Cytokine & Growth Factor Reviews最新文献

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Interleukin-6 (IL-6)-associated tumor microenvironment remodelling and cancer immunotherapy. 白细胞介素-6 （IL-6）相关的肿瘤微环境重塑和癌症免疫治疗。

IF 9.3 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cytokine & Growth Factor Reviews

Pub Date : 2025-01-10 DOI: 10.1016/j.cytogfr.2025.01.001

Songsong Wu, Zhumin Cao, Rongying Lu, Zhenwang Zhang, Gautam Sethi, Yulai You

Interleukin-6 (IL-6) is a pro-inflammatory cytokine playing a pivotal role during inflammation and immune responses. In the recent years, the function of IL-6 in the tumor microenvironment (TME) for affecting tumorigenesis and immunotherapy response has been investigated. The genetic mutations are mainly responsible for the development of cancer, while interactions in TME are also important, involving both cancers and non-cancerous cells. IL-6 plays a significant role in these interactions, enhancing the proliferation, survival and metastasis of tumor cells through inflammatory pathways, highlighting its carcinogenic function. Multiple immune cells including macrophages, T cells, myeloid-derived suppressor cells, dendritic cells and natural killer cells can be affected by IL-6 to develop immunosuppressive TME. IL-6 can also participate in the immune evasion through increasing levels of PD-L1, compromising the efficacy of therapeutics. Notably, IL-6 exerts a double-edge sword function and it can dually increase or decrease cancer immunotherapy, providing a challenge for targeting this cytokine in cancer therapy. Highlighting the complicated function of IL-6 in TME can lead to the development of effective therapeutics for cancer immunity.

白细胞介素-6 （IL-6）是一种促炎细胞因子，在炎症和免疫反应中起关键作用。近年来，人们对IL-6在肿瘤微环境（tumor microenvironment， TME）中影响肿瘤发生和免疫治疗应答的功能进行了研究。基因突变是癌症发生的主要原因，而TME中的相互作用也很重要，涉及癌症和非癌细胞。IL-6在这些相互作用中发挥重要作用，通过炎症途径增强肿瘤细胞的增殖、存活和转移，突出其致癌功能。包括巨噬细胞、T细胞、髓源性抑制细胞、树突状细胞和自然杀伤细胞在内的多种免疫细胞可受IL-6的影响而产生免疫抑制性TME。IL-6也可以通过增加PD-L1的水平参与免疫逃避，从而影响治疗的疗效。值得注意的是，IL-6具有双刃剑功能，可以双重增加或减少癌症免疫治疗，这为靶向治疗癌症提供了挑战。强调IL-6在TME中的复杂功能有助于开发有效的癌症免疫治疗方法。

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引用次数: 0

Mechanisms coupling the mTOR pathway to chronic obstructive pulmonary disease (COPD) pathogenesis mTOR通路与慢性阻塞性肺疾病（COPD）发病机制的耦合

IF 9.3 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cytokine & Growth Factor Reviews

Pub Date : 2025-01-03 DOI: 10.1016/j.cytogfr.2024.12.005

Ankita Goyal , Vishal Chopra , Kranti Garg , Siddharth Sharma

Chronic Obstructive Pulmonary Disease (COPD) is a poorly reversible respiratory disorder distinguished by dyspnea, cough, expectoration and exacerbations due to abnormality of airways or emphysema. In this review, we consider the therapeutic potential of targeting Mammalian target of Rapamycin (mTOR) for treating COPD. The mTOR is a highly conserved serine-threonine protein kinase that integrates signals from growth factors and nutrients to control protein synthesis, lipid biogenesis and metabolism. Dysregulated mTOR pathway signaling due to genetic factors or cigarette smoking impairs autophagy, driving the buildup of abnormal cells and damaged proteins, resulting in inflammation and oxidative stress. Persistent mTOR activation also contributes to pulmonary vascular cell proliferation, facilitating the development of pulmonary resistance in COPD. Rapamycin, an inhibitor of mTOR, prevents the buildup of senescent cells in the lungs of COPD patients and inhibits the release of lung tissue-damaging proteases. mTOR also impacts the corticosteroid sensitivity in COPD patients by regulating the levels of histone deacetylases. The emerging role of gut-lung axis dysbiosis in the progression of COPD and its influence on mTOR further highlights the relevance of the mTOR pathway in COPD pathophysiology.

