胃肠癌发生和预防中表观遗传修饰与信号通路的相关研究

仁济消化学科胃肠肿瘤研究团队是教育部"创新团队",长期从事消化系肿瘤发生机制和防治研究.在胃癌发生和预防中的表观遗传学与信号通路相关研究中作了一定工作.初步明确了我国胃癌癌前疾病慢性萎缩性胃炎的转归情况;建立并验证了预测慢性萎缩性胃炎发生与转归的数学模型.分析了我国症状人群中大肠癌癌前疾病大肠腺瘤患病情况及变迁状况,腺瘤内镜下摘除后再发情况.进一步明确了胃肠癌发生中包括DNA甲基化、组蛋白修饰和非编码RNA(miRNA和天然反义转录本)的作用;阐明了与细胞增殖相关的JAK/STAT信号通路的作用意义;并初步证实了上述表观遗传修饰和信号通路的相互关系.证明了大肠腺瘤患者血浆叶酸和粪便短链脂肪酸及产短链脂肪酸的肠道菌群情况,为有效得干预预防奠定基础.多中心随机对照研究证明,叶酸可有效预防超过50岁人群的大肠腺瘤的发生,且作用与干预前后叶酸含量上升情况有关.并以第一完成单位和第一完成人获2005年上海市科技进步一等奖("表观遗传修饰及其在胃癌发生和预防中的应用")、2007年中华医学科技一等奖和2008年国家科技进步二等奖("叶酸和丁酸盐在胃肠癌发生和预防中的作用")及2014年教育部高等学校科学研究优秀成果(科技进步)一等奖.     

Spatio‐Temporal Parameters of Endosomal Signaling in Cancer: Implications for New Treatment Options

The endo/lysosomal system in cells provides membranous platforms to assemble specific signaling complexes and to terminate signal transduction, thus, is essential for physiological signaling. Endocytic organelles can significantly extend signaling of activated cell surface receptors, and may additionally provide distinct locations for the generation of specific signaling outputs. Failures of regulation at different levels of endocytosis, recycling, degradation as well as aberrations in specific endo/lysosomal signaling pathways, such as mTORC1, might lead to different diseases including cancer. Therefore, a better understanding of spatio‐temporal compartmentalization of sub‐cellular signaling might provide an opportunity to interfere with aberrant signal transduction in pathological processes by novel combinatorial therapeutic approaches. J. Cell. Biochem. 117: 836–843, 2016. © 2015 The Authors. Journal of Cellular Biochemistry Published by Wiley Periodicals Inc.     

The Evolution of the MAP Kinase Pathways: Coduplication of Interacting Proteins Leads to New Signaling Cascades

The MAP-kinase pathways are intracellular signaling modules that are likely to exist in all eukaryotes. We provide an evolutionary model for these signaling pathways by focusing on the gene duplications that have occurred since the divergence of animals from yeast. Construction of evolutionary trees with confidence assessed by bootstrap clearly shows that the mammalian JNK and p38 pathways arose from an ancestral hyperosmolarity pathway after the split from yeast and before the split from C. elegans. These coduplications of interacting proteins at the MAPK and MEK levels have since evolved toward substrate specificity, thus giving distinct pathways. Mammalian duplications since the split from C. elegans are often associated with divergent tissue distribution but do not appear to confer detectable substrate specificity. The yeast kinase cascades have undergone similar fundamental functional changes since the split from mammals, with duplications giving rise to central signaling components of the filamentous and hypoosmolarity pathways. Experimentally defined cross-talk between yeast pheromone and hyperosmolarity pathways is mirrored with corresponding cross-talk in mammalian pathways, suggesting the existence of ancient orthologous cross-talk; our analysis of gene duplications at all levels of the cascade is consistent with this model but does not always provide significant bootstrap support. Our data also provide insights at different levels of the cascade where conflicting experimental evidence exists. Received: 2 December 1998 / Accepted: 9 June 1999     

Breast Cancer Stem Cell Therapeutics,Multiple Strategies Versus Using Engineered Mesenchymal Stem Cells With Notch Inhibitory Properties: Possibilities and Perspectives

