治疗研究进展

目前研究表明,胶质瘤的恶性进展涉及调节细胞增殖的信号通道的分子或基因异常,癌基因的过度表达或肿瘤抑制基因的突变.近年来的研究热点是针对肿瘤细胞内传导通路(包括肿瘤生长、侵袭和转移等)上的特异或相对特异分子的靶向治疗,有望成为传统细胞毒化疗以外的肿瘤化疗的突破口.全文总结了近年来在脑肿瘤研究和临床试验中应用小分子物质和单克隆抗体的文献.     

长链酰基辅酶A合成酶家族的功能及在肿瘤中的研究进展

脂肪酸是维持人体正常生理功能的必需营养物质,在体内需被相关酶激活后才可以进入正常代谢途径,脂肪酸代谢失调与肿瘤发生密切相关。长链酰基辅酶A合成酶(ACSLs)负责激活长链脂肪酸, ACSLs家族包括5个成员,分别为ACSL1、ACSL3、ACSL4、ACSL5、ACSL6,不同亚型具有不同细胞定位及功能,可以催化不同脂类并影响其代谢去路。ACSLs通过调节脂肪酸代谢,广泛参与内质网应激、铁死亡、耐药和肿瘤炎症微环境,ACSLs在肿瘤中经常去调控,可以影响脂肪酸代谢,而脂肪酸可以通过激活多种转录因子与基因反应原件结合激活不同的ACSLs,肿瘤细胞和蛋白泛素化可以调节ACSLs基因的表达,从而导致肿瘤发生代谢紊乱和其他代谢性疾病的发生。Triacsin C是一种ACSLs抑制剂,对开发抗肿瘤药物有巨大潜力。本文就ACSLs在细胞中的表达与定位、生理作用、在肿瘤中的功能、分子机制进行综述,结果表明,ACSLs与肿瘤中的炎症反应、脂质代谢紊乱、肿瘤侵袭与转移相关,对肿瘤发生、发展具有重要意义,可能成为肿瘤治疗有价值的生物标志物和治疗靶点。     

多途径丝裂原激活的蛋白激酶介导一氧化氮引起的肝癌细胞凋亡

目的研究非离子型的diazeniumdiolate类一氧化氮供体引起肝癌细胞凋亡的分子机制.方法利用免疫印迹、免疫沉淀、凝胶阻滞实验研究一氧化氮供体处理Hep3B肝癌细胞后,丝裂原激活的蛋白激酶、AP-1的激活以及和Hep3B肝癌细胞凋亡的关系.结果一氧化氮可引起细胞外信号调节蛋白激酶、c-jun N末端激酶和p38激酶的激活,特别是细胞外信号调节的蛋白激酶的持续激活,其中细胞外信号调节的蛋白激酶和c-jun N末端激酶的特异的阻断剂U0126和JNK抑制剂Ⅱ可阻断AP-1的激活和Hep3B细胞的凋亡,而p38激酶的阻断剂SB203580不能阻断AP-1的激活和Hep3B肝癌细胞的凋亡.结论一氧化氮通过激活细胞外信号调节蛋白激酶、c-jun N末端激酶,进而激活AP-1而引起Hep3B肝癌细胞的凋亡.     

微波辐射对血脑屏障通透性改变的影响

微波辐射现在在恶性肿瘤的诊疗中逐渐受到重视,微波辐射可否通过改变血脑屏障(BBB)通透性,进而改善化疗药物对颅内肿瘤的疗效是当前研究热点。目前认为微波辐射可以通过热效应及非热效应改善BBB的通透性,其机制可能与血管内皮生长因子、跨膜蛋白Occludin、水通道蛋白4、连接黏附分子-1等分子蛋白的调节相关,但在温度、微波频率、比吸收率以及暴露时间等物理参数尚存在争议。     

HGF/ Met与甲状腺癌侵袭性的研究进展

HGF/Met系统相关分子的激活与多种肿瘤的发生、侵袭和转移相关。本文综述了其在甲状腺癌的研究近况。通过对肿瘤表达Met水平及其机制的探讨,对Met的激活与肿瘤移动、血管生成和炎症反应的分析,认为HGF/Met相关分子的研究将提高对甲状腺癌的诊治水平,同时也将深化对肿瘤侵袭机制的认识。     