慢性阻塞性肺疾病（COPD）是一种可逆性较差的呼吸系统疾病，以呼吸困难、咳嗽、咳痰和因气道异常或肺气肿而加重为特征。在这篇综述中，我们考虑靶向雷帕霉素（mTOR）的哺乳动物靶点治疗COPD的治疗潜力。mTOR是一种高度保守的丝氨酸-苏氨酸蛋白激酶，整合来自生长因子和营养物质的信号，控制蛋白质合成、脂质生物发生和代谢。由于遗传因素或吸烟导致的mTOR通路信号失调会损害自噬，导致异常细胞和受损蛋白质的积聚，导致炎症和氧化应激。持续的mTOR激活也有助于肺血管细胞增殖，促进COPD肺阻力的发展。雷帕霉素是mTOR的一种抑制剂，可以防止慢性阻塞性肺病患者肺部衰老细胞的积累，并抑制肺组织损伤蛋白酶的释放。mTOR还通过调节组蛋白去乙酰化酶水平影响COPD患者的皮质类固醇敏感性。肠-肺轴失调在COPD进展中的新作用及其对mTOR的影响进一步强调了mTOR通路在COPD病理生理中的相关性。

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引用次数: 0

The immunopathogenesis of a cytokine storm: The key mechanisms underlying severe COVID-19

IF 9.3 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cytokine & Growth Factor Reviews

Pub Date : 2025-01-02 DOI: 10.1016/j.cytogfr.2024.12.003

Luka Hiti , Tijana Markovič , Mitja Lainscak , Jerneja Farkaš Lainščak , Emil Pal , Irena Mlinarič-Raščan

A cytokine storm is marked by excessive pro-inflammatory cytokine release, and has emerged as a key factor in severe COVID-19 cases – making it a critical therapeutic target. However, its pathophysiology was poorly understood, which hindered effective treatment. SARS-CoV-2 initially disrupts angiotensin signalling, promoting inflammation through ACE-2 downregulation. Some patients’ immune systems then fail to shift from innate to adaptive immunity, suppressing interferon responses and leading to excessive pyroptosis and neutrophil activation. This amplifies tissue damage and inflammation, creating a pro-inflammatory loop. The result is the disruption of Th1/Th2 and Th17/Treg balances, lymphocyte exhaustion, and extensive blood clotting. Cytokine storm treatments include glucocorticoids to suppress the immune system, monoclonal antibodies to neutralize specific cytokines, and JAK inhibitors to block cytokine receptor signalling. However, the most effective treatment options for mitigating SARS-CoV-2 infection remain vaccines as a preventive measure and antiviral drugs for the early stages of infection. This article synthesizes insights into immune dysregulation in COVID-19, offering a framework to better understand cytokine storms and to improve monitoring, biomarker discovery, and treatment strategies for COVID-19 and other conditions involving cytokine storms.

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引用次数: 0

Ubiquitination in pyroptosis pathway: A potential therapeutic target for sepsis 热蛋白沉积途径中的泛素化：败血症的潜在治疗靶点

IF 9.3 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cytokine & Growth Factor Reviews

Pub Date : 2024-12-01 DOI: 10.1016/j.cytogfr.2024.09.001

Yan Liao , Wangzheqi Zhang , Miao Zhou , Chenglong Zhu , Zui Zou

Sepsis remains a significant clinical challenge, causing numerous deaths annually and representing a major global health burden. Pyroptosis, a unique form of programmed cell death characterized by cell lysis and the release of inflammatory mediators, is a crucial factor in the pathogenesis and progression of sepsis, septic shock, and organ dysfunction. Ubiquitination, a key post-translational modification influencing protein fate, has emerged as a promising target for managing various inflammatory conditions, including sepsis. This review integrates the current knowledge on sepsis, pyroptosis, and the ubiquitin system, focusing on the molecular mechanisms of ubiquitination within pyroptotic pathways activated during sepsis. By exploring how modulating ubiquitination can regulate pyroptosis and its associated inflammatory signaling pathways, this review provides insights into potential therapeutic strategies for sepsis, highlighting the need for further research into these complex molecular networks.

