Cancer Cell International最新文献

Glucose metabolism in glioma: an emerging sight with ncRNAs 胶质瘤中的葡萄糖代谢：ncRNA 的新发现

IF 5.8 2区医学 Q1 ONCOLOGY

Cancer Cell International

Pub Date : 2024-09-13 DOI: 10.1186/s12935-024-03499-8

Jun Rong, Qifu Wang, Tingzheng Li, Jin Qian, Jinchao Cheng

Glioma is a primary brain tumor that grows quickly, has an unfavorable prognosis, and can spread intracerebrally. Glioma cells rely on glucose as the major energy source, and glycolysis plays a critical role in tumorigenesis and progression. Substrate utilization shifts throughout glioma progression to facilitate energy generation and biomass accumulation. This metabolic reprogramming promotes glioma cell proliferation and metastasis and ultimately decreases the efficacy of conventional treatments. Non-coding RNAs (ncRNAs) are involved in several glucose metabolism pathways during tumor initiation and progression. These RNAs influence cell viability and glucose metabolism by modulating the expression of key genes of the glycolytic pathway. They can directly or indirectly affect glycolysis in glioma cells by influencing the transcription and post-transcriptional regulation of oncogenes and suppressor genes. In this review, we discussed the role of ncRNAs in the metabolic reprogramming of glioma cells and tumor microenvironments and their abnormal expression in the glucometabolic pathway in glioma. In addition, we consolidated the existing theoretical knowledge to facilitate the use of this emerging class of biomarkers as biological indicators and potential therapeutic targets for glioma.

胶质瘤是一种原发性脑肿瘤，生长迅速，预后不良，并可在脑内扩散。胶质瘤细胞依赖葡萄糖作为主要能量来源，糖酵解在肿瘤发生和发展过程中起着至关重要的作用。在胶质瘤的整个发展过程中，底物利用会发生变化，以促进能量生成和生物量积累。这种代谢重编程会促进胶质瘤细胞的增殖和转移，并最终降低传统疗法的疗效。非编码 RNA（ncRNA）参与了肿瘤发生和发展过程中的几种葡萄糖代谢途径。这些 RNA 通过调节糖酵解途径关键基因的表达来影响细胞活力和葡萄糖代谢。它们可以通过影响癌基因和抑制基因的转录和转录后调控，直接或间接影响胶质瘤细胞的糖酵解。在这篇综述中，我们讨论了 ncRNA 在胶质瘤细胞和肿瘤微环境代谢重编程中的作用，以及它们在胶质瘤糖代谢通路中的异常表达。此外，我们还整合了现有的理论知识，以便将这类新兴的生物标志物用作胶质瘤的生物学指标和潜在治疗靶点。

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引用次数: 0

Wee1 inhibitor PD0166285 sensitized TP53 mutant lung squamous cell carcinoma to cisplatin via STAT1 Wee1 抑制剂 PD0166285 通过 STAT1 使 TP53 突变的肺鳞癌对顺铂敏感

IF 5.8 2区医学 Q1 ONCOLOGY

Cancer Cell International

Pub Date : 2024-09-13 DOI: 10.1186/s12935-024-03489-w

Qi Li, Wenjie Yang, Qingyi Zhang, Daoming Zhang, Jun Deng, Binxin Chen, Ping Li, Huanqi Zhang, Yiming Jiang, Yangling Li, Bo Zhang, Nengming Lin

Lung squamous cell carcinoma (LUSCs) is associated with high mortality (20–30%) and lacks of effective treatments. Almost all LUSC exhibit somatic mutations in TP53. Wee1, a tyrosine kinase, regulates the cell cycle at the G2/M checkpoint. In TP53-deficient cells, the dependence on G2/M checkpoints increases. PD0166285 is the first reported drug with inhibitory activity against both Wee1 and PKMYT1. Protein expression was determined by Western blot analysis. Cell proliferation was assessed using cell colony formation and CCK-8 assays. Cell cycle was performed by PI staining with flow cytometry. Apoptosis was evaluated using Annexin V-Phycoerythrin double staining and flow cytometry. DNA damage was detected through comet assay and immunofluorescence assay. In vivo, apoptosis and anti-tumor effects were assessed using the TUNEL assay, a nude mouse model, and immunohistochemistry (IHC). Co-immunoprecipitation assay was used to detect protein–protein interactions. We analyzed Wee1, PKMYT1, and Stat1 expression in pan-cancer studies using the Ualcan public database and assessed their prognostic implications with Kaplan–Meier curves. PD0166285, a Wee1 inhibitor, effectively inhibits Wee1 activity, promoting cell entry into a mitotic crisis. Moreover, PD0166285 sensitizes cells to cisplatin, enhancing clinical outcomes. Our study demonstrated that PD016628 regulates the cell cycle through Rad51 and results in cell cycle arrest at the G2/M phase. We observed increased apoptosis in tumor cells treated with PD0166285, particularly when combined with cisplatin, indicating an enhanced apoptotic response. The upregulation of γ-H2AX serves as an indicator of mitotic catastrophe. Co-immunoprecipitation and data analysis revealed that apoptosis in LUSC is mediated through the Stat1 pathway, accompanied by decreased levels of Socs3. Furthermore, IHC staining confirmed significant differences in the expression of Phospho-CDK1 and γ-H2AX in LUSCs, suggesting involvement in DNA damage. In summary, our study suggests that PD0166285, an inhibitor of Wee1, sensitizes LUSC cells to cisplatin and modulates DNA damage and apoptosis pathways through Rad51 and Stat1, respectively. These findings highlight the combination of PD0166285 and cisplatin as a promising therapeutic approach for treating LUSC.