肝脏炎癌转化调控机制的研究进展

慢性非可控性炎症在肝细胞癌（hepatocellular carcinoma,HCC）发生过程中发挥关键作用。在慢性病毒性肝炎、酒精性肝炎和非酒精性脂肪性肝炎等HCC发生危险因素中,慢性非可控性炎症的发生发展是HCC发生的核心因素。在慢性炎症发生发展过程中,损伤或死亡的肝细胞能够介导肝脏中的免疫细胞活化,进而促发炎症,迁延不愈的肝脏炎症促进了肿瘤的发生;其中肝细胞的损伤或死亡方式和不同免疫细胞活化导致的炎症进展在HCC发生中的作用不尽相同,涉及肝损伤、炎症和代偿性增殖等多个病理或病理生理过程,以及多种细胞、信号通路和调控分子的功能改变。深入研究肝脏炎癌转化的调控机制有助于为HCC发生的干预提供理论基础。本文就肝脏炎癌转化及其调控机制的研究进展作一综述     

Transient receptor potential channels in multiple myeloma

Multiple myeloma is the second most commonly diagnosed hematologic malignancy. As an incurable disease, the molecular mechanisms underlying its many aspects remain unclear. Intracellular calcium ion is an essential signaling molecule that modulates malignant cell behavior, and abnormal regulation of cellular calcium homeostasis may promote cancer cell survival and induce drug resistance. Transient receptor potential (TRP) cation channels are a superfamily of non-selective Ca²⁺-permeable channels that regulate intracellular calcium signaling and are involved in the regulation of various characteristics of cancer cells. Emerging evidence shows a close connection between TRP channels and multiple myeloma. This review summarizes the roles of TRP channels in multiple myeloma progression, metastasis, bone destruction, and drug resistance. TRPV1 and TRPV2 orchestrate the progression of multiple myeloma, while TRPM7 promotes myeloma cell dissemination and spreading. TRPV2 and TRPV4, that activate osteoclasts, contribute to the development of osteolytic bone disease caused by multiple myeloma. Both TRPV1 inhibition and TRPV2 activation synergize with bortezomib in the chemotherapy of multiple myeloma, and TRPC1 can determine the responsiveness of multiple myeloma to MTI-101, a cyclic beta-hairpin peptide. Antagonizing TRPA1 can alleviate bortezomib-induced painful peripheral neuropathy. Future studies in this field may identify certain TRP channels as markers or therapeutic targets for predicting the prognosis, preventing progression, and improving drug responsiveness in patients with multiple myeloma.     

Eph receptors in breast cancer: roles in tumor promotion and tumor suppression

Eph receptor tyrosine kinase signaling regulates cancer initiation and metastatic progression through multiple mechanisms. Studies of tumor-cell-autonomous effects of Eph receptors demonstrate their dual roles in tumor suppression and tumor promotion. In addition, Eph molecules function in the tumor microenvironment, such as in vascular endothelial cells, influencing the ability of these molecules to promote carcinoma progression and metastasis. The complex nature of Eph receptor signaling and crosstalk with other receptor tyrosine kinases presents a unique challenge and an opportunity to develop therapeutic intervention strategies for targeting breast cancer.     

Ultraviolet irradiation-induced K(+) channel activity involving p53 activation in corneal epithelial cells

Recent studies from our lab found that ultraviolet (UV) irradiation induces a voltage-gated potassium (Kv) channel activation and subsequently activates JNK signaling pathway resulting in apoptosis. The present study in rabbit corneal epithelial (RCE) cells is to investigate mechanisms of UV irradiation-induced Kv channel activity involving p53 activation in parallel to DNA damage-induced signaling pathway. UV irradiation-induced signaling events were characterized by measurements of JNK activation and further downstream p53 phosphorylation. UV irradiation elicited an early response in the cell membrane through activation of Kv channels to activate the JNK signaling pathway and p53 phosphorylation. Exposure of RCE cells to UV irradiation within a few min resulted in JNK and p53 activations that were markedly inhibited by suppression of Kv channel activity. However, suppression of Kv channel activity failed to prevent p53 activation induced by extended DNA damages through prolonging UV exposure time (more than 15 min). In addition, caffeine inhibited UV-induced activation of SEK, an upstream MAPK kinase of JNK, resulting in suppression of both Kv channel-involved and DNA damage-induced p53 activation. Our results indicate in these cells that UV irradiation induces earlier and later intracellular events that link to activation of JNK and p53. The early event in response to UV irradiation is initiated by activating Kv channels in the cell membrane, and the later event is predominated by UV irradiation-caused DNA damage.     

