Wnt信号转导通路与肝纤维化关系的研究现况

阻断该通路可以 Wnt 信号转导通路是近年来分子生物学、细抑制癌细胞的增殖和诱导凋亡.胞生物学和肿瘤研究中的一大热点,其参与调 控细胞分化、癌变、凋亡及机体免疫、应激 等多种病理生理过程.目前许多关于癌症方面 的研究均已证实,阻断Wnt 信号通路可以诱导 癌症细胞的凋亡.肝纤维化的发生与多种信号 通路的激活相关,有研究...     

Role of epigenetics in transformation of inflammation into colorectal cancer

Molecular mechanisms associated with inflammation-promoted tumorigenesis have become an important topic in cancer research. Various abnormal epigenetic changes, including DNA methylation, histone modification, chromatin remodeling, and noncoding RNA regulation, occur during the transformation of chronic inflammation into colorectal cancer(CRC). These changes not only accelerate transformation but also lead to cancer progression and metastasis by activating carcinogenic signaling pathways. The NF-κB and STAT3 signaling pathways play a particularly important role in the transformation of inflammation into CRC, and both are critical to cellular signal transduction and constantly activated in cancer by various abnormal changes including epigenetics. The NF-κB and STAT3 signals contribute to the microenvironment for tumorigenesis through secretion of a large number of pro-inflammatory cytokines and their crosstalk in the nucleus makes it even more difficult to treat CRC. Compared with gene mutation that is irreversible, epigenetic inheritance is reversible or can be altered by the intervention. Therefore, understanding the role of epigenetic inheritance in the inflammation-cancer transformation may elucidate the pathogenesis of CRC and promote the development of innovative drugs targeting transformation to prevent and treat this malignancy. This review summarizes the literature on the roles of epigenetic mechanisms in the occurrence and development of inflammation-induced CRC. Exploring the role of epigenetics in the transformation of inflammation into CRC may help stimulate futures studies on the role of molecular therapy in CRC.     

Epigallocatechin gallate inhibits dimethylhydrazine-induced colorectal cancer in rats

BACKGROUND Epigallocatechin gallate(EGCG) is a polyhydroxy phenolic compound extracted from tea and its antitumor effect has received widespread attention. We explored the inhibitory effect of EGCG on dimethylhydrazine(DMH)-induced colorectal cancer(CRC) using a rat model, predicted the interaction between EGCG and CRC target genes using a database, and explained the EGCG associated target pathways and mechanisms in CRC.AIM To understand the inhibitory mechanisms of EGCG on CRC cell proliferation and identify its pharmacological targets by network pharmacology analysis.METHODS DMH(40 mg/kg, s.c., twice weekly for eight weeks) was used to induce CRC in rats. After model establishment, the rats were administered with EGCG(50, 100,or 200 mg/kg, p.o., once daily for eight weeks) and killed 12 and 20 wk after the start of the experiment. Formation of aberrant crypt foci and tumor was studied by histological analysis. Using network pharmacology analysis, candidate and collective targets of EGCG and CRC were identified, and Gene ontology(GO)and Kyoto Encyclopedia of Genes and Genomes analyses were used to predict the pathways altered by EGCG.RESULTS At week 12, high-dose EGCG treatment significantly reduced the tumor formation rate, total number of tumors, cancerous and non-cancerous tumors,tumor volume, ascites formation, and aberrant crypt foci count. At week 20, all three doses of EGCG were effective. Seventy-eight collective targets of EGCG and CRC were identified, of which 28 genes were dysregulated in CRC. Kyoto Encyclopedia of Genes and Genomes and GO analyses showed that the dysregulated genes were enriched in hsa05210(CRC), hsa04115(p53 signaling pathway), and hsa04151(PI3K-Akt signaling pathway), GO:0043124(negative regulation of I-kappaB kinase/NF-kappaB signaling pathway), GO:0043409(negative regulation of mitogen-activated protein kinase cascade), and GO:2001244(positive regulation of intrinsic apoptotic signaling pathway)respectively.CONCLUSION EGCG inhibits the formation of DMH-induced CRC by regulating key pathways involved in tumorigenesis.     