肺鳞状细胞癌（LUSCs）死亡率高（20%-30%），且缺乏有效的治疗方法。几乎所有肺鳞状细胞癌都表现出 TP53 的体细胞突变。Wee1是一种酪氨酸激酶，在G2/M检查点调节细胞周期。在 TP53 缺失的细胞中，对 G2/M 检查点的依赖性增加。PD0166285 是首个报道的同时对 Wee1 和 PKMYT1 具有抑制活性的药物。蛋白表达通过 Western 印迹分析确定。细胞增殖采用细胞集落形成和 CCK-8 检测法进行评估。细胞周期通过流式细胞仪进行 PI 染色。细胞凋亡通过 Annexin V-Phycoerythrin 双染色和流式细胞仪进行评估。DNA 损伤通过彗星试验和免疫荧光试验进行检测。体内凋亡和抗肿瘤效果通过 TUNEL 试验、裸鼠模型和免疫组织化学（IHC）进行评估。共免疫共沉淀试验用于检测蛋白质与蛋白质之间的相互作用。我们利用 Ualcan 公共数据库分析了泛癌症研究中 Wee1、PKMYT1 和 Stat1 的表达情况，并利用 Kaplan-Meier 曲线评估了它们对预后的影响。Wee1抑制剂PD0166285能有效抑制Wee1的活性，促进细胞进入有丝分裂危机。此外，PD0166285还能使细胞对顺铂敏感，从而提高临床疗效。我们的研究表明，PD016628 通过 Rad51 调节细胞周期，导致细胞周期停滞在 G2/M 期。我们观察到用 PD0166285 治疗的肿瘤细胞凋亡增加，尤其是与顺铂联合治疗时，表明凋亡反应增强。γ-H2AX 的上调可作为有丝分裂灾难的指标。共免疫沉淀和数据分析显示，LUSC 的细胞凋亡是通过 Stat1 途径介导的，同时伴随着 Socs3 水平的降低。此外，IHC 染色证实，LUSCs 中 Phospho-CDK1 和 γ-H2AX 的表达存在显著差异，表明其参与了 DNA 损伤。总之，我们的研究表明，Wee1抑制剂PD0166285可使LUSC细胞对顺铂敏感，并分别通过Rad51和Stat1调节DNA损伤和凋亡通路。这些研究结果突出表明，PD0166285与顺铂的结合是治疗LUSC的一种很有前景的治疗方法。

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引用次数: 0

Sialylation-associated long non-coding RNA signature predicts the prognosis, tumor microenvironment, and immunotherapy and chemotherapy options in uterine corpus endometrial carcinoma Sialylation相关长非编码RNA特征可预测子宫内膜癌的预后、肿瘤微环境以及免疫疗法和化疗方案

IF 5.8 2区医学 Q1 ONCOLOGY

Cancer Cell International

Pub Date : 2024-09-11 DOI: 10.1186/s12935-024-03486-z

Jun Chen, Tingting Wu, Yongwen Yang

Sialylation in uterine corpus endometrial carcinoma (UCEC) differs significantly from apoptotic and ferroptosis pathways. It plays a crucial role in cancer progression and immune response modulation. Exploring how sialylation affects tumor behavior and its link with long non-coding RNAs (lncRNAs) may provide new insights into UCEC prognosis and treatment. We obtained RNA transcriptome, clinical, and mutation data of UCEC samples from the TCGA database. Our approach involved developing a risk model based on the co-expression patterns of sialylation genes and lncRNAs. Prognostic lncRNAs were identified through Cox regression and further refined using LASSO analysis. To understand the biological functions and pathways of model-associated differentially expressed genes (MADEGs), we conducted enrichment analyses. We also assessed the immune infiltration status of MADEGs using eight different algorithms, which helped in evaluating the potential for immunotherapy. Additionally, we validated the expression of these lncRNAs in UCEC using cell lines and clinical samples. We developed a UCEC risk model using five sialylation-related lncRNAs (AC004884.2, AC026202.2, LINC01579, LINC00942, SLC16A1-AS1). This model, confirmed through Cox analysis and clinical evaluation, effectively predicted patient outcomes. Survival data analysis across entire cohort, as well as within training and test groups, indicated better survival in low-risk UCEC patients. Enrichment analyses linked MADEGs to sialylation functions and cancer pathways. High-risk patients showed increased responsiveness to immune checkpoint inhibitors (ICIs), as indicated by immunological assessments. Subgroup C2 patients showed superior outcomes and a robust response to immunotherapy and chemotherapy. Notably, LINC01579, LINC00942, and SLC16A1-AS1 were significantly overexpressed in UCEC clinical tumor samples as well as in Ishikawa and HEC-1-B cell lines, compared to the normal groups. This lncRNA signature associated with sialylation could guide prognosis, enhance the understanding of molecular mechanisms, and inform treatment strategies in UCEC. It highlights the potential for the use of ICIs and chemotherapy.

