头颈部鳞癌生物标志物的预后作用

头颈部鳞癌(HNSCC)是世界上常见的恶性肿瘤之一。尽管现有治疗手段不断完善,HNSCC的5年生存率仍徘徊在50%。肿瘤生物标志物是由肿瘤细胞合成、释放或是宿主对肿瘤的反应而释放的物质。它有助于肿瘤的分子诊断、预后判断及疗效预测。因此生物标志物具有诊断、预后和预测三大作用。本文分别就与HNSCC相关的临床确定的和正在热研的,主要具有预后作用的生物标志物进行阐述。临床确定的标志物包括EBV和HPV。迄今为止众多生物标志物被研究且结果喜人。本文介绍的热研的标志物包括细胞周期调控、转录因子和信号传导三个方面。除了综述生物标志物预后作用的最新研究信息,还对研究中出现预后作用不一致的原因进行分析。分子细胞生物学的发展促使更多的生物标志物及潜在治疗靶点被发现。从预后到预测的发展是实施肿瘤个体化治疗的目标。以生物标志物为治疗靶点,有望改善HNSCC的预后,实现个体化精准治疗。     

PEG10基因在肝癌中的表达及研究意义

PEG10基因是由反转座子衍生而来的遗传印记基因,研究表明,PEG10是肝细胞癌(HCC)发生的重要促进作用之一,在绝大多数肝癌中特异性高表达,具有作为更有效的肝癌诊断标志物和基因治疗新靶点的潜力。本文概述PEG10基因与肝癌发生、发展和转移的关系及其作用与肝癌的机制,并对其前景进行展望,以期为肝癌的标志物诊断和基因靶向治疗的研究提供理论参考依据。     

SIRT3与肾脏疾病

研究肾脏疾病的发病机制,寻找新的治疗靶点及其对应的治疗药物和方案,对于预防肾脏疾病的发病和降低病死率具有重要意义。研究发现:Sirtuin3(SIRT3)是通过维持线粒体功能和结构的稳定性,在肾小管上皮细胞损伤中发挥保护作用。为了更深入地了解SIRT3在不同类型肾病产生和发展过程中的作用及其机制,本文综述了SIRT3参与调节肾脏的生理学机制,分析了SIRT3在肾脏疾病中参与的信号通路及分子作用靶点,有助于今后临床上采用中西医结合防治肾病,降低并发症及其病死率,提供了思路。     

LncRNA TUG1在肝癌中的研究进展

肝细胞癌(hepatocellular carcinoma, HCC)是我国最常见且死亡率最高的恶性肿瘤之一。由于目前缺乏灵敏的早期诊断指标,许多患者发现时已是晚期,导致预后不佳,5年生存率低。因此,找到相应的肿瘤标记物将有助于早期肝癌的诊断。近些年的研究发现,牛磺酸上调基因1 (taurine upregulated gene 1,TUG1)在肝癌中的表达明显上调,与肝癌的发生、发展以及预后都密切相关。同时,进一步研究发现,下调TUG1可以降低肝癌细胞的侵袭、转移、增殖等能力,还可以促进细胞的凋亡。TUG1在肿瘤的早期诊断、疗效判断及预后评估等方面具有重要的潜在价值。该文将重点介绍TUG1作为癌基因在HCC中发挥的功能和作用机制,以及它作为HCC诊断和治疗的潜在靶点的可能性。     