Relapse cases of cancers are more vigorous and difficult to control due to the preponderance of cancer stem cells (CSCs). Such CSCs that had been otherwise dormant during the first incidence of cancer gradually appear as radiochemoresistant cancer cells. Hence, cancer therapeutics aimed at CSCs would be an effective strategy for mitigating the cancers during relapse. Alternatively, CSC therapy can also be proposed as an adjuvant therapy, along‐with the conventional therapies. As regenerative stem cells (RSCs) are known for their trophic effects, anti‐tumorogenicity, and better migration toward an injury site, this review aims to address the use of adult stem cells such as dental pulp derived; cord blood derived pure populations of regenerative stem cells for targeting CSCs. Indeed, pro‐tumorogenicity of RSCs is of concern and hence has also been dealt with in relation to breast CSC therapeutics. Furthermore, as notch signaling pathways are upregulated in breast cancers, and anti‐notch antibody based and sh‐RNA based therapies are already in the market, this review focuses the possibilities of engineering RSCs to express notch inhibitory proteins for breast CSC therapeutics. Also, we have drawn a comparison among various possibilities of breast CSC therapeutics, about, notch1 inhibition. J. Cell. Biochem. 119: 141–149, 2018. © 2017 Wiley Periodicals, Inc.     

Developmental Pathways Among Adaptive Functioning and Externalizing and Internalizing Behavioral Problems: Cascades From Childhood Into Adolescence

Here, a 3-wave multivariate design and developmental cascade analysis were used to investigate pathways among adaptive functioning and externalizing and internalizing behavioral problems in a community sample of 134 children seen at 4, 10, and 14 years. Adaptive functioning in early adolescence was predicted by early childhood adaptive functioning and externalizing behavioral problems, with both effects mediated by late childhood adaptive functioning and internalizing behavioral problems; externalizing behavioral problems in early adolescence were predicted by early childhood internalizing behavioral problems with the effect mediated by late childhood externalizing behavioral problems. These developmental cascades were obtained independent of child intelligence. Strategically timed and targeted interventions designed to address young children's behavioral problems may return investment in terms of an enhanced epidemiology of adaptively functioning teens.     

巨噬细胞免疫调变信号——PKA与PKC对MAPK信号通路的调节

以前的研究工作表明,细菌脂多糖（ＬＰＳ）可以调变抑制性巨噬细胞为增强Ｔ、Ｂ淋巴细胞及ＮＫ细胞活性,同时又能保持或增强其抗肿瘤效应。忆报道了在这一复杂的免疫调变过程中伴随有蛋白激酶Ｃ（ＰＫＣ）和促分裂原活化蛋白激酶（ＭＡＰＫ）信号转导通路的激活。为了探索免疫调变过程中其他信号对ＭＡＰＫ通路的影响,以ＬＰＳ调变小鼠腹腔抑制性巨噬细胞为模型,研究了ｃＡＭＰ／ＰＫＡ和佛波酯（ＰＭＡ）／ＰＫＣ信号对ＭＡＰＫ     

综述: MicroRNA与细胞信号通路的相互作用

MicroRNA(miRNA),广泛存在于多种生物中,在基因表达调控的转录后水平上发挥着重要的调节作用．细胞信号通路转导外界刺激进而引发一系列生理和病理效应,决定着细胞的功能和命运．而miRNA和细胞信号通路间的相互作用对于二者的功能发挥起着关键作用,本文将从信号通路对miRNA的调控和miRNA对信号通路的调节两方面综述二者的相互作用,揭示整合miRNA的细胞信号通路及其生物学意义．     

Hunger and Satiety Signaling: Modeling Two Hypothalamomedullary Pathways for Energy Homeostasis

The recent discovery of the medullary circuit driving “hunger responses” – reduced thermogenesis and promoted feeding – has greatly expanded our knowledge on the central neural networks for energy homeostasis. However, how hypothalamic hunger and satiety signals generated under fasted and fed conditions, respectively, control the medullary autonomic and somatic motor mechanisms remains unknown. Here, in reviewing this field, we propose two hypothalamomedullary neural pathways for hunger and satiety signaling. To trigger hunger signaling, neuropeptide Y activates a group of neurons in the paraventricular hypothalamic nucleus (PVH), which then stimulate an excitatory pathway to the medullary circuit to drive the hunger responses. In contrast, melanocortin‐mediated satiety signaling activates a distinct group of PVH neurons, which then stimulate a putatively inhibitory pathway to the medullary circuit to counteract the hunger signaling. The medullary circuit likely contains inhibitory and excitatory premotor neurons whose alternate phasic activation generates the coordinated masticatory motor rhythms to promote feeding.     