子宫内膜癌（UCEC）中的硅氨酰化与凋亡和铁凋亡途径有很大不同。它在癌症进展和免疫反应调节中起着至关重要的作用。探索Sialylation如何影响肿瘤行为及其与长非编码RNA（lncRNA）之间的联系可能会为UCEC的预后和治疗提供新的见解。我们从 TCGA 数据库中获得了 UCEC 样本的 RNA 转录组、临床和突变数据。我们的方法是根据硅烷化基因和lncRNA的共同表达模式建立一个风险模型。通过Cox回归确定了预后性lncRNA，并利用LASSO分析进一步完善了这些lncRNA。为了了解模型相关差异表达基因（MADEGs）的生物学功能和通路，我们进行了富集分析。我们还使用八种不同的算法评估了 MADEG 的免疫浸润状态，这有助于评估免疫疗法的潜力。此外，我们还利用细胞系和临床样本验证了这些 lncRNA 在 UCEC 中的表达。我们利用五个与ialylation相关的lncRNA（AC004884.2、AC026202.2、LINC01579、LINC00942、SLC16A1-AS1）建立了一个UCEC风险模型。经 Cox 分析和临床评估证实，该模型能有效预测患者的预后。对整个队列以及训练组和测试组的生存数据分析显示，低风险 UCEC 患者的生存率更高。富集分析将 MADEGs 与糖基化功能和癌症通路联系起来。免疫学评估显示，高风险患者对免疫检查点抑制剂（ICIs）的反应性增强。C2 亚组患者的疗效更优，对免疫疗法和化疗的反应更强。值得注意的是，与正常组相比，LINC01579、LINC00942和SLC16A1-AS1在UCEC临床肿瘤样本以及石川和HEC-1-B细胞系中显著过表达。这种与ialylation相关的lncRNA特征可以指导UCEC的预后，加深对分子机制的理解，并为治疗策略提供依据。它凸显了使用 ICIs 和化疗的潜力。

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引用次数: 0

Long-term zinc treatment alters the mechanical properties and metabolism of prostate cancer cells 长期锌处理可改变前列腺癌细胞的机械特性和新陈代谢

IF 5.8 2区医学 Q1 ONCOLOGY

Cancer Cell International

Pub Date : 2024-09-11 DOI: 10.1186/s12935-024-03495-y

Jiri Navratil, Monika Kratochvilova, Martina Raudenska, Jan Balvan, Tomas Vicar, Katerina Petrlakova, Kanako Suzuki, Lucie Jadrna, Jiri Bursa, Martin Kräter, Kyoohyun Kim, Michal Masarik, Jaromir Gumulec

The failure of intracellular zinc accumulation is a key process in prostate carcinogenesis. Although prostate cancer cells can accumulate zinc after long-term exposure, chronic zinc oversupply may accelerate prostate carcinogenesis or chemoresistance. Because cancer progression is associated with energetically demanding cytoskeletal rearrangements, we investigated the effect of long-term zinc presence on biophysical parameters, ATP production, and EMT characteristics of two prostate cancer cell lines (PC-3, 22Rv1). Prolonged exposure to zinc increased ATP production, spare respiratory capacity, and induced a response in PC-3 cells, characterized by remodeling of vimentin and a shift of cell dry mass density and caveolin-1 to the perinuclear region. This zinc-induced remodeling correlated with a greater tendency to maintain actin architecture despite inhibition of actin polymerization by cytochalasin. Zinc partially restored epithelial characteristics in PC-3 cells by decreasing vimentin expression and increasing E-cadherin. Nevertheless, the expression of E-cadherin remained lower than that observed in predominantly oxidative, low-invasive 22Rv1 cells. Following long-term zinc exposure, we observed an increase in cell stiffness associated with an increased refractive index in the perinuclear region and an increased mitochondrial content. The findings of the computational simulations indicate that the mechanical response cannot be attributed exclusively to alterations in cytoskeletal composition. This observation suggests the potential involvement of an additional, as yet unidentified, mechanical contributor. These findings indicate that long-term zinc exposure alters a group of cellular parameters towards an invasive phenotype, including an increase in mitochondrial number, ATP production, and cytochalasin resistance. Ultimately, these alterations are manifested in the biomechanical properties of the cells.