糖尿病肾病蛋白质组学研究进展

糖尿病肾病(diabetic kidney disease, DKD)是糖尿病的主要并发症之一,严重威胁人类健康与生命.截至目前, DKD的致病机制尚未阐释清楚,且临床常用诊断方法的灵敏性和准确性并不十分理想,从而导致DKD确诊后治疗方案的确定比一般性肾脏疾病更为棘手.蛋白质作为生命活动的主要承担者与体现者,直接参与和调控各种生命过程.从蛋白质组学水平开展DKD研究,能够从整体、动态、互作网络等视角探究该疾病相关分子机制.针对不同生理病理条件下的DKD临床样本开展蛋白质组学研究,可全面探查与DKD显著相关的关键蛋白质;通过对这些蛋白质进行深入分析和验证,能够更直观地理解DKD发生发展的分子机制,并获得DKD进程相关候选标志物和后续疾病的潜在治疗靶点,为DKD的早期诊断和治疗新方法的探究奠定基础.近年来,随着蛋白质组学技术的不断发展,在蛋白质分离、质谱鉴定、生物信息学分析等蛋白质组学核心技术基础上衍生出了许多新兴技术,进一步推动了蛋白质组学在疾病生物标志物筛选、致病分子机制揭示、药物作用蛋白质靶点等研究中的应用.本文基于蛋白质组学研究技术,主要从DKD致病机制研究、早期诊断潜在生物标志物筛选、治疗靶点及效果评估三个方面对蛋白质组学在DKD研究中的应用进展进行了系统性综述.尽管蛋白质组学在DKD研究中取得了长足的进步,但仍具有较大的发展空间,特别是现已识别的大量潜在DKD分子标志物的相关性分析、药物蛋白质作用靶点临床验证与应用将是DKD未来研究的重点.     

SIRT1基因在抑郁症中的作用及机制研究进展

抑郁症是一类高致残率且难治愈的精神类疾病,目前其临床诊断和治疗都面临很大的困难,因此研究抑郁症患病机制,寻找抑郁症的潜在治疗靶点,并开发有效临床治疗手段刻不容缓。沉默信息调节因子2同源体1 (silent mating type information regulator 2 homolog 1, SIRT1)作为一种去乙酰化酶,参与细胞衰老、癌症、心血管疾病等多种生物学过程。近年来,越来越多的研究发现SIRT1基因在抑郁症发病过程中发挥了重要的作用,但是其机制尚不明确。本文主要总结了海马、前额叶皮层、杏仁核、下丘脑视交叉上核脑区和伏隔核中SIRT1基因影响抑郁症病理过程的相关研究进展,以期为抑郁症机制研究和抗抑郁药物的研发提供一定的参考和帮助。     

沉默信息调节因子1在消化系统肿瘤中的作用

沉默信息调节因子1(SIRT1)是Sirtuin 家族中的一员,属于烟酰胺（NAD⁺）依赖的Ⅲ类组蛋白去乙酰化酶,能通过对多种非组蛋白及组蛋白赖氨酸残基进行去乙酰化修饰调节基因表达。近来的研究发现,SIRT1不仅能使肿瘤抑制因子去乙酰化,促进肿瘤发生,还能使肿瘤促进因子去乙酰化,抑制肿瘤发生。SIRT1与肿瘤的生物学特性密切相关,影响肿瘤分期及患者预后。在消化系统肿瘤中,SIRT1具有双面性,既可作为抑癌因子,也可发挥癌因子的作用。近年来,许多研究对SIRT1在肿瘤中的作用靶点及相关信号通路做了深入研究,关于SIRT1在肿瘤中作用机制的新研究不断出现。SIRT1已成为人们攻克肿瘤的一个研究热点。本文通过对SIRT1在肿瘤中的双重作用,尤其是在消化系统肿瘤中的不同作用靶点和参与的信号通路作一综述,希望为临床上治疗消化系统肿瘤提供更有说服力的证据。     

lncRNA在肿瘤中的表达及作用机制

长链非编码RNA(long non-coding RNAs,lncRNAs)是一类转录本长度大于200 nt,不具有蛋白编码功能的非编码RNA.近年来,随着高通量测序技术的发展,越来越多的功能性lncRNAs逐渐被发现,且已成为研究的热点.研究发现,lncRNAs可以作为致癌或抑癌基因参与肿瘤的发生发展.通过比对肿瘤细胞和正常细胞的表达谱显示,多种lncRNAs在不同类型肿瘤中异常表达.除了表型上的研究,目前已有部分报道深入研究了lncRNAs在肿瘤中的作用机制.例如,lncRNAs与肿瘤细胞凋亡、转移及耐药等过程密切相关.此外,在肿瘤患者的临床常规检验中检测到lncRNAs,提示其能够作为一种潜在的肿瘤诊断和预后因子. lncRNAs有望成为新型肿瘤标志物和肿瘤治疗的靶点,用于诊断、治疗、预测预后.本文将通过对lncRNAs在肿瘤中的作用及其分子机制进行综述.     