Crosstalk between tumor cells and microenvironment via Wnt pathway in colorectal cancer dissemination

Invasion and metastasis are the deadly face of malignant tumors. Considering the high rate of incidence and mortality of colorectal cancer, it is critical to determine the mechanisms of its dissemination. In the parallel investigation of the invasive front and tumor center area of colorectal cancer （CRC）, observation of heterogeneous β-catenin distribution and epithelial-mesenchymal transition （EMT） at the invasive front suggested that there might be a crosstalk between tumor cells and the tumor microenvironment. Wnt signaling pathway is also involved in the cancer progression due to its key role in CRC tumorigenesis. Moreover, in recent years, there is increasing evidence that the regulators of microenvironment, including extracellular matrix, growth factors and inflammatory factors, are associated with the activation of Wnt pathway and the mobility of tumor cells. In this review, we will try to explain how these molecules trigger metastasis via the Wnt pathway.     

Pleiotrophin, a multifunctional angiogenic factor: mechanisms and pathways in normal and pathological angiogenesis

PURPOSE OF REVIEW: This study seeks to integrate recent studies that identify new critical mechanisms through which the 136 amino acid secreted heparin-binding cytokine pleiotrophin (PTN, Ptn) stimulates both normal and pathological angiogenesis. RECENT FINDINGS: Pleiotrophin is directly angiogenic; it initiates an angiogenic switch in different cancer models in vivo. It acts as an angiogenic factor through multiple mechanisms that include a unique signaling pathway that activates newly identified downstream tyrosine kinases through a unique mechanism, an interaction with endothelial cells to initiate proliferation, migration, and tube formation, the regulation of basic fibroblast growth factor and vascular endothelial growth factor signaling, the remodeling of the stromal microenvironment, and induction of transdifferentiation of monocytes into endothelial cells. Recently also, domains of PTN that stimulate angiogenesis and peptides that function to inhibit PTN signaling have been identified. SUMMARY: Recent studies have identified new mechanisms dependent on activation of the PTN signaling pathway that regulate angiogenesis and new targets to use PTN to both stimulate angiogenesis and block its activity to control pathological angiogenesis.     

NF-κB与胃癌的靶向治疗研究进展

胃癌是世界上导致癌症相关死亡的主要原因之一.虽然普遍认为幽门螺杆菌感染是导致胃癌发生的重要原因,但胃癌发生的确切机制尚未被阐明.癌症的发生、发展主要与细胞生存和死亡信号的平衡相关,致癌物质和炎症因子能活化大多数细胞的生存信号,从本质上促成肿瘤的形成.核转录因子-kappaB(NF-κB)是细胞主要的生存信号之一,近年来在一些细胞学和动物模型实验中均发现NF-κB的活化与胃癌发生和化疗抵抗等过程密切相关,抑制NF-κB的活化可提高胃癌细胞对化疗药物的敏感性.本文对NF-κB转录途径在胃癌演进中的机制以及其靶向治疗的相关进展综述如下.     

Targeting the MET gene for the treatment of non-small-cell lung cancer

Recently, a better understanding of the specific mechanisms of oncogene addiction has led to the development of antitumor strategies aimed at blocking these abnormalities in different malignancies, including lung cancer. These abnormalities trigger constitutive activation of tyrosine kinase receptors (RTKs) involved in fundamental cell mechanisms such as proliferation, survival, differentiation and migration, and consequently the aberrant signaling of RTKs leads to cancer growth and survival. The inhibition of aberrant RTKs and downstream signaling pathways has opened the door to the targeted therapy era.In non-small-cell lung cancer (NSCLC), molecular research has allowed the discrimination of different aberrant RTKs in lung cancer tumorigenesis and progression, and thus the identification of several targetable oncogenic drivers. Following the development of small molecules (gefitinib/erlotinib and crizotinib) able to reversibly inhibit the epidermal growth factor receptor (EGFR) and signaling pathways mediated by anaplastic lymphoma kinase (ALK), respectively, the MET signaling pathway has also been recognized as a potential target. Moreover, according to current knowledge, MET could be considered both as a secondary oncogenic mechanism and as a prognostic factor. Several therapeutic strategies for inhibiting activated hepatocyte growth factor receptor (HGFR) and the subsequent downstream signaling transduction have been improved in order to block tumor growth. This review will focus on the MET pathway and its role in resistance to EGFR TK (tyrosine kinase) inhibitors, the different strategies of its inhibition, and the potential approaches to overcoming acquired resistance.     

Application of nanotechnology in reversing therapeutic resistance and controlling metastasis of colorectal cancer

Colorectal cancer(CRC) is the most common digestive malignancy across the world. Its first-line treatments applied in the routine clinical setting include surgery, chemotherapy, radiotherapy, targeted therapy, and immunotherapy. However, resistance to therapy has been identified as the major clinical challenge that fails the treatment method, leading to recurrence and distant metastasis. An increasing number of studies have been attempting to explore the underlying mechanisms of the resistance o...     

