Advances in biological regulation最新文献_第3页

DNA intercalating drugs: Mechanisms of action in cancer treatment DNA嵌入药物：在癌症治疗中的作用机制。

IF 2.4 Q1 Biochemistry, Genetics and Molecular Biology

Advances in biological regulation

Pub Date : 2025-09-24 DOI: 10.1016/j.jbior.2025.101115

Marvellous Oyeyode , Mathew Tempel , Ted M. Lakowski , James R. Davie

DNA-intercalating drugs (e.g., doxorubicin) have been used in cancer treatment since the 1960s. Multiple mechanisms have been observed with these drugs. These drugs intercalate into nucleosome-free regions of chromatin, which play a crucial role in regulating gene expression and genome organization. DNA intercalation by these drugs results in a plethora of events, including DNA damage, chromatin damage (histone eviction), erosion of chromatin organization, nucleolar condensation, RNA polymerase I and/or RNA polymerase II degradation, transcription arrest, deubiquitination of histone H2B ubiquitinated at lysine 120, topoisomerase I and/or II inhibition and/or trapping, and disruption of proteins associated with the elongating RNA polymerase II. These events may occur within hours following the addition of these drugs. At later times, changes to the DNA structure (e.g., the formation of Z DNA) occur, and eventually, the cells will die via apoptosis. This review will examine the mechanisms of action of DNA-intercalating drugs, specifically two anthracyclines (doxorubicin and aclarubicin) and a heteroaromatic compound (BMH-21). Doxorubicin and aclarubicin are used clinically to treat cancer, while BMH-21 remains in preclinical development. Reports on plasma pharmacokinetics of these anthracyclines will be tabulated, and the clinical relevance of the observed mechanisms of action for doxorubicin and aclarubicin will be assessed based on this information.

自20世纪60年代以来，dna插入药物（如阿霉素）已用于癌症治疗。这些药物已经观察到多种机制。这些药物嵌入到染色质的无核小体区域，在调节基因表达和基因组组织中起着至关重要的作用。这些药物嵌入DNA会导致大量的事件，包括DNA损伤、染色质损伤（组蛋白脱落）、染色质组织侵蚀、核仁凝聚、RNA聚合酶I和/或RNA聚合酶II降解、转录阻滞、赖氨酸120泛素化的组蛋白H2B去泛素化、拓扑异构酶I和/或II抑制和/或捕获，以及与延长RNA聚合酶II相关的蛋白质破坏。这些事件可在加入这些药物后数小时内发生。随后，DNA结构发生变化（例如，Z DNA的形成），最终，细胞将通过凋亡死亡。本文综述了dna插入药物的作用机制，特别是两种蒽环类药物（阿霉素和阿克拉霉素）和一种杂芳香族化合物（BMH-21）。阿霉素和阿克拉比星在临床上用于治疗癌症，而BMH-21仍处于临床前开发阶段。这些蒽环类药物的血浆药代动力学报告将被制成表格，并根据这些信息评估阿霉素和阿克拉霉素观察到的作用机制的临床相关性。

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引用次数: 0

Continuous fractionated irradiation with irradiation-free intervals enhances survival and clonogenicity in osteosarcoma MG-63 cells via adaptive DNA damage response 通过适应性DNA损伤反应，以无照射间隔连续分次照射提高MG-63骨肉瘤细胞的存活率和克隆原性。

IF 2.4 Q1 Biochemistry, Genetics and Molecular Biology

Advances in biological regulation

Pub Date : 2025-09-10 DOI: 10.1016/j.jbior.2025.101114

Hiroko Ikeda , Yuka Amano , Koki Hara , Yuito Tanaka , Eiki Isa , Nanami Shimomura , Toshifumi Tsujiuchi