败血症仍然是一项重大的临床挑战，每年造成无数人死亡，是全球健康的主要负担。脓毒症是一种独特的程序性细胞死亡，其特点是细胞裂解和释放炎症介质，是脓毒症、脓毒性休克和器官功能障碍发病和进展的关键因素。泛素化是影响蛋白质命运的一种关键的翻译后修饰，已成为治疗包括败血症在内的各种炎症的一个有前途的靶点。本综述整合了目前有关脓毒症、热毒血症和泛素系统的知识，重点关注脓毒症期间激活的热毒血症通路中泛素化的分子机制。本综述通过探讨泛素化调节如何调控热蛋白沉积及其相关的炎症信号通路，为脓毒症的潜在治疗策略提供了见解，并强调了进一步研究这些复杂分子网络的必要性。

引用次数: 0

Adeno-associated virus therapies: Pioneering solutions for human genetic diseases 腺相关病毒疗法：人类遗传疾病的开创性解决方案。

IF 9.3 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cytokine & Growth Factor Reviews

Pub Date : 2024-12-01 DOI: 10.1016/j.cytogfr.2024.09.003

Dequan Liu , Tian Li , Lei Liu , Xiangyu Che , Xiaorui Li , Chang Liu , Guangzhen Wu

Adeno-associated virus (AAV) has emerged as a fundamental component in the gene therapy landscape, widely acknowledged for its effectiveness in therapeutic gene delivery. The success of AAV-based therapies, such as Luxturna and Zolgensma, underscores their potential as a leading vector in gene therapy. This article provides an in-depth review of the development and mechanisms of AAV vector-based therapies, offering a comprehensive analysis of the latest clinical trial outcomes in central nervous system (CNS) diseases, ocular conditions, and hemophilia, where AAV therapies have shown promising results. Additionally, we discusse the selection of administration methods and serotypes tailored to specific diseases. Our objective is to showcase the innovative applications and future potential of AAV-based gene therapy, laying the groundwork for continued clinical advancements.

腺相关病毒（AAV）已成为基因治疗领域的基本组成部分，其在治疗基因递送方面的有效性已得到广泛认可。以 AAV 为基础的疗法（如 Luxturna 和 Zolgensma）取得的成功凸显了其作为基因疗法主要载体的潜力。本文深入评述了基于 AAV 载体的疗法的发展和机制，全面分析了 AAV 疗法在中枢神经系统（CNS）疾病、眼部疾病和血友病方面的最新临床试验结果，这些领域的 AAV 疗法都取得了可喜的成果。此外，我们还讨论了针对特定疾病的给药方法和血清型的选择。我们的目标是展示基于 AAV 的基因疗法的创新应用和未来潜力，为继续推进临床研究奠定基础。

引用次数: 0

Molecular mechanisms of regulation of IL-1 and its receptors 调节 IL-1 及其受体的分子机制。

IF 9.3 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cytokine & Growth Factor Reviews

Pub Date : 2024-12-01 DOI: 10.1016/j.cytogfr.2024.09.004

J.V. Zhukova , J.A. Lopatnikova , A.A. Alshevskaya , S.V. Sennikov

Interleukin 1 (IL-1) is a pro-inflammatory cytokine that plays a key role in the development and regulation of nonspecific defense and specific immunity. However, its regulatory influence extends beyond inflammation and impacts a range of immune and non-immune processes. The involvement of IL-1 in numerous biological processes, including modulation of inflammation, necessitates strict regulation at multiple levels. This review focuses on these regulatory processes and discusses their underlying mechanisms. IL-1 activity is controlled at various levels, including receptor binding, gene transcription, expression as inactive proforms, and regulated post-translational processing and secretion. Regulation at the level of the receptor expression - alternative splicing, tissue-specific isoforms, and gene polymorphism - is also crucial to IL-1 functional activity. Understanding these regulatory features of IL-1 will not only continue to shape future research directions but will also highlight promising therapeutic strategies to modulate the biological effects of IL-1.