Hedgehog信号通路与肿瘤转移

Hedgehog(Hh)信号通路在果蝇、多种脊椎动物及人类胚胎发育过程中对细胞分化和增生起重要作用.该通路中各信号分子的突变、异常激活和过表达都可能导致肿瘤的发生.最近研究表明,Hh信号通路与多种恶性肿瘤侵袭和转移有密切的关系,其机制与肿瘤干细胞、上皮细胞间质转化、自分泌/旁分泌途径、肿瘤新生血管和淋巴管等有关.对Hh...     

Involvement of PI3K/Akt pathway in cell cycle progression, apoptosis, and neoplastic transformation: a target for cancer chemotherapy.

The PI3K/Akt signal transduction cascade has been investigated extensively for its roles in oncogenic transformation. Initial studies implicated both PI3K and Akt in prevention of apoptosis. However, more recent evidence has also associated this pathway with regulation of cell cycle progression. Uncovering the signaling network spanning from extracellular environment to the nucleus should illuminate biochemical events contributing to malignant transformation. Here, we discuss PI3K/Akt-mediated signal transduction including its mechanisms of activation, signal transducing molecules, and effects on gene expression that contribute to tumorigenesis. Effects of PI3K/Akt signaling on important proteins controlling cellular proliferation are emphasized. These targets include cyclins, cyclin-dependent kinases, and cyclin-dependent kinase inhibitors. Furthermore, strategies used to inhibit the PI3K/Akt pathway are presented. The potential for cancer treatment with agents inhibiting this pathway is also addressed.     

Roles and regulation of Wnt signaling and beta-catenin in prostate cancer

The Wnt signaling pathway and its key component beta-catenin play critical roles in embryonic development as well as in human diseases, including various malignancies. Accumulated evidence has demonstrated a significant role for the Wnt pathway in the development and progression of human prostate cancer. The recent discovery of an interaction between beta-catenin and the androgen receptor (AR) suggests a possible mechanism of cross talk between Wnt and androgen signaling pathways. In this review, we summarize the recent progresses in this interesting and growing field. Particularly, we focus on the observation that the activation of the Wnt-mediated signal occurs in a different manner in prostate cancer than in colorectal cancer or other human malignancies. Since mutations in Adenomatous polyposis coli (APC), beta-catenin, and other components of the beta-catenin destruction complex are rare in prostate cancer cells, other regulatory mechanisms appear to play dominant roles in the activation of beta-catenin, such as loss or reduction of E-cadherin, a component of cell adhesion complex, and abnormal expression of Wnt ligands, receptors, inhibitors, and other co-regulators. Understanding the role and regulation of the Wnt signaling pathway in prostate cancer cells may help identify new targets for the prostate cancer therapy.     

SOX2 promotes tumor metastasis by stimulating epithelial-to-mesenchymal transition via regulation of WNT/β-catenin signal network

SOX2 was reported to promote metastasis in various tumor tissues; however the underlying mechanisms remain elusive. Here, we disclosed that SOX2 improves metastasis of breast and prostate cancer cells by promoting epithelial-to-mesenchymal transition (EMT) through WNT/β-catenin, but not TGF-β or Snail1 signaling. Dual luciferase assay and chromatin immunoprecipitation revealed activation and binding of SOX2 on promoter region of β-catenin. In addition, SOX2 affects the protein expression levels of DKK3, DVL1 and DVL3, which are regulators or downstream molecules of WNT signaling. Taken together, our findings demonstrated β-catenin as one of vital downstream molecules that mediate the EMT induced by SOX2.     

Src-family kinases in B-cell development and signaling

The Src-family protein tyrosine kinases (SFKs) are known to play key roles in initiating signal transduction by the B-cell antigen receptor (BCR). In addition, numerous studies have shown that this family of molecules also contributes to signaling by BCR surrogates during B-lymphocyte lineage development and maturation. Paradoxically, ablation of SFKs not only results in obvious defects in B-cell development but also in the onset of autoimmunity. Thus SFKs, most notably Lyn, play both activating and inhibitory roles in B-cell function. Confounding analyses of SFK function in B cells is the varied coexpression of family members that mediate redundant as well as unique functions. In this review, we will focus mainly on the role of Lyn in mediating positive and negative roles in B-cell activation and how these affect immune signaling and disease progression.