Radiotherapy is a widely used treatment modality for various types of cancer. However, the adaptive resistance of tumor cells during radiotherapy poses a major challenge to therapeutic efficacy. This study aimed to evaluate whether continuous fractionated irradiation induces radioresistance in osteosarcoma MG-63 cells compared with single-dose exposure. To assess the effects of fractionated irradiation on cell survival, MG-63 cells were subjected to either single irradiation (SR; 0, 5, or 10 Gy) or continuous fractionated irradiation (5-CFR; 0, 1, or 2 Gy per day for five consecutive days), resulting in total doses of 0, 5, or 10 Gy, respectively. Compared with SR, 5-CFR significantly increased survival and promoted the formation of larger colonies, indicating enhanced clonogenicity. We further examined the effects of additional irradiation (AR) following 5-CFR and an irradiation-free interval. Cells pretreated with 5-CFR (0, 1, or 2 Gy) were subsequently exposed to a single dose of AR (2 Gy), resulting in total doses of 0, 7, or 12 Gy, respectively. MG-63 cells that received 5-CFR + AR exhibited significantly greater survival and increased colony size compared to those treated with SR + AR. To explore the cellular response to DNA damage following 5-CFR, we analyzed γ-H2AX and 53BP1 foci formation. Both markers increased in a dose-dependent manner after 5-CFR, suggesting effective recognition and repair of DNA double-strand breaks. Collectively, these results indicate that continuous fractionated irradiation with irradiation-free intervals confers greater radioresistance to MG-63 cells by enhancing survival and clonogenicity via an adaptive DNA damage response compared with SR.

放射治疗是一种广泛应用于各种类型癌症的治疗方式。然而，肿瘤细胞在放疗过程中的适应性抵抗对治疗效果构成了重大挑战。本研究旨在评估与单剂量照射相比，连续分次照射是否会诱导MG-63骨肉瘤细胞的放射抗性。为了评估分次辐照对细胞存活的影响，MG-63细胞接受单次辐照（SR； 0、5或10 Gy）或连续分次辐照（5- cfr；每天0、1或2 Gy，连续5天），总剂量分别为0、5或10 Gy。与SR相比，5-CFR显著提高了成活率，促进了更大菌落的形成，表明克隆原性增强。我们进一步研究了5-CFR和无辐照间隔后额外辐照（AR）的影响。用5-CFR（0、1或2 Gy）预处理的细胞随后暴露于单剂量AR (2 Gy)，导致总剂量分别为0、7或12 Gy。与接受SR + AR治疗的MG-63细胞相比，接受5-CFR + AR治疗的细胞存活率显著提高，集落大小也增加。为了探索5-CFR后细胞对DNA损伤的反应，我们分析了γ-H2AX和53BP1灶的形成。5-CFR后，两种标记物均呈剂量依赖性增加，提示DNA双链断裂的有效识别和修复。总的来说，这些结果表明，与SR相比，无辐照间隔的连续分段辐照通过适应性DNA损伤反应提高了MG-63细胞的存活率和克隆原性，从而使MG-63细胞具有更强的辐射抗性。

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引用次数: 0

Unveiling the role of biomolecular condensates in cellular function and cancer 揭示生物分子凝聚物在细胞功能和癌症中的作用

IF 2.4 Q1 Biochemistry, Genetics and Molecular Biology

Advances in biological regulation

Pub Date : 2025-09-03 DOI: 10.1016/j.jbior.2025.101105

Herencia-Lagunar Elena , Carrera-Bravo Claudia , Castano Enrique , Sztacho Martin

Biomolecular condensates (BMCs) are membrane-less organelles formed through liquid-liquid phase separation, primarily driven by multivalent interactions between scaffold and client molecules. These dynamic compartments enable cells to spatially and temporally organize biochemical reactions by locally concentrating specific biomolecules, thereby enhancing the frequency of productive molecular interactions and increasing reaction rates. BMCs are integral to normal cellular physiology, with well-characterized examples including the nucleolus and Cajal bodies. However, aberrant formation or regulation of condensates has been implicated in the pathogenesis of several diseases, including neurodegenerative disorders, cancer, and immune-related conditions. Intrinsically disordered regions and disease-associated mutations in key residues often promote pathological phase separation, contributing to condensate dysregulation. A comprehensive understanding of the molecular principles governing BMC biogenesis is critical for the development of novel, non-invasive therapeutic strategies aimed at modulating condensate dynamics in disease contexts.