白细胞介素 1（IL-1）是一种促炎细胞因子，在非特异性防御和特异性免疫的发展和调节中发挥着关键作用。然而，它的调节作用超出了炎症范围，对一系列免疫和非免疫过程都有影响。IL-1 参与了许多生物过程，包括炎症的调节，因此有必要在多个层面进行严格的调控。本综述将重点讨论这些调控过程及其内在机制。IL-1 的活性在不同水平上受到控制，包括受体结合、基因转录、以非活性原形表达以及翻译后处理和分泌调节。受体表达水平的调控--替代剪接、组织特异性异构体和基因多态性--对 IL-1 的功能活性也至关重要。了解 IL-1 的这些调控特征不仅将继续塑造未来的研究方向，还将凸显调节 IL-1 生物效应的有前途的治疗策略。

引用次数: 0

Mechanisms of Rho GTPases in regulating tumor proliferation, migration and invasion Rho GTPases 调节肿瘤增殖、迁移和侵袭的机制。

IF 9.3 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cytokine & Growth Factor Reviews

Pub Date : 2024-12-01 DOI: 10.1016/j.cytogfr.2024.09.002

Cheng Liu , Shutao Chen , Yu Zhang , Xinyi Zhou , Haiwei Wang , Qigui Wang , Xi Lan

The occurrence of most cancers is due to the clonal proliferation of tumor cells, immune evasion, and the ability to spread to other body parts. Rho GTPases, a family of small GTPases, are key regulators of cytoskeleton reorganization and cell polarity. Additionally, Rho GTPases are key proteins that induce the proliferation and metastasis of tumor cells. This review focuses on the complex regulatory mechanisms of Rho GTPases, exploring their critical role in promoting tumor cell proliferation and dissemination. Regarding tumor cell proliferation, attention is given to the role of Rho GTPases in regulating the cell cycle and mitosis. In terms of tumor cell dissemination, the focus is on the role of Rho GTPases in regulating cell migration and invasion. Overall, this review elucidates the mechanisms of Rho GTPases members in the development of tumor cells, aiming to provide theoretical references for the treatment of mammalian tumor diseases and related applications.

大多数癌症的发生都是由于肿瘤细胞的克隆增殖、免疫逃避以及向身体其他部位扩散的能力。Rho GTPases 是一种小型 GTPases，是细胞骨架重组和细胞极性的关键调节因子。此外，Rho GTPases 还是诱导肿瘤细胞增殖和转移的关键蛋白。本综述将重点关注 Rho GTPases 的复杂调控机制，探讨它们在促进肿瘤细胞增殖和扩散方面的关键作用。在肿瘤细胞增殖方面，重点关注 Rho GTPases 在调节细胞周期和有丝分裂中的作用。在肿瘤细胞扩散方面，重点关注 Rho GTPases 在调节细胞迁移和侵袭方面的作用。总之，这篇综述阐明了 Rho GTPases 成员在肿瘤细胞发展过程中的作用机制，旨在为哺乳动物肿瘤疾病的治疗及相关应用提供理论参考。

引用次数: 0

Glioblastoma-associated macrophages: A key target in overcoming glioblastoma therapeutic resistance 胶质母细胞瘤相关巨噬细胞：克服胶质母细胞瘤耐药性的关键靶点

IF 9.3 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cytokine & Growth Factor Reviews

Pub Date : 2024-12-01 DOI: 10.1016/j.cytogfr.2024.10.009

Aymane Kricha, Najat Bouchmaa, Sanae Ben Mkaddem, Abdellatif Abbaoui, Reda Ben Mrid, Rachid El Fatimy

Glioblastoma multiforme (GBM) is recognized as the most aggressive and malignant form of brain cancer, characterized by a highly heterogeneous phenotype, poor prognosis, and a median survival time of less than 16 months. Recent studies have highlighted the critical role of glioblastoma-associated macrophages (GAMs) in promoting tumor progression and resistance not only to immunotherapy but also to radiotherapy and chemotherapy. GAMs actively suppress immune responses, promote angiogenesis, facilitate tumor metastasis, and induce therapy resistance, through various mechanisms such as cytokines production, signaling pathways regulation, and angiogenesis. In this context, understanding these regulatory mechanisms is essential for developing efficient therapies. Preclinical studies have investigated diverse approaches to target these cells, both as monotherapies or in combination with other treatments. While these approaches have shown promise in strengthening antitumor immune responses in animal models, their clinical success remains to be fully determined. Herein, we provide a comprehensive overview of GAMs's role in GBM therapeutic resistance and summarizes existing approaches to target GAMs in overcoming tumor resistance.