细胞内锌积累失败是前列腺癌发生的一个关键过程。虽然前列腺癌细胞在长期接触锌后可以积累锌，但长期锌过量供应可能会加速前列腺癌的发生或化疗耐药性。由于癌症进展与高能量的细胞骨架重排有关，我们研究了锌的长期存在对两种前列腺癌细胞系（PC-3、22Rv1）的生物物理参数、ATP生成和EMT特征的影响。长期接触锌会增加 ATP 的产生、剩余呼吸能力，并诱导 PC-3 细胞产生反应，其特征是波形蛋白重塑、细胞干物质密度和洞穴素-1 转移到核周区域。这种锌诱导的重塑与维持肌动蛋白结构的更大趋势相关，尽管细胞松抑制了肌动蛋白的聚合。锌通过减少波形蛋白的表达和增加 E-cadherin，部分恢复了 PC-3 细胞的上皮特征。尽管如此，E-cadherin 的表达仍然低于在以氧化为主的低侵袭性 22Rv1 细胞中观察到的表达。长期锌暴露后，我们观察到细胞硬度增加，这与核周折射率增加和线粒体含量增加有关。计算模拟的结果表明，机械反应不能完全归因于细胞骨架组成的改变。这一观察结果表明，还有一种尚未确定的机械因素可能参与其中。这些研究结果表明，长期锌暴露会改变一组细胞参数，使其趋向侵袭性表型，包括线粒体数量、ATP 产量和细胞松素抗性的增加。这些改变最终体现在细胞的生物力学特性上。

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引用次数: 0

Exosome-mediated transfer of lncRNA RP3-340B19.3 promotes the progression of breast cancer by sponging miR-4510/MORC4 axis 外泌体介导的lncRNA RP3-340B19.3通过疏导miR-4510/MORC4轴促进乳腺癌的进展

IF 5.8 2区医学 Q1 ONCOLOGY

Cancer Cell International

Pub Date : 2024-09-10 DOI: 10.1186/s12935-024-03490-3

Bo Wang, Jiahui Mao, Linxia Wang, Yuexin Zhao, Bingying Wang, Huan Yang

This study aims to explore the molecular mechanism of lncRNA RP3-340B19.3 on breast cancer cell proliferation and metastasis and clinical significance of lncRNA RP3-340B19.3 for breast cancer. The subcellular localization of lncRNA RP3-340B19.3 was identified using RNA fluorescence in situ hybridization (FISH). The expression of lncRNA RP3-340B19.3 in breast cancer cells, breast cancer tissues, as well as the serum and serum exosomes of breast cancer patients, was measured through quantitative RT-PCR. In the in vitro setting, we conducted experiments to observe the effects of RP3-340B19.3 on both cell migration and proliferation. This was achieved through the utilization of transwell migration assays as well as clone formation assays. Meanwhile, transwell migration assays and clone formation assays were used to observe the effects of MDA-MB-231-exosomes enriched in RP3-340B19.3 on breast cancer microenvironment cells MCF7 and BMMSCs. Additionally, western blotting techniques were used to assess the expression levels of proteins associated with essential cellular processes such as proliferation, apoptosis, and metastasis. In vivo, the impact of RP3-340B19.3 knockdown on tumour weight and volume was observed within a nude mice model. We aimed to delve into the intricate molecular mechanisms involving RP3-340B19.3 by using bioinformatics analysis, dual luciferase reporter gene experiments and western blotting. Moreover, the potential correlations between RP3-340B19.3 expression and various clinical pathological characteristics were analyzed. Our investigation revealed that RP3-340B19.3 was expressed in both the cytoplasm and nucleus, with a noteworthy increase in breast cancer cells. Notably, we found that RP3-340B19.3 exerted a promoting influence on the proliferation and migration of breast cancer cells, both in vitro and in vivo. MDA-MB-231-exosomes enriched in RP3-340B19.3 promoted the proliferation and migration of MCF7 and BMMSCs in vitro. Mechanistically, RP3-340B19.3 demonstrated the capability to modulate the expression of MORC4 by forming a complex with miR-4510. This interaction subsequently triggered the activation of the NF-κB and Wnt-β-catenin signaling pathways. Furthermore, our study highlighted the potential diagnostic utility of RP3-340B19.3. We discovered its presence in the serum and exosomes of breast cancer patients, showing promising efficacy as a diagnostic marker. Notably, the diagnostic potential of RP3-340B19.3 was particularly significant in relation to distinguishing between different pathological types of breast cancer and correlating with tumour diameter. Our findings establish that RP3-340B19.3 plays a pivotal role in driving the proliferation and metastasis of breast cancer. Additionally, exosomes enriched in RP3-340B19.3 could influence MCF7 and BMMSCs in tumour microenvironment, promoting the progression of breast cancer. This discovery positions RP3-340B19.3 as a prospective novel candidate for a tumour marker, of