生物分子凝聚物（BMCs）是通过液-液相分离形成的无膜细胞器，主要由支架分子和客户分子之间的多价相互作用驱动。这些动态区室使细胞能够在空间和时间上通过局部集中特定的生物分子来组织生化反应，从而提高了生产分子相互作用的频率，提高了反应速率。bmc是正常细胞生理的组成部分，核仁和Cajal小体都是典型的例子。然而，冷凝物的异常形成或调节与几种疾病的发病机制有关，包括神经退行性疾病、癌症和免疫相关疾病。关键残基的内在紊乱区域和疾病相关突变通常会促进病理性相分离，导致凝析液失调。全面了解BMC生物发生的分子原理对于开发新的非侵入性治疗策略至关重要，这些策略旨在调节疾病背景下的凝聚动力学。

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引用次数: 0

The role of glycolytic condensates in the cellular stress response during cancer progression 糖酵解凝聚物在癌症进展过程中细胞应激反应中的作用

IF 2.4 Q1 Biochemistry, Genetics and Molecular Biology

Advances in biological regulation

Pub Date : 2025-08-29 DOI: 10.1016/j.jbior.2025.101104

Elena Herencia-Lagunar, Claudia Carrera-Bravo, Martin Sztacho

Biomolecular condensates are key organizers of the intracellular environment, which are formed through liquid–liquid phase separation. Glycolytic condensates constitute a subtype of biomolecular condensates that enable compartmentalized ATP production and efficient metabolite channeling under stress conditions. This review explores how stressors, such as hypoxia, glucose deprivation, hyperosmotic stress, and hyperthermia, induce the formation of glycolytic condensates. These stressors are notably prevalent in the tumor microenvironment, where they may support cancer cell survival, metabolic adaptation, and invasion. We discuss the role of scaffold molecules, such as TPM4, F-actin, and RNA, in mediating condensate assembly and stabilization. A deeper understanding of the regulation and function of glycolytic condensates could reveal new vulnerabilities in tumor metabolism and generate strategies to hinder cancer cell adaptation to stress.

生物分子凝聚体是细胞内环境的关键组织者，是通过液-液相分离形成的。糖酵解凝聚物是生物分子凝聚物的一个亚型，它能够在应激条件下产生区隔化的ATP和有效的代谢物通道。这篇综述探讨了应激源，如缺氧、葡萄糖剥夺、高渗应激和热疗，如何诱导糖酵解凝聚物的形成。这些应激源在肿瘤微环境中非常普遍，它们可能支持癌细胞存活、代谢适应和侵袭。我们讨论了支架分子，如TPM4， f -肌动蛋白和RNA，在调解凝聚物组装和稳定中的作用。更深入地了解糖酵解凝聚物的调控和功能，可以揭示肿瘤代谢的新脆弱性，并产生阻碍癌细胞适应应激的策略。

引用次数: 0

The wheat VIH2-3B, a functional PPIP5K controls the localization of fasciclin-like arabinogalactan protein 小麦VIH2-3B是一个功能性的PPIP5K，它控制着筋状蛋白样阿拉伯半乳聚糖蛋白的定位

Q1 Biochemistry, Genetics and Molecular Biology

Advances in biological regulation

Pub Date : 2025-07-25 DOI: 10.1016/j.jbior.2025.101103

Anuj Shukla , Reshma Gopal , Riya Ghosh , Ankur Chaudhuri , Kanupriya Agrwal , Rahul Tanwar , Henning Jacob Jessen , Debabrata Laha , Ajay Kumar Pandey

Inositol pyrophosphates (PP-InsPs) are important signalling molecules that participate in multiple physiological processes across a wide range of eukaryotes. Metabolic pathway kinases (VIP1/VIHs) leading to the production of PP-InsPs are now well characterized in yeast and plants. Previously, the wheat (Triticum aestivum L.) inositol pyrophosphate kinase (TaVIH2) was shown to encode a catalytic active kinase domain. Heterologous expression of TaVIH2 in Arabidopsis thaliana was shown to enhance drought tolerance by modulating the cell composition. In this study, we attempted to identify the interacting protein targets of wheat VIH2-3B using a yeast two-hybrid (Y2H) cDNA library screen, which led to the identification of 52 putative interactors that are primarily involved in cell wall-related functions. Notably, fasciclin-like arabinogalactan protein (FLA7), a glycosylphosphatidyl inositol (GPI)-anchored protein, emerged as the most frequently interacting partner. Further analysis using pulldown assays validated the interaction between TaVIH2-3B and TaFLA7 in vivo. Using the reporter fusion studies, we observed the localization of TaFLA7 to be a plasma membrane and this localization of the TaFLA7 was perturbed in the yeast vip1Δ strain. The expression of TaVIH2-3B bearing PPIP5K enzymatic activity in yeast mutants rescued the level of IP₈ and restore the localization of the TaFLA7 to the membrane. Expression analysis of TaFLA7 revealed a differential expression response to drought in wheat shoot tissues. TaFLA7 was also found to be highly expressed during grain development, particularly in the endosperm and seed coat during grain maturation. Taken together, these findings highlight the potential role of TaVIH2 in cell wall remodelling and stress response pathways, offering new insights into the functional roles of VIH proteins in plants.