Possible biological and translational significance of mast cells density in colorectal cancer

Mast cells (MCs), located ubiquitously near blood vessels, are descended from CD34⁺ hematopoietic stem cells. Initially, although their role has been well defined in hypersensitivity reactions, the discovery of their sharing in both innate and adaptive immunity has allowed to redefine their crucial interplay on the regulatory function between inflammatory and tumor cells through the release of mediators granule-associated (mainly tryptase and vascular endothelial growth factor). In particular, in several animal and human malignancies it has been well demonstrated that activated c-Kit receptor (c-KitR) and tryptase (an agonist of the proteinase-activated receptor-2) take pivotal part in tumor angiogenesis after the MCs activation, contributing to tumor cells invasion and metastasis. In this review, we focused on crucial MCs density (MCD) role in colorectal cancer (CRC) development and progression angiogenesis-mediated; then, we will analyze the principal studies that have focused on MCD as possible prognostic factor. Finally, we will consider a possible role of MCD as novel therapeutic target mainly by c-KitR tyrosine kinase inhibitors (imatinib, masitinib) and tryptase inhibitors (gabexate and nafamostat mesylate) with the aim to prevent CRC progression.     

Is there a genetic signature for liver metastasis in colorectal cancer？

Even though liver metastasis accounts for the vast majority of cancer deaths in patients with colorectal cancer （CRC）, fundamental questions about the molecular and cellular mechanisms of liver metastasis still remain unanswered. Determination of gene expression profiles by microarray technology has improved our knowledge of CRC molecular pathways. However, defined gene signatures are highly variable among studies. Expression profiles and molecular markers have been specifically linked to liver metastases mechanistic paths in CRC. However, to date, none of the identified signatures or molecular markers has been successfully validated as a diagnostic or prognostic tool applicable to routine clinical practice. To obtain a genetic signature for liver metastasis in CRC, measures to improve reproducibility, to increase consistency, and to validate results need to be implemented. Alternatives to expression profiling with microarray technology are continuing to be used. In the recent past, many genes codifying for proteins that are directly or indirectly involved in adhesion, invasion, angiogenesis, survival and cell growth have been linked to mechanisms of liver metastases in CRC.     

Role of diet and gut microbiota on colorectal cancer immunomodulation

Colorectal cancer(CRC) is one of the most commonly diagnosed cancers, and it is characterized by genetic and epigenetic alterations, as well as by inflammatory cell infiltration among malignant and stromal cells. However, this dynamic infiltration can be influenced by the microenvironment to promote tumor proliferation, survival and metastasis or cancer inhibition. In particular, the cancer microenvironment metabolites can regulate the inflammatory cells to induce a chronic inflammatory response that can be a predisposing condition for CRC retention. In addition, some nutritional components might contribute to a chronic inflammatory condition by regulating various immune and inflammatory pathways. Besides that, diet strongly modulates the gut microbiota composition,which has a key role in maintaining gut homeostasis and is associated with the modulation of host inflammatory and immune responses. Therefore, diet has a fundamental role in CRC initiation, progression and prevention. In particular,functional foods such as probiotics, prebiotics and symbiotics can have a potentially positive effect on health beyond basic nutrition and have antiinflammatory effects. In this review, we discuss the influence of diet on gut microbiota composition, focusing on its role on gut inflammation and immunity.Finally, we describe the potential benefits of using probiotics and prebiotics to modulate the host inflammatory response, as well as its application in CRC prevention and treatment.     