微小RNAs在肝癌中的作用机制及相关应用研究进展

微小RNAs(miRNAs)是一类内源性小型非编码RNA,可通过调控靶基因表达参与大多数生物学过程。近年来,miRNAs在肝癌发生发展进程中相关作用机制的研究逐渐深入,miRNAs作为其中关键调控因子和主要参与者,已成为肝癌早期诊断、靶向治疗和预后评估中的一个关键靶标。本文着重强调miRNAs在肝癌发生发展、多重耐药性中的作用以及作为肝癌潜在治疗靶点的价值,并就miRNAs在肝癌中的功能、分子作用通路以及应用三方面的相关研究进展进行综述。     

淋巴细胞胞质蛋白2在恶性肿瘤发生与发展过程中的免疫调节机制

淋巴细胞胞质蛋白2(lymphocyte cytosolic protein 2,LCP2)是一种衔接蛋白质,在T细胞受体信号通路中扮演重要角色,激活下游信号因子以完成机体的免疫应答过程。LCP2也在恶性肿瘤的发生发展与转移中发挥重要作用,其高表达会导致不良的预后效果,降低患者生存率,其具体作用机制涉及多条信号通路。本文不仅对LCP2的分子结构以及基本功能进行了介绍,而且重点综合评述了LCP2通过参与NF-κB、MAPK、JAK/STAT以及PD-1/PD-L1信号通路调控恶性肿瘤发生与发展的分子机制。总结了LCP2作为肿瘤治疗靶点的潜在作用,为将来用于相关疾病的诊断、治疗和标志物筛选等提供理论基础和参考依据。     

SIRT7琥珀酰化修饰对肝癌生存、免疫浸润及预后的相关性分析

摘要 目的：探究SIRT7基因琥珀酰化修饰对肝癌患者的生存、免疫浸润及预后的相关性分析。方法：采用生物信息分析法对SIRT7在肝癌组织中的表达情况及其对肝癌患者预后的影响进行分析；采用蛋白免疫印迹法（Western blot）检测其转染效果。结果：（1）生物信息分析结果显示：SIRT7在多种肿瘤（包括肝癌）组织中呈高表达（P<0.05）；SIRT7的表达与肿瘤的生存曲线相关（P<0.05）；肝癌患者的SIRT7相对表达量与其预后相关，高表达组肝癌患者的总生存情况（P=0.017）和无进展生存情况较低表达组缩短（P=0.004）；免疫浸润和肿瘤微环境分析结果显示，SIRT7表达水平与多数免疫细胞浸润水平、肿瘤微环境(ESTIMATES core)均有明显负相关。（2）Western blot显示，SIRT7在肝癌细胞中表达高于正常细胞。因此，SIRT7 可作为肝癌的潜在预后标志物。结论：SIRT7表达水平与肝癌(HCC)患者的预后、免疫细胞浸润性、肿瘤微环境免疫细胞和基质细胞浸润等相关。     

Small regulatory polypeptide of amino acid response negatively relates to poor prognosis and controls hepatocellular carcinoma progression via regulating microRNA-5581-3p/human cardiolipin synthase 1

Hepatocellular carcinoma (HCC) is one of the most common malignancies with extremely high rates of occurrence and death. Long noncoding RNAs (lncRNAs) have been increasingly revealed to participate in tumorigenesis and development of multiple human cancers, including HCC. LINC00961 is a novel lncRNA which has been uncovered as a tumor suppressor in lung cancer and glioma. However, the role of LINC00961 in HCC has never been probed yet. Herein, we revealed a marked downregulation of LINC00961 in HCC tissues and cell lines. Correlation of low LINC00961 expression with poor outcomes in patients with HCC suggested LINC00961 as an independent predictor for HCC prognosis. Functionally, LINC00961 overexpression obviously inhibited cell proliferation, migration, and invasion in HCC cells. Mechanistically, LINC00961 regulated cardiolipin synthase 1 (CRLS1) expression via sponging miR-5581-3p. Importantly, both miR-5581-3p upregulation and CRLS1 inhibition led to an acceleration in cellular processes in HCC cells. At length, the rescue assays suggested that LINC00961 functioned in HCC through the miR-5581-3p/CRLS1 axis. On the whole, our findings disclosed that LINC00961 played a suppressive role in HCC progression via modulating miR-5581-3p/CRLS1, thus providing a potentially effective target for the prognosis and treatment of patients with HCC.     