肌醇焦磷酸（PP-InsPs）是一种重要的信号分子，参与多种真核生物的多种生理过程。导致PP-InsPs产生的代谢途径激酶（VIP1/VIHs）现在已经在酵母和植物中得到了很好的表征。此前，小麦（Triticum aestivum L.）肌醇焦磷酸激酶（TaVIH2）编码一个催化活性激酶结构域。TaVIH2在拟南芥中的异源表达通过调节细胞组成来增强耐旱性。在这项研究中，我们试图利用酵母双杂交（Y2H） cDNA文库筛选小麦VIH2-3B的相互作用蛋白靶点，从而鉴定出52个主要参与细胞壁相关功能的推定相互作用蛋白。值得注意的是，一种糖基磷脂酰肌醇（GPI）锚定蛋白fasicillin -样阿拉伯半乳聚糖蛋白（fl7）是最常见的相互作用伙伴。进一步的下拉实验验证了tvih2 - 3b和TaFLA7在体内的相互作用。通过报告融合研究，我们观察到TaFLA7定位为质膜，并且在酵母vip1Δ菌株中TaFLA7的定位受到干扰。携带PPIP5K酶活性的TaVIH2-3B在酵母突变体中的表达挽救了IP8水平，恢复了TaFLA7在膜上的定位。TaFLA7的表达分析揭示了干旱对小麦茎部组织的差异表达响应。TaFLA7在籽粒发育过程中也被发现高表达，尤其是在籽粒成熟过程中的胚乳和种皮中。综上所述，这些发现突出了TaVIH2在细胞壁重塑和胁迫反应途径中的潜在作用，为植物中VIH蛋白的功能作用提供了新的见解。

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引用次数: 0

In-depth review of breast cancer and inflammation pre-and post-treatment strategies with conventional and novel Steroid agents 深入回顾乳腺癌和炎症治疗前后的策略与传统和新型类固醇药物

Q1 Biochemistry, Genetics and Molecular Biology

Advances in biological regulation

Pub Date : 2025-07-15 DOI: 10.1016/j.jbior.2025.101102

Panneerselvam Theivendren , Punitha Narayanasamy , Kumarappan Chidamabaram , Sangeetha Menon , Josephin Arockia Dhivya Antony Sahayaraj , Natarajan Kiruthiga , Balaji Pandiyan

Breast cancer leads to many women's cancer deaths worldwide and inflammation is essential for tumors to develop, advance and spread within the body. High levels of ongoing inflammation within the tumor help cancer cells multiply, encourage blood vessel formation and allow the cancer cells to evade detection by the immune system, so it is a target of choice for many cancer treatments. The relationship between breast cancer and inflammation is explored, stressing how important both early and late stages are, with both traditional and novel steroid options. For many years, corticosteroids and other conventional steroids have been used to help relieve side effects of treatment and boost the well-being of patients. Even so, steroids only working in certain patients and side effects have pushed scientists to discover new type of steroid derivatives that are better and safer. Targeted inflammation control and altered immune response in tumors by these new steroids could make therapy more successful. This review looks at current evidence from different types of studies to determine steroids' role in treating breast cancer-related inflammation. It also reviews options for using steroids together with chemotherapy, radiotherapy and immunotherapy, focusing on achieving the best anti-inflammatory results while keeping the inability to respond to treatment low. The study also looks at potential future progress in developing steroids, personalized medicine and therapies guided by biomarkers that could greatly improve how breast cancer is managed. Knowing how steroids affect tumors as well as inflammation is necessary for creating good treatment plans that improve breast cancer patients' chances of survival and lower their risk of disease recurrence.