Inflammatory pathways and insulin action

Obesity and type 2 diabetes are associated with a state of abnormal inflammatory response. While this correlation has also been recognized in the clinical setting, its molecular basis and physiological significance are not yet fully understood. Studies in recent years have provided important insights into this curious phenomenon. The state of chronic inflammation typical of obesity and type 2 diabetes occurs at metabolically relevant sites, such as the liver, muscle, and most interestingly, adipose tissues. The biological relevance of the activation of inflammatory pathways became evident upon the demonstration that interference with these pathways improve or alleviate insulin resistance. The abnormal production of tumor necrosis factor alpha (TNF-alpha) in obesity is a paradigm for the metabolic significance of this inflammatory response. When TNF-alpha activity is blocked in obesity, either biochemically or genetically, the result is improved insulin sensitivity. Studies have since focused on the identification of additional inflammatory mediators critical in metabolic control and on understanding the molecular mechanisms by which inflammatory pathways are coupled to metabolic control. Recent years have seen a critical progress in this respect by the identification of several downstream mediators and signaling pathways, which provide the crosstalk between inflammatory and metabolic signaling. These include the discovery of c-Jun N-terminal kinase (JNK) and I kappa beta kinase (I kappa K) as critical regulators of insulin action activated by TNF-alpha and other inflammatory and stress signals, and the identification of potential targets. Here, the role of the JNK pathway in insulin receptor signaling, the impact of blocking this pathway in obesity and the mechanisms underlying JNK-induced insulin resistance will be discussed.     

不同肺转移潜能的大鼠肝癌细胞外泌体对巨噬细胞转录组的影响

目的 比较不同肺转移潜能的大鼠肝癌细胞来源外泌体对巨噬细胞转录组的影响.方法 通过转录组测序技术,比较经两株不同肺转移潜能的大鼠肝癌细胞(WB1和WN1)来源外泌体处理的巨噬细胞的转录组差异,筛选差异基因并使用KEGG分析、GO分析和蛋白互作网络分析,探索癌细胞来源外泌体影响巨噬细胞功能促进肺转移的潜在机制.结果 对比...     

Tropomyosin-related kinase B/brain derived-neurotrophic factor signaling pathway as a potential therapeutic target for colorectal cancer

Colorectal cancer(CRC) is the second most common cause of cancer-related death in western countries. Approximately one-quarter of newly diagnosed patients for CRC have metastases, and a further 40%-50% experience disease recurrence or develop metastases after all standard therapies. Therefore, understanding the molecular mechanisms involved in the progression of CRC and subsequently developing novel therapeutic targets is crucial to improve management of CRC and patients' long-term survival. Several tyrosine kinase receptors have been implicated in CRC development, progression and metastasis, including epidermal growth factor receptor(EGFR) and vascular EGFR. Recently, tropomyosin-related kinase B(Trk B), a tyrosine kinase receptor, has been reported in CRC and found to clearly exert several biological and clinical features, such as tumor cell growth and survival in vitro and in vivo, metastasis formation and poor prognosis. Here we review the significance of Trk B and its ligand brain derived-neurotrophic factor in CRC. We focus on their expression in CRC tumor samples, and their functional roles in CRC cell lines and in in vivo models. Finally we discuss therapeutic approaches that can lead to the development of novel therapeutic agents for treating Trk B-expressing CRC tumors.     

Research progress on chemopreventive effects of phytochemicals on colorectal cancer and their mechanisms

Colorectal cancer(CRC) is a type of cancer with high morbidity and mortality rates worldwide and has become a global health problem. The conventional radiotherapy and chemotherapy regimen for CRC not only has a low cure rate but also causes side effects. Many studies have shown that adequate intake of fruits and vegetables in the diet may have a protective effect on CRC occurrence, possibly due to the special biological protective effect of the phytochemicals in these foods. Numerous in vitro and in vivo studies have demonstrated that phytochemicals play strong antioxidant, anti-inflammatory and anti-cancer roles by regulating specific signaling pathways and molecular markers to inhibit the occurrence and development of CRC. This review summarizes the progress on CRC prevention using the phytochemicals sulforaphane, curcumin and resveratrol, and elaborates on the specific underlying mechanisms. Thus, we believe that phytochemicals might provide a novel therapeutic approach for CRC prevention, but future clinical studies are needed to confirm the specific preventive effect of phytochemicals on cancer.     

RhoA/ROCK信号通路与动脉粥样硬化关系的研究进展

动脉粥样硬化是一种常见的全身性血管疾病,同时也是多种急性心血管疾病的病理基础。而急性心血管疾病的死亡率高,严重危害人们的生命健康。近年来,越来越多的研究表明RhoA/ROCK信号通路与动脉粥样硬化的形成有密切联系。抑制RhoA/ROCK信号通路可以通过稳定血管内皮功能、抑制血管平滑肌细胞增殖和迁移、抑制血管钙化、调控炎症细胞聚集以及抑制血小板增殖变形来延缓或抑制动脉粥样硬化的形成。     

Probiotics and postbiotics in colorectal cancer: Prevention and complementary therapy