Novel Insights into Interleukin 6 (IL-6) Cis- and Trans-signaling Pathways by Differentially Manipulating the Assembly of the IL-6 Signaling Complex

The IL-6 signaling complex is described as a hexamer, formed by the association of two IL-6·IL-6 receptor (IL-6R)·gp130 trimers, with gp130 being the signal transducer inducing cis- and trans-mediated signaling via a membrane-bound or soluble form of the IL-6R, respectively. 25F10 is an anti-mouse IL-6R mAb that binds to both membrane-bound IL-6R and soluble IL-6R with the unique property of specifically inhibiting trans-mediated signaling events. In this study, epitope mapping revealed that 25F10 interacts at site IIb of IL-6R but allows the binding of IL-6 to the IL-6R and the recruitment of gp130, forming a trimer complex. Binding of 25F10 to IL-6R prevented the formation of the hexameric complex obligate for trans-mediated signaling, suggesting that the cis- and trans-modes of IL-6 signaling adopt different mechanisms for receptor complex assembly. To study this phenomenon also in the human system, we developed NI-1201, a mAb that targets, in the human IL-6R sequence, the epitope recognized by 25F10 for mice. Interestingly, NI-1201, however, did not selectively inhibit human IL-6 trans-signaling, although both mAbs produced beneficial outcomes in conditions of exacerbated IL-6 as compared with a site I-directed mAb. These findings shed light on the complexity of IL-6 signaling. First, triggering cis- versus trans-mediated IL-6 signaling occurs via distinctive mechanisms for receptor complex assembly in mice. Second, the formation of the receptor complex leading to cis- and trans-signaling biology in mice and humans is different, and this should be taken into account when developing strategies to inhibit IL-6 clinically.     

Post-Weaning Treatment with Probiotic Inhibited Stress-Induced Amnesia in Adulthood Rats: The Mediation of GABAergic System and BDNF/c-Fos Signaling Pathways

Neurochemical Research - The current study aimed to examine the effect of post-weaning treatment with probiotics on memory formation under stress during the adult period in male Wistar rats....     

The Crossroads of Synaptic Growth Signaling,Membrane Traffic and Neurological Disease: Insights from Drosophila

Neurons require target‐derived autocrine and paracrine growth factors to maintain proper identity, innervation, homeostasis and survival. Neuronal growth factor signaling is highly dependent on membrane traffic, both for the packaging and release of the growth factors themselves, and for regulation of intracellular signaling by their transmembrane receptors. Here, we review recent findings from the Drosophila larval neuromuscular junction (NMJ) that illustrate how specific steps of intracellular traffic and inter‐organelle interactions impinge on signaling, particularly in the bone morphogenic protein, Wingless and c‐Jun‐activated kinase pathways, regulating elaboration and stability of NMJ arbors, construction of synapses and synaptic transmission and homeostasis. These membrane trafficking and signaling pathways have been implicated in human motor neuron diseases including amyotrophic lateral sclerosis and hereditary spastic paraplegia, highlighting their importance for neuronal health and survival.      

Epigenetic Impact of Long-Term Shiftwork: Pilot Evidence From Circadian Genes and Whole-Genome Methylation Analysis

Epigenetic association studies have demonstrated differential promoter methylation in the core circadian genes in breast cancer cases relative to cancer-free controls. The current pilot study aims to investigate whether epigenetic changes affecting breast cancer risk could be caused by circadian disruption through exposure to light at night. Archived DNA samples extracted from whole blood of 117 female subjects from a prospective cohort conducted in Denmark were included in this study. A polymerase chain reaction (PCR)-based method was used for detection of gene-promoter methylation, whereas genome-wide methylation analysis was performed using the Illumina Infinium Methylation Chip. Long-term shiftwork resulted in the same promoter hypomethylation of CLOCK and hypermethylation of CRY2, as was previously observed in breast cancer case-control studies. Genome-wide methylation analysis further discovered widespread methylation alterations in shiftworkers, including changes in many methylation- and cancer-relevant genes. Pathway analysis of the genes with altered methylation patterns revealed several cancer-related pathways. One of the top three networks generated was designated as “DNA replication, recombination, and repair, gene expression, behavior” with ESR1 (estrogen receptor α) featured most prominently in the network, underscoring the potential breast cancer relevance of the genes differentially methylated in long-term shiftworkers. These results, although exploratory, demonstrate the first evidence of the cancer-relevant epigenetic effects of night shiftwork, which warrant further investigation. Considering there are millions of shiftworkers worldwide, understanding the effects of this exposure may lead to novel strategies for cancer prevention and new policies regulating shiftwork. (Author correspondence: yong.zhu@yale.edu)