乳腺癌导致全世界许多妇女因癌症死亡，而炎症是肿瘤在体内发展、发展和扩散的必要条件。肿瘤内持续的高水平炎症有助于癌细胞繁殖，促进血管形成，并使癌细胞逃避免疫系统的检测，因此它是许多癌症治疗的首选目标。探讨了乳腺癌和炎症之间的关系，强调了早期和晚期的重要性，以及传统和新型类固醇选择。多年来，皮质类固醇和其他常规类固醇一直被用来帮助减轻治疗的副作用，提高患者的健康水平。即便如此，类固醇只对某些病人有效，而且还有副作用，这促使科学家们去发现更好、更安全的新型类固醇衍生物。通过这些新的类固醇靶向炎症控制和改变肿瘤的免疫反应可以使治疗更加成功。这篇综述着眼于目前来自不同类型研究的证据，以确定类固醇在治疗乳腺癌相关炎症中的作用。它还回顾了类固醇与化疗、放疗和免疫疗法一起使用的选择，重点是实现最佳的抗炎效果，同时保持对治疗的无反应性。该研究还展望了未来在类固醇、个性化药物和生物标志物指导下的治疗方面的潜在进展，这些将极大地改善乳腺癌的治疗方式。了解类固醇如何影响肿瘤和炎症对于制定良好的治疗计划，提高乳腺癌患者的生存机会和降低疾病复发的风险是必要的。

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引用次数: 0

Norepinephrine mediates adrenergic receptor transcription and oncogenic gene expression in pancreatic ductal adenocarcinoma 去甲肾上腺素介导胰腺导管腺癌中肾上腺素能受体转录和致癌基因表达

Q1 Biochemistry, Genetics and Molecular Biology

Advances in biological regulation

Pub Date : 2025-05-05 DOI: 10.1016/j.jbior.2025.101097

Henry H. Brak, Noelle R.J. Thielman

Adrenergic stimulation of β₂ receptors has shown to increase pancreatic ductal adenocarcinoma (PDAC) proliferation and migration in an in vitro setting; however, the role of α₁ receptors in these adrenergic signaling pathways is unclear. Previous research has suggested that the MAPK signaling pathway is upregulated in response to β-adrenergic signaling, but other signaling pathways and downstream targets of mutant KRAS have yet to be investigated. This study investigates the role of adrenergic signaling through α₁ and β-receptors in two human-derived PDAC cell lines, examining proliferation, wound healing, and protein expression after treatment with norepinephrine (NE) and in the presence of β and α₁-receptor antagonism. Using RT-qPCR, the expression of adrenergic receptors and downstream KRAS effector proteins was evaluated. We found that NE has varying effects on proliferation and wound healing in different PDAC cell lines. Moreover, adrenergic receptor expression is under negative feedback control through α₁ signaling in both cell lines. Furthermore, NE decreases expression of MMP9 while also affecting expression of VIM, CCND1, mTOR, and rhoA. We demonstrate genotype dependent effects of adrenergic stimulation on downstream molecular signaling pathways in PDAC that are important for oncogenicity. Based on our findings, genotypic characterization of cell signaling pathways in PDAC may aid further research in effective therapeutics for PDAC.

在体外环境中，肾上腺素能刺激β2受体可增加胰腺导管腺癌（PDAC）的增殖和迁移；然而，α1受体在这些肾上腺素能信号通路中的作用尚不清楚。先前的研究表明，MAPK信号通路响应β-肾上腺素能信号而上调，但突变体KRAS的其他信号通路和下游靶点尚未被研究。本研究探讨了肾上腺素能信号通过α1和β-受体在两种人源性PDAC细胞系中的作用，检测了去甲肾上腺素（NE）处理后以及β和α -受体拮抗剂存在下的增殖、伤口愈合和蛋白表达。RT-qPCR检测肾上腺素能受体和KRAS下游效应蛋白的表达。我们发现NE对不同PDAC细胞系的增殖和伤口愈合有不同的影响。此外，肾上腺素能受体的表达在两种细胞系中均受α1信号的负反馈控制。此外，NE降低MMP9的表达，同时也影响VIM、CCND1、mTOR和rhoA的表达。我们证明了肾上腺素能刺激对PDAC下游分子信号通路的基因型依赖性作用，这对致癌性很重要。基于我们的发现，PDAC细胞信号通路的基因型表征可能有助于进一步研究PDAC的有效治疗方法。

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引用次数: 0

Lipin phosphatidic acid phosphatases: Structure, function, regulation, and disease association 脂质磷脂酸磷酸酶：结构、功能、调节和疾病关联。