本研究旨在探讨lncRNA RP3-340B19.3对乳腺癌细胞增殖和转移的分子机制，以及lncRNA RP3-340B19.3对乳腺癌的临床意义。利用RNA荧光原位杂交（FISH）技术确定了lncRNA RP3-340B19.3的亚细胞定位。通过RT-PCR定量检测了lncRNA RP3-340B19.3在乳腺癌细胞、乳腺癌组织以及乳腺癌患者血清和血清外泌体中的表达。在体外实验中，我们观察了 RP3-340B19.3 对细胞迁移和增殖的影响。这是通过使用经孔迁移试验和克隆形成试验来实现的。同时，还使用了经孔迁移试验和克隆形成试验来观察富含 RP3-340B19.3 的 MDA-MB-231 外泌体对乳腺癌微环境细胞 MCF7 和 BMMSCs 的影响。此外，还使用了 Western 印迹技术来评估与增殖、凋亡和转移等重要细胞过程相关的蛋白质的表达水平。在裸鼠模型中，我们观察了 RP3-340B19.3 基因敲除对肿瘤重量和体积的影响。我们的目的是通过生物信息学分析、双荧光素酶报告基因实验和 Western 印迹法，深入研究涉及 RP3-340B19.3 的复杂分子机制。此外，我们还分析了RP3-340B19.3的表达与各种临床病理特征之间的潜在相关性。我们的研究发现，RP3-340B19.3 在细胞质和细胞核中均有表达，在乳腺癌细胞中的表达量显著增加。值得注意的是，我们发现 RP3-340B19.3 在体外和体内都对乳腺癌细胞的增殖和迁移有促进作用。富含 RP3-340B19.3 的 MDA-MB-231 外泌体在体外促进了 MCF7 和 BMMSCs 的增殖和迁移。从机理上讲，RP3-340B19.3 能通过与 miR-4510 形成复合物来调节 MORC4 的表达。这种相互作用随后引发了 NF-κB 和 Wnt-β-catenin 信号通路的激活。此外，我们的研究还强调了 RP3-340B19.3 的潜在诊断作用。我们发现它存在于乳腺癌患者的血清和外泌体中，显示出作为诊断标记物的良好疗效。值得注意的是，RP3-340B19.3 的诊断潜力在区分不同病理类型的乳腺癌以及与肿瘤直径相关方面尤为显著。我们的研究结果表明，RP3-340B19.3 在乳腺癌的扩散和转移过程中起着关键作用。此外，富含 RP3-340B19.3 的外泌体可影响肿瘤微环境中的 MCF7 和 BMMSC，促进乳腺癌的进展。这一发现将 RP3-340B19.3 定位为肿瘤标志物的潜在新候选者，为乳腺癌诊断和治疗策略提供了巨大的潜力。

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引用次数: 0

Pan-cancer analysis reveals CCL5/CSF2 as potential predictive biomarkers for immune checkpoint inhibitors 泛癌症分析发现 CCL5/CSF2 是免疫检查点抑制剂的潜在预测性生物标记物

IF 5.8 2区医学 Q1 ONCOLOGY

Cancer Cell International

Pub Date : 2024-09-10 DOI: 10.1186/s12935-024-03496-x

Yi-Chao Chen, Wei-Zhong Zheng, Chun-Peng Liu, Yong-Qiang Zhao, Jun-Wei Li, Ze-Sen Du, Tian-Tian Zhai, Hao-Yu Lin, Wen-Qi Shi, Shan-Qing Cai, Feng Pan, Si-Qi Qiu

Currently, there are no optimal biomarkers available for distinguishing patients who will respond to immune checkpoint inhibitors (ICIs) therapies. Consequently, the exploration of novel biomarkers that can predict responsiveness to ICIs is crucial in the field of immunotherapy. We estimated the proportions of 22 immune cell components in 10 cancer types (6,128 tumors) using the CIBERSORT algorithm, and further classified patients based on their tumor immune cell proportions in a pan-cancer setting using k-means clustering. Differentially expressed immune genes between the patient subgroups were identified, and potential predictive biomarkers for ICIs were explored. Finally, the predictive value of the identified biomarkers was verified in patients with urothelial carcinoma (UC) and esophageal squamous cell carcinoma (ESCC) who received ICIs. Our study identified two subgroups of patients with distinct immune infiltrating phenotypes and differing clinical outcomes. The patient subgroup with improved outcomes displayed tumors enriched with genes related to immune response regulation and pathway activation. Furthermore, CCL5 and CSF2 were identified as immune-related hub-genes and were found to be prognostic in a pan-cancer setting. Importantly, UC and ESCC patients with high expression of CCL5 and low expression of CSF2 responded better to ICIs. We demonstrated CCL5 and CSF2 as potential novel biomarkers for predicting the response to ICIs in patients with UC and ESCC. The predictive value of these biomarkers in other cancer types warrants further evaluation in future studies.