多形性胶质母细胞瘤（GBM）被认为是最具侵袭性的恶性脑癌，其特点是表型高度异质性、预后差、中位生存期不到 16 个月。最近的研究突显了胶质母细胞瘤相关巨噬细胞（GAMs）在促进肿瘤进展和抵抗免疫疗法以及放疗和化疗方面的关键作用。GAMs 通过产生细胞因子、调节信号通路和血管生成等多种机制，积极抑制免疫反应、促进血管生成、促进肿瘤转移和诱导耐药性。在这种情况下，了解这些调控机制对于开发高效疗法至关重要。临床前研究已经研究了针对这些细胞的多种方法，既可作为单一疗法，也可与其他疗法联合使用。虽然这些方法已在动物模型中显示出加强抗肿瘤免疫反应的前景，但其临床成功与否仍有待全面确定。在此，我们全面概述了 GAMs 在 GBM 治疗耐药性中的作用，并总结了针对 GAMs 克服肿瘤耐药性的现有方法。

{"title":"Glioblastoma-associated macrophages: A key target in overcoming glioblastoma therapeutic resistance","authors":"Aymane Kricha, Najat Bouchmaa, Sanae Ben Mkaddem, Abdellatif Abbaoui, Reda Ben Mrid, Rachid El Fatimy","doi":"10.1016/j.cytogfr.2024.10.009","DOIUrl":"10.1016/j.cytogfr.2024.10.009","url":null,"abstract":"<div><div>Glioblastoma multiforme (GBM) is recognized as the most aggressive and malignant form of brain cancer, characterized by a highly heterogeneous phenotype, poor prognosis, and a median survival time of less than 16 months. Recent studies have highlighted the critical role of glioblastoma-associated macrophages (GAMs) in promoting tumor progression and resistance not only to immunotherapy but also to radiotherapy and chemotherapy. GAMs actively suppress immune responses, promote angiogenesis, facilitate tumor metastasis, and induce therapy resistance, through various mechanisms such as cytokines production, signaling pathways regulation, and angiogenesis. In this context, understanding these regulatory mechanisms is essential for developing efficient therapies. Preclinical studies have investigated diverse approaches to target these cells, both as monotherapies or in combination with other treatments. While these approaches have shown promise in strengthening antitumor immune responses in animal models, their clinical success remains to be fully determined. Herein, we provide a comprehensive overview of GAMs's role in GBM therapeutic resistance and summarizes existing approaches to target GAMs in overcoming tumor resistance.</div></div>","PeriodicalId":11132,"journal":{"name":"Cytokine & Growth Factor Reviews","volume":"80 ","pages":"Pages 97-108"},"PeriodicalIF":9.3,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142603050","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Distinct roles of MIF in the pathogenesis of ischemic heart disease MIF 在缺血性心脏病发病机制中的不同作用。

IF 9.3 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cytokine & Growth Factor Reviews

Pub Date : 2024-12-01 DOI: 10.1016/j.cytogfr.2024.10.005

Ling Zhao , Bang-Hao Zhao , Amanguli Ruze , Qiu-Lin Li , An-Xia Deng , Xiao-Ming Gao

The role of macrophage migration inhibitory factor (MIF) as a multifunctional cytokine in immunomodulation and inflammatory response is increasingly appreciated. Ischemic heart disease (IHD), the leading cause of global mortality, remains a focal point of research owing to its intricate pathophysiology. MIF has been identified as a critical player in IHD, where it exerts distinct roles. On one hand, MIF plays a protective role by enhancing energy metabolism through activation of AMPK, resisting oxidative stress, inhibiting activation of the JNK pathway, and maintaining intracellular calcium ion homeostasis. Additionally, MIF exerts protective effects through mesenchymal stem cells and exosomes. On the other hand, MIF can assume a pro-inflammatory role, which contributes to the exacerbation of IHD's development and progression. Furthermore, MIF levels significantly increase in IHD patients, and its genetic polymorphisms are positively correlated with prevalence and severity. These findings position MIF as a potential biomarker and therapeutic target in the management of IHD. This review summarizes the structure, source, signaling pathways and biological functions of MIF and focuses on its roles and clinical characteristics in IHD. The genetic variants of MIF associated with IHD is also discussed, providing more understandings of its complex interplay in the disease's pathology.