Colorectal cancer (CRC) is a leading cause of human mortality worldwide. As conventional anticancer therapy not always being effective, there is growing interest in innovative “drug-free” cancer treatments or interventions that improve the efficacy of established therapy. CRC is associated with microbiome alterations, a process known as dysbiosis that involves depletion and/or enrichment of particular gut bacterial species and their metabolic functions. Supplementing patient treatment with traditional probiotics (with or without prebiotics), next-generation probiotics (NGP), or postbiotics represents a potentially effective and accessible complementary anticancer strategy by restoring gut microbiota composition and/or by signaling to the host. In this capacity, restoration of the gut microbiota in cancer patients can stabilize and enhance intestinal barrier function, as well as promote anticarcinogenic, anti-inflammatory, antimutagenic or other biologically important biochemical pathways that show high specificity towards tumor cells. Potential benefits of traditional probiotics, NGP, and postbiotics include modulating gut microbiota composition and function, as well as the host inflammatory response. Their application in CRC prevention is highlighted in this review, where we consider supportive in vitro, animal, and clinical studies. Based on emerging research, NGP and postbiotics hold promise in establishing innovative treatments for CRC by conferring physiological functions via the production of dominant natural products and metabolites that provide new host-microbiota signals to combat CRC. Although favorable results have been reported, further investigations focusing on strain and dose specificity are required to ensure the efficacy and safety of traditional probiotics, NGP, and postbiotics in CRC prevention and treatment.     

The IGF-1 Signaling Pathway in Viral Infections

Insulin-like growth factor-1 (IGF-1) and the IGF-1 receptor (IGF-1R) belong to the insulin-like growth factor family, and IGF-1 activates intracellular signaling pathways by binding specifically to IGF-1R. The interaction between IGF-1 and IGF-1R transmits a signal through a number of intracellular substrates, including the insulin receptor substrate (IRS) and the Src homology collagen (Shc) proteins, which activate two major intracellular signaling pathways: the phosphatidylinositol 3-kinase (PI3K)/AKT and mitogen-activated protein kinase (MAPK) pathways, specifically the extracellular signal-regulated kinase (ERK) pathways. The PI3K/AKT kinase pathway regulates a variety of cellular processes, including cell proliferation and apoptosis. IGF1/IGF-1R signaling also promotes cell differentiation and proliferation via the Ras/MAPK pathway. Moreover, upon IGF-1R activation of the IRS and Shc adaptor proteins, Shc stimulates Raf through the GTPase Ras to activate the MAPKs ERK1 and ERK2, phosphorylate and several other proteins, and to stimulate cell proliferation. The IGF-1 signaling pathway is required for certain viral effects in oncogenic progression and may be induced as an effect of viral infection. The mechanisms of IGF signaling in animal viral infections need to be clarified, mainly because they are involved in multifactorial signaling pathways. The aim of this review is to summarize the current data obtained from virological studies and to increase our understanding of the complex role of the IGF-1 signaling axis in animal virus infections.     

Eicosanoid pathway in colorectal cancer:Recent updates

Enzymatic metabolism of the 20 C polyunsaturated fatty acid(PUFA) arachidonic acid(AA) occurs via the cyclooxygenase(COX) and lipoxygenase(LOX) pathways, and leads to the production of various bioactive lipids termed eicosanoids. These eicosanoids have a variety of functions, including stimulation of homeostatic responses in the cardiovascular system, induction and resolution of inflammation, and modulation of immune responses against diseases associated with chronic inflammation, such as cancer. Because chronic inflammation is essential for the development of colorectal cancer(CRC), it is not surprising that many eicosanoids are implicated in CRC. Oftentimes, these autacoids work in an antagonistic and highly temporal manner in inflammation; therefore, inhibition of the pro-inflammatory COX-2 or 5-LOX enzymes may subsequently inhibit the formation of their essential products, or shunt substrates from one pathway to another, leading to undesirable side-effects. A better understanding of these different enzymes and their products is essential not only for understanding the importance of eicosanoids, but also for designing more effective drugs that solely target the inflammatory molecules found in both chronic inflammation and cancer. In this review, we have evaluated the cancer promoting and anti-cancer roles of different eicosanoids in CRC, and highlighted the most recent literature which describes how those molecules affect not only tumor tissue, but also the tumor microenvironment. Additionally, we have attempted to delineate the roles that eicosanoids with opposing functions play in neoplastic transformation in CRC through their effects on proliferation, apoptosis, motility, metastasis, and angiogenesis.