目前，还没有最佳的生物标志物来区分哪些患者会对免疫检查点抑制剂（ICIs）疗法产生反应。因此，探索能预测对 ICIs 反应性的新型生物标记物在免疫疗法领域至关重要。我们使用CIBERSORT算法估算了10种癌症类型（6128个肿瘤）中22种免疫细胞成分的比例，并在泛癌症环境中使用k-means聚类方法根据肿瘤免疫细胞比例对患者进行了进一步分类。确定了患者亚组之间表达不同的免疫基因，并探索了 ICIs 的潜在预测生物标志物。最后，在接受 ICIs 治疗的尿路上皮癌（UC）和食管鳞状细胞癌（ESCC）患者中验证了所发现的生物标志物的预测价值。我们的研究发现了两个具有不同免疫浸润表型和不同临床结果的患者亚组。预后较好的患者亚群的肿瘤富含与免疫反应调节和通路激活相关的基因。此外，CCL5和CSF2被确定为免疫相关的枢纽基因，并被发现在泛癌症环境中具有预后作用。重要的是，CCL5 高表达和 CSF2 低表达的 UC 和 ESCC 患者对 ICIs 的反应更好。我们证明了 CCL5 和 CSF2 是预测 UC 和 ESCC 患者对 ICIs 反应的潜在新型生物标记物。这些生物标志物在其他癌症类型中的预测价值值得在未来的研究中进一步评估。

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引用次数: 0

A novel risk stratification approach and molecular subgroup characterization based on coagulation related genes in colon adenocarcinoma 基于结肠腺癌凝血相关基因的新型风险分层方法和分子亚组特征描述

IF 5.8 2区医学 Q1 ONCOLOGY

Cancer Cell International

Pub Date : 2024-09-09 DOI: 10.1186/s12935-024-03491-2

Xiangxin Wu, Lichong Zhu, Xizhe Sun, Mingyu Xia, Shihui Zhao, Bomiao Zhang, Tianyi Xia

Colon adenocarcinoma (COAD) represents a significant health concern within the population. Advancing our understanding of COAD is imperative for early detection, enabling personalized treatment interventions, and facilitating the development of effective preventive measures. The coagulation system plays a role in tumor-related pathological processes; however, its specific involvement in COAD and potential contributors remain unclear. This study aimed to establish a novel risk stratification approach by analyzing coagulation related genes (CRGs) associated with COAD. Through a comprehensive bioinformatics analysis of data from public databases, we screened COAD associated CRGs and characterized the associated molecular subtypes. After a comprehensive analysis of the characteristics of each subtype, we applied differentially expressed genes in CRG subtypes to establish a new risk stratification method. Clinical subgroup analysis, immunoinfiltration analysis, therapeutic reactivity prediction and other analytical methods suggest the potential clinical value of the established risk stratification method. As one of the selected targets, the effect of MS4A4A on the proliferation and invasion of COAD was confirmed by in vitro experiments, which partially verified the reliability of bioinformatics results. Our findings delineate CRGs potentially implicated in COAD pathogenesis and offer fresh insights into the influence of the coagulation process on tumorigenesis and progression.

结肠腺癌（COAD）是人类健康的一大隐患。加深对结肠腺癌的了解对于早期发现、实现个性化治疗干预以及促进有效预防措施的开发至关重要。凝血系统在与肿瘤相关的病理过程中起着一定的作用；然而，凝血系统在 COAD 中的具体参与情况和潜在诱因仍不清楚。本研究旨在通过分析与 COAD 相关的凝血相关基因 (CRG)，建立一种新的风险分层方法。通过对来自公共数据库的数据进行全面的生物信息学分析，我们筛选出了与 COAD 相关的 CRGs，并确定了相关分子亚型的特征。在对每种亚型的特征进行综合分析后，我们应用 CRG 亚型中的差异表达基因建立了一种新的风险分层方法。临床亚组分析、免疫渗透分析、治疗反应性预测和其他分析方法表明，所建立的风险分层方法具有潜在的临床价值。作为选定的靶点之一，MS4A4A对COAD增殖和侵袭的影响通过体外实验得到了证实，这在一定程度上验证了生物信息学结果的可靠性。我们的研究发现了可能与 COAD 发病机制有关的 CRGs，并为凝血过程对肿瘤发生和发展的影响提供了新的见解。

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引用次数: 0

A comprehensive prognostic and immunological implications of PFKP in pan-cancer PFKP 在泛癌症中的综合预后和免疫学意义