巨噬细胞迁移抑制因子（MIF）是一种多功能细胞因子，在免疫调节和炎症反应中的作用日益受到重视。缺血性心脏病（IHD）是导致全球死亡的主要原因，由于其病理生理学错综复杂，它仍然是研究的焦点。MIF 被认为是缺血性心脏病的关键因素，在其中发挥着不同的作用。一方面，MIF 通过激活 AMPK 加强能量代谢、抵抗氧化应激、抑制 JNK 通路的激活以及维持细胞内钙离子的平衡，从而发挥保护作用。此外，MIF 还通过间充质干细胞和外泌体发挥保护作用。另一方面，MIF 可发挥促炎作用，从而加剧 IHD 的发展和恶化。此外，IHD 患者体内的 MIF 水平明显升高，其基因多态性与发病率和严重程度呈正相关。这些发现使 MIF 成为治疗 IHD 的潜在生物标志物和治疗靶点。本综述总结了 MIF 的结构、来源、信号传导途径和生物功能，并重点讨论了其在 IHD 中的作用和临床特征。此外，还讨论了与 IHD 相关的 MIF 基因变异，使人们对其在疾病病理中的复杂相互作用有了更多的了解。

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引用次数: 0

The role of transforming growth factor β in cervical carcinogenesis 转化生长因子β在宫颈癌变中的作用。

IF 9.3 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cytokine & Growth Factor Reviews

Pub Date : 2024-12-01 DOI: 10.1016/j.cytogfr.2024.10.006

Kleber Paiva Trugilo , Guilherme Cesar Martelossi Cebinelli , Eliza Pizarro Castilha , Mariane Ricciardi da Silva , Fernanda Costa Brandão Berti , Karen Brajão de Oliveira

Human papillomavirus (HPV) is involved in virtually all cases of cervical cancer. However, HPV alone is not sufficient to cause malignant development. The effects of chronic inflammation and the interaction of immune components with the microenvironment infected with the high-risk HPV type (HR) may contribute to cancer development. Transforming growth factor β (TGFB) appears to play an important role in cervical carcinogenesis. Protein and mRNA levels of this cytokine gradually increase as normal tissue develops into malignant tissue and are closely related to the severity of HPV infection. At the onset of infection, TGFB can inhibit the proliferation of infected cells and viral amplification by inhibiting cell growth and downregulating the transcriptional activity of the long control region (LCR) of HPV, thereby reducing the expression of early genes. When infected cells progress to a malignant phenotype, the response to the cell growth inhibitory effect of TGFB1 is lost and the suppression of E6 and E7 expression decreases. Subsequently, TGFB1 expression is upregulated by high levels of E6 and E7 oncoproteins, leading to an increase in TGFB1 in the tumor microenvironment, where this molecule promotes epithelial-to-mesenchymal transition (EMT), cell motility, angiogenesis, and immunosuppression. This interaction between HPV oncoproteins and TGFB1 is an important mechanism promoting the development and progression of cervical cancer.

几乎所有宫颈癌病例都与人类乳头瘤病毒（HPV）有关。然而，仅靠 HPV 并不足以导致恶性发展。慢性炎症的影响以及免疫成分与感染高危型 HPV（HR）的微环境的相互作用可能会导致癌症的发生。转化生长因子β（TGFB）似乎在宫颈癌的发生中起着重要作用。当正常组织发展为恶性组织时，这种细胞因子的蛋白和 mRNA 水平会逐渐升高，并且与 HPV 感染的严重程度密切相关。在感染初期，TGFB 可通过抑制细胞生长和下调 HPV 长控制区（LCR）的转录活性，从而降低早期基因的表达，抑制感染细胞的增殖和病毒的扩增。当受感染的细胞发展到恶性表型时，TGFB1 对细胞生长抑制作用的反应就会消失，对 E6 和 E7 表达的抑制作用也会减弱。随后，高水平的 E6 和 E7 肿瘤蛋白会上调 TGFB1 的表达，导致肿瘤微环境中的 TGFB1 增加，而这种分子会促进上皮细胞向间质转化（EMT）、细胞运动、血管生成和免疫抑制。HPV 癌蛋白与 TGFB1 之间的这种相互作用是促进宫颈癌发生和发展的重要机制。

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