慢病毒介导的靶向沉默信息调节因子1（SIRT1）的RNA干扰对肝癌细胞生长及凋亡的影响

目的探讨慢病毒介导的靶向SIRTlshRNA对肝癌细胞生长和凋亡的影响。方法Western印迹分析SIRT1在多个肝癌细胞系中的表达;通过慢病毒介导的shRNA干扰技术靶向沉默SIRT1的表达,并通过Western印迹验证SIRTl基因的沉默效果。台盼蓝排斥实验分析SIRT1基因沉默对肝癌细胞生长的影响;流式细胞术和Western印迹检测PARP蛋白的剪切物观察细胞凋亡状态。结果SIRT1在多个肝癌细胞系中表达水平明显上调;慢病毒介导的shRNA能显著抑制细胞中SIRT1的表达。流式细胞术及Western印迹结果均显示SIRT1表达沉默显著诱导了肝癌细胞的凋亡。结论慢病毒介导的靶向SIRT1shRNA显著地抑制SIRT1的表达;SIRT1基因沉默抑制肝癌细胞生长并促进了细胞凋亡。     

Modulation of antioxidant enzymes,SIRT1 and NF‐κB by resveratrol and nicotinamide in alcohol‐aflatoxin B1‐induced hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the fifth most commonly diagnosed cancer worldwide and is associated with poor prognosis. The current study aimed to assess the therapeutic efficacy of resveratrol when administered alone and in combination with nicotinamide against alcohol‐aflatoxin B1‐induced HCC. Results reveal that during the development and progression of cancer, there was a decline in the level of antioxidant enzymes catalase, glutathione peroxidase, glutathione reductase (GR), antioxidant glutathione, and glutathione S‐transferase, which is an enzyme of detoxification pathways. Treatment of resveratrol restored the level of catalase and glutathione peroxidase toward normal in alcohol‐aflatoxin B1‐induced HCC; however, nicotinamide worked in concert with resveratrol only in upregulating the activity of glutathione reductase, glutathione level, and glutathione S‐transferase. SIRT1 agonist resveratrol was observed to modulate the activity of antioxidant enzymes by negatively regulating the expression of nuclear factor‐κB (NF‐κB) in alcohol‐aflatoxin B1‐induced HCC, thereby suggesting a cross‐talk between antioxidant enzymes SIRT1 and NF‐κB during the development and progression of HCC and its therapeutics by resveratrol and nicotinamide.     

SIRT6 Depletion Suppresses Tumor Growth by Promoting Cellular Senescence Induced by DNA Damage in HCC

The role of Sirtuin 6 (SIRT6) as a tumor suppressor or oncogene in liver cancer remains controversial. Thus, we identified the specific role of SIRT6 in the progression of hepatocellular carcinoma (HCC). SIRT6 expression was significantly higher in HCC cell lines and HCC tissues from 138 patients than in an immortalized hepatocyte cell line, THLE-2 and non-tumor tissues, respectively. SIRT6 knockdown by shRNA suppressed the growth of HCC cells and inhibited HCC tumor growth in vivo. In addition, SIRT6 silencing significantly prevented the growth of HCC cell lines by inducing cellular senescence in the p16/Rb- and p53/p21-pathway independent manners. Microarray analysis revealed that the expression of genes involved in nucleosome assembly was apparently altered in SIRT6-depleted Hep3B cells. SIRT6 knockdown promoted G2/M phase arrest and downregulation of genes encoding histone variants associated with nucleosome assembly, which could be attributed to DNA damage. Taken together, our findings suggest that SIRT6 acts as a tumor promoter by preventing DNA damage and cellular senescence, indicating that SIRT6 represents a potential therapeutic target for the treatment of HCC.     