IF 5.8 2区医学 Q1 ONCOLOGY

Cancer Cell International

Pub Date : 2024-09-09 DOI: 10.1186/s12935-024-03497-w

Xiaodong Ling, Luquan Zhang, Chengyuan Fang, Hao Liang, Jianqun Ma

Phosphofructokinase P (PFKP) is a key rate-limiting enzyme in glycolysis, playing a crucial role in various pathophysiological processes. However, its specific function in tumors remains unclear. This study aims to evaluate the expression and specific role of PFKP across multiple tumor types (Pan-cancer) and to explore its potential clinical significance as a therapeutic target in cancer treatment. We analyzed the expression of PFKP, immune cell infiltration, and patient prognosis across various cancers using data from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Additionally, we conducted a series of experiments in lung cancer cells, including Western blot, CCK-8 assay, colony formation assay, transwell migration assay, scratch wound healing assay, LDH release assay, and flow cytometry, to evaluate the impact of PFKP on tumor cells. PFKP was found to be highly expressed in most cancers and identified as a prognostic risk factor. Elevated PFKP expression is associated with poorer clinical outcomes, particularly in lung adenocarcinoma (LUAD). Receiver operating characteristic (ROC) curve analysis indicated that PFKP can effectively differentiate between cancerous and normal tissues. The expression of PFKP in most tumors showed significant correlations with tumor mutational burden (TMB), microsatellite instability (MSI), immune score, and immune cell infiltration. In vitro experiments demonstrated that PFKP overexpression promotes lung cancer cell proliferation and migration while inhibiting apoptosis, whereas PFKP deficiency results in the opposite effects. PFKP acts as an oncogene involved in tumorigenesis and may influence the immune microenvironment within the tumor. Our findings suggest that PFKP could serve as a potential biomarker for predicting prognosis and the efficacy of immunotherapy in tumors.

磷酸果激酶 P（PFKP）是糖酵解过程中的一种关键限速酶，在各种病理生理过程中发挥着至关重要的作用。然而，它在肿瘤中的具体功能仍不清楚。本研究旨在评估 PFKP 在多种肿瘤类型（泛癌）中的表达和特定作用，并探讨其作为癌症治疗靶点的潜在临床意义。我们利用癌症基因组图谱（TCGA）和基因表达总库（GEO）数据库中的数据分析了各种癌症中 PFKP 的表达、免疫细胞浸润和患者预后。此外，我们还在肺癌细胞中进行了一系列实验，包括 Western 印迹、CCK-8 检测、集落形成检测、Transwell 迁移检测、划痕伤口愈合检测、LDH 释放检测和流式细胞术，以评估 PFKP 对肿瘤细胞的影响。研究发现，PFKP 在大多数癌症中高度表达，并被确定为预后风险因素。PFKP 表达升高与较差的临床预后有关，尤其是在肺腺癌（LUAD）中。接收操作特征曲线（ROC）分析表明，PFKP 能有效区分癌组织和正常组织。大多数肿瘤中 PFKP 的表达与肿瘤突变负荷（TMB）、微卫星不稳定性（MSI）、免疫评分和免疫细胞浸润有显著相关性。体外实验表明，PFKP 过度表达会促进肺癌细胞的增殖和迁移，同时抑制细胞凋亡，而 PFKP 缺乏则会导致相反的效果。PFKP 是一种参与肿瘤发生的癌基因，可能会影响肿瘤内的免疫微环境。我们的研究结果表明，PFKP 可作为预测肿瘤预后和免疫疗法疗效的潜在生物标记物。

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引用次数: 0

GALNT6 promotes bladder cancer malignancy and immune escape by epithelial-mesenchymal transition and CD8⁺ T cells. GALNT6 通过上皮-间充质转化和 CD8+ T 细胞促进膀胱癌恶变和免疫逃逸。

IF 5.3 2区医学 Q1 ONCOLOGY

Cancer Cell International

Pub Date : 2024-09-08 DOI: 10.1186/s12935-024-03492-1

Xiaoxin Sun, Haotian Wu, Ling Tang, Abdullah Al-Danakh, Yuli Jian, Li Gong, Congchen Li, Xiao Yu, Guang Zeng, Qiwei Chen, Deyong Yang, Shujing Wang

Bladder cancer (BC) ranks as the sixth cancer in males and the ninth most common cancer worldwide. Conventional treatment modalities, including surgery, radiation, chemotherapy, and immunotherapy, have limited efficacy in certain advanced instances. The involvement of GALNT6-mediated aberrant O-glycosylation modification in several malignancies and immune evasion is a subject of speculation. However, its significance in BC has not been investigated. Through the integration of bioinformatics analysis and laboratory experimentation, we have successfully clarified the role of GALNT6 in BC. Our investigation revealed that GALNT6 has significant expression in BC, and its high expression level correlates with advanced stage and high grade, leading to poor overall survival. Moreover, both in vitro and in vivo experiments demonstrate a strong correlation between elevated levels of GALNT6 and tumor growth, migration, and invasion. Furthermore, there is a negative correlation between elevated GALNT6 levels, the extent of CD8⁺ T cell infiltration in the tumor microenvironment, and the prognosis of patients. Functional experiments have shown that the increased expression of GALNT6 could enhance the malignant characteristics of cancer cells by activating the epithelial-mesenchymal transition (EMT) pathway. In brief, this study examined the impact of GALNT6-mediated abnormal O-glycosylation on the occurrence and progression of bladder cancer and its influence on immune evasion. It also explored the possible molecular mechanism underlying the interaction between tumor cells and immune cells, as well as the bidirectional signaling involved. These findings offer a novel theoretical foundation rooted in glycobiology for the clinical application of immunotherapy in BC.