Q1 Biochemistry, Genetics and Molecular Biology

Advances in biological regulation

Pub Date : 2025-05-01 DOI: 10.1016/j.jbior.2025.101082

Franceine S. Welcome, Taisha C.M. Elizaire, Michael V. Airola

Lipids play essential roles as structural barriers in cell membranes, long-term energy storage, and as signaling molecules. One class of enzymes involved in lipid synthesis are lipins. Lipins are magnesium-dependent phosphatidic acid phosphatases that produce diacylglycerol, playing key roles in TAG synthesis, de novo phospholipid synthesis and metabolism. Here, we review recent advances on the structure, function, and regulation of lipins with a particular focus on the structural impacts of missense mutations associated with rhabdomyolysis, Majeed syndrome and neuropathies. Structural insights reveal that while some disease-associated mutations directly disrupt catalysis, many missense mutations are not near the active site, but still play a key role in PAP activity. With the resolved crystal structure of a lipin homolog Tt Pah2, AlphaFold, and AlphaMissense it has become increasingly possible to predict the pathogenicity and structural contributions of individual residues and mutations. Going forward, this structural information can be used to predict and understand new mutations as they arise.

脂质作为细胞膜的结构屏障、长期能量储存和信号分子发挥着重要作用。参与脂质合成的一类酶是脂质酶。脂质是镁依赖性磷脂酸磷酸酶，产生二酰基甘油，在TAG合成、新生磷脂合成和代谢中起关键作用。在这里，我们回顾了最近在脂质结构、功能和调控方面的进展，特别关注与横纹肌溶解、马吉德综合征和神经病变相关的错义突变的结构影响。结构洞察揭示，虽然一些疾病相关突变直接破坏催化，但许多错义突变不在活性位点附近，但仍在PAP活性中发挥关键作用。随着脂质同源物Tt Pah2、AlphaFold和AlphaMissense的晶体结构的解析，预测单个残基和突变的致病性和结构贡献变得越来越可能。展望未来，这些结构信息可以用来预测和理解新突变的出现。

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引用次数: 0

Solid pancancer analysis reveals immune and hematopoietic stem cell and DNA damage repair signatures to distinguish different cancer subtypes 实体胰腺癌分析揭示了免疫和造血干细胞和DNA损伤修复特征，以区分不同的癌症亚型

Q1 Biochemistry, Genetics and Molecular Biology

Advances in biological regulation

Pub Date : 2025-05-01 DOI: 10.1016/j.jbior.2025.101090

Nayila Abulimiti , Rongzhuo Long , Yin He , Junze Dong , Xiaosheng Wang

Purpose

Immunity, stemness, and DNA damage repair (DDR) are crucial for cancer development and therapy resistance. With advancements in multiomics technology, the exploration of cancers related to immunity, stemness, and the DDR has triggered interest, but the combination of these levels for analyzing multiple cancers remains insufficient.

Methods

In this study, 9906 solid tumor samples from 31 TCGA cancer types were clustered on the basis of the enrichment levels of 13 gene sets associated with stemness, immunity, and DDR. Moreover, a soft ensemble model was constructed on the basis of the enrichment levels of these 13 gene sets to predict cancer subtypes via other omics data.

Results

We identified four pancancer subtypes, termed C1, C2, C3, and C4, which presented distinct molecular and clinical features, including the immune microenvironment, stemness, genome instability, intratumor heterogeneity, methylation levels, tumor progression, sensitivity to chemotherapy and immunotherapy, and survival prognosis. The soft ensemble model validated this subtyping method in two breast cancer datasets (gene expression level), a pancancer proteomic dataset (protein expression level), and a pancancer cell line dataset (cell line gene expression level).

Conclusion

Our findings indicate that immune, stemness, and DDR signature-based subtyping offers new perspectives on cancer biology and holds promise for improving the clinical management of cancers.

目的免疫、干细胞和DNA损伤修复（DDR）是肿瘤发生和耐药的关键。随着多组学技术的进步，对与免疫、干细胞和DDR相关的癌症的探索引发了人们的兴趣，但将这些水平结合起来分析多种癌症仍然不足。方法基于13个与干性、免疫和DDR相关的基因集的富集水平，对31种TCGA肿瘤类型的9906个实体瘤样本进行聚类。此外，基于这13个基因集的富集水平，构建了一个软集合模型，通过其他组学数据预测癌症亚型。结果我们确定了四种胰腺癌亚型，分别为C1、C2、C3和C4，它们具有不同的分子和临床特征，包括免疫微环境、干性、基因组不稳定性、肿瘤内异质性、甲基化水平、肿瘤进展、对化疗和免疫治疗的敏感性以及生存预后。软集成模型在两个乳腺癌数据集（基因表达水平）、一个胰腺癌蛋白质组学数据集（蛋白质表达水平）和一个胰腺癌细胞系数据集（细胞系基因表达水平）中验证了这种亚型方法。结论基于免疫、干性和DDR特征的亚型为研究癌症生物学提供了新的视角，并有望改善癌症的临床管理。