Upregulation of SIRT1 deacetylase in phenylephrine-treated cardiomyoblasts

The sirtuin SIRT1 is an ubiquitous NAD⁺ dependent deacetylase that plays a role in biological processes such as longevity and stress response. In cardiac models, SIRT1 is associated to protection against many stresses. However, the link between SIRT1 and heart hypertrophy is complex and not fully understood. This study focuses specifically on the response of SIRT1 to the α-adrenergic agonist phenylephrine in H9c2 cardiac myoblasts, a cell model of cardiac hypertrophy. After 24 and 48 h of phenylephrine treatment, SIRT1 expression and deacetylase activity were significantly increased. SIRT1 upregulation by phenylephrine was not associated to changes in NAD⁺ levels, but was blocked by inhibitors of AMP-activated Protein Kinase (AMPK) or by AMPK knockdown by siRNA. When SIRT1 was inhibited with sirtinol or downregulated by siRNA, H9c2 cell viability was significantly decreased following phenylephrine treatment, showing that SIRT1 improves cell survival under hypertrophic stress. We so then propose that the increase in SIRT1 activity and expression in H9c2 cells treated with phenylephrine is an adaptive response to the hypertrophic stress, suggesting that adrenergic stimulation of heart cells activates hypertrophic programming and at the same time also promotes a self-protecting and self-regulating mechanism.     

沉默信息调节因子1通过诱导miR-221/222表达促进细胞自噬

微小RNA（microRNAs, miRNAs,）是一类强大的基因表达调控子,可在转录及转录后水平负调控靶基因的表达来参与生物学过程。沉默信息调节因子1 (silent information regulator1, SIRT1)底物众多,可通过去乙酰化作用参与多种细胞生命活动进程。尽管如此,SIRT1与非编码RNA如miRNA的表达调控关系仍有待深入研究。本文利用荧光定量PCR 检测发现,SIRT1与miR-221和miR-222的表达呈正相关：干扰SIRT1后,miR-221/222呈低水平表达;而过表达SIRT1则促进miR-221/222的表达。将miR-221/222基因簇启动子区序列插入pEZX-GA01构建双荧光素酶报告载体,与SIRT1过表达质粒或干扰序列共转至细胞。结果显示,SIRT1可显著提高miR-221/222启动子区活性,提示SIRT1可在转录水平调节miR-221/222的表达。进一步运用Western 印迹研究发现,在HEK293细胞中过表达miR-221/222可促进细胞的自噬能力,而抑制miR-221/222的表达可减弱自噬。此外,过表达SIRT1的同时抑制miR-221/222 的表达可减弱SIRT1的自噬诱导作用。综上所述,SIRT1可通过诱导miR-221/222的表达促进细胞自噬,其具体作用机制有待进一步探讨。     

SIRT1-ZEB1-positive feedback promotes epithelial-mesenchymal transition process and metastasis of osteosarcoma

Osteosarcoma is the most common malignant bone cancer that mainly affects children and young adults. Recently, the NAD⁺-dependent deacetylase, sirtuin 1 (SIRT1), has been reported to play a key role in the development of malignant tumors. The study aimed to investigate the role of SIRT1 in osteosarcoma and explore its underlying oncogenic mechanisms. The prognostic value of SIRT1 in osteosarcoma was assessed through detection of SIRT1 expression based on osteosarcoma biopsy tissue. Then, to further investigate the effect of SIRT1 in osteosarcoma, osteosarcoma cells were treated with small interfering RNA SIRT1 and overexpressed SIRT1 to detect the cell migration, invasion, and epithelial-mesenchymal transition (EMT). The levels of SIRT1 expression were significantly higher in osteosarcoma tissues than those in adjacent normal tissues, and the SIRT1 protein level may be coupled with metastatic and poor prognosis risk in patients with osteosarcoma. Moreover, SIRT1 silencing inhibited the migration as well as invasion ability of osteosarcoma cells in vitro, and SIRT1 upregulation reversed those effects. Finally, we found that SIRT1-ZEB1-positive feedback enhanced the EMT process and metastasis of osteosarcoma. Altogether, the results of the current study revealed that high levels of SIRT1 might be a biomarker for a high metastatic rate in patients with osteosarcoma, which suggested that inhibition of SIRT1 might be promising for the therapeutics of osteosarcoma.