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引用次数: 0

Lysophosphatidic acid (LPA) receptor signaling modulates cellular functions of colon cancer cells under cobalt chloride-induced hypoxic conditions 溶血磷脂酸（LPA）受体信号在氯化钴诱导的缺氧条件下调节结肠癌细胞的细胞功能

Q1 Biochemistry, Genetics and Molecular Biology

Advances in biological regulation

Pub Date : 2025-05-01 DOI: 10.1016/j.jbior.2025.101098

Mao Yamamoto, Miwa Takai, Narumi Yashiro, Moemi Tamura, Yuka Kusumoto, Shion Nagano, Anri Taniguchi, Nanami Shimomura, Toshifumi Tsujiuchi

In the tumor microenvironment (TME), hypoxia is critical in promoting tumor invasiveness and progression. Cobalt chloride (CoCl₂) mimics hypoxia by inducing comparable cellular responses. Lysophosphatidic acid (LPA) receptors (LPA₁ to LPA₆) play key roles in regulating cancer cell functions. In this study, we investigated the impact of LPA receptor signaling on malignant properties of colon cancer DLD-1 cells under hypoxic condition induced by CoCl₂. LPAR1 and LPAR2 expression levels were elevated in DLD-1 cells treated with CoCl₂. CoCl₂ treatment also stimulated DLD-1 cell motility. This enhanced motility induced by CoCl₂ was reduced with LW6 (HIF-1 inhibitor). Additionally, the motility of CoCl₂-treated DLD-1 cells was suppressed by AM966 (LPA₁ antagonist) and enhanced by GRI-977143 (LPA₂ agonist). Conversely, CoCl₂ treatment decreased DLD-1 cell invasion. While AM966 further inhibited cell invasion, GRI-977143 elevated it. The cell viability to fluorouracil (5-FU) was higher in CoCl₂-treated DLD-1 cells. This increased viability to 5-FU was further enhanced by both AM966 and GRI-977143. When CoCl₂-treated DLD-1 cells were cultured in low-glucose media, LPAR1 expression was upregulated compared to high-glucose media, while LPAR2 expression was downregulated. Additionally, motility and invasion in CoCl₂-treated DLD-1 cells were further stimulated under low-glucose conditions. These results suggest that LPA receptor signaling contributes to the malignant potential of DLD-1 cells in a hypoxic environment induced by CoCl₂ treatment.

在肿瘤微环境（TME）中，缺氧是促进肿瘤侵袭和进展的关键。氯化钴（CoCl2）通过诱导类似的细胞反应来模拟缺氧。溶血磷脂酸（LPA）受体（LPA1 ~ LPA6）在调节癌细胞功能中起关键作用。在本研究中，我们研究了在CoCl2诱导的缺氧条件下LPA受体信号传导对结肠癌DLD-1细胞恶性特性的影响。在CoCl2处理的DLD-1细胞中，LPAR1和LPAR2表达水平升高。CoCl2处理也刺激了DLD-1细胞的运动。CoCl2诱导的这种增强的运动性被LW6 （HIF-1抑制剂）所降低。此外，cocl2处理的DLD-1细胞的运动性被AM966 （LPA1拮抗剂）抑制，而被GRI-977143 （LPA2激动剂）增强。相反，CoCl2处理降低了DLD-1细胞的侵袭。AM966进一步抑制细胞侵袭，而GRI-977143则提高细胞侵袭。cocl2处理的DLD-1细胞对氟尿嘧啶（5-FU）的存活率较高。AM966和GRI-977143进一步增强了对5-FU的活性。当cocl2处理的DLD-1细胞在低糖培养基中培养时，与高糖培养基相比，LPAR1表达上调，而LPAR2表达下调。此外，在低糖条件下，cocl2处理的DLD-1细胞的运动性和侵袭性进一步受到刺激。这些结果表明，在CoCl2诱导的缺氧环境下，LPA受体信号传导有助于DLD-1细胞的恶性潜能。

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引用次数: 0