膀胱癌（BC）是男性第六大癌症，也是全球第九大常见癌症。传统的治疗方式，包括手术、放疗、化疗和免疫疗法，在某些晚期病例中疗效有限。GALNT6介导的异常O-糖基化修饰参与多种恶性肿瘤和免疫逃避是一个猜测的主题。然而，其在 BC 中的重要性尚未得到研究。通过整合生物信息学分析和实验室实验，我们成功地阐明了 GALNT6 在 BC 中的作用。我们的研究发现，GALNT6在BC中有显著表达，其高水平表达与晚期和高分级相关，导致总生存率低下。此外，体外和体内实验均表明，GALNT6 水平的升高与肿瘤的生长、迁移和侵袭密切相关。此外，GALNT6 水平的升高、肿瘤微环境中 CD8+ T 细胞的浸润程度与患者的预后呈负相关。功能实验表明，GALNT6 表达的增加可通过激活上皮-间质转化（EMT）途径增强癌细胞的恶性特征。简而言之，本研究探讨了 GALNT6 介导的异常 O 型糖基化对膀胱癌发生和发展的影响，以及其对免疫逃避的影响。研究还探讨了肿瘤细胞与免疫细胞之间相互作用的可能分子机制，以及其中涉及的双向信号转导。这些发现为免疫疗法在膀胱癌中的临床应用提供了植根于糖生物学的新理论基础。

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引用次数: 0

Hypoxia-induced BAP1 enhances erastin-induced ferroptosis in nasopharyngeal carcinoma by stabilizing H2A. 缺氧诱导的 BAP1 可通过稳定 H2A 增强依拉斯汀诱导的鼻咽癌铁突变。

IF 5.3 2区医学 Q1 ONCOLOGY

Cancer Cell International

Pub Date : 2024-09-08 DOI: 10.1186/s12935-024-03494-z

Weisong Cai, Sa Wu, Zehua Lin, Xiaoping Ming, Xiuping Yang, Minlan Yang, Xiong Chen

Background: Hypoxia plays an important role in the chemotherapy resistance of nasopharyngeal carcinoma (NPC). Ferroptosis is a newly discovered form of programmed cell death and ferroptosis inducers showed promising therapeutic effects in some cancers. However, the sensibility of NPC cells to ferroptosis under the hypoxic microenvironment is still unclear, and this study was designed to clarify it.

Methods: NPC cells, treated with erastin, were placed in a normoxia or hypoxic environment (5% CO₂, 94% N₂ and 1% O₂) at 37℃for 24 h. After exposed to hypoxia, ferroptosis-associated phenotypes were detected by CCK8, MDA, GSH, lipid ROS and Fe. The gene expression profiles of head and neck squamous cell carcinoma (HNSCC) tissues were downloaded from the TCGA database to screen construction molecule. BAP1 was screened out and its functions on erastin-induced ferroptosis in NPC cells were detected by knockdown of BAP1. Luciferase reporter assay and co-IP experiment were performed to explore the molecular mechanism. Finally, the tumour xenograft model was applied to further verify these results in vivo.

Results: CCK8 assay showed that IC₅₀ of NPC cells treated with erastin under hypoxia was significantly lower than that under normoxia. Hypoxia significantly increased the levels of lipid ROS and MDA, and decreased GSH content induced by erastin. A prognostic risk model for HNSCC with six ferroptosis-related genes was constructed and validated based on TCGA database. BAP1 was significantly up-regulated under hypoxia, and luciferase reporter assay showed that HIF-1α was an upstream transcription regulator of BAP1. Knockdown of BAP1 in NPC cells significantly increased the IC₅₀ value of erastin under hypoxia and significantly ameliorated erastin-induced ferroptosis under hypoxia in aspect of lipid ROS, MDA content and GSH. Co-IP results showed that BAP1 mediated deubiquitination of H2A and decreased SLC7A11 expression. Finally, knockdown of BAP1 reduced sensitivity to erastin-induced ferroptosis in a tumour xenograft model. And the level of H2A was significantly decreased in xenograft tumors of BAP1 knockdown cells.

Conclusion: Hypoxia-induced BAP1 enhances erastin-induced ferroptosis in NPC by stabilizing H2A. Ferroptosis inducers targeting BAP1 may be an effective way to improve chemotherapy resistance in NPC, especially in the hypoxic microenvironment.

背景：缺氧在鼻咽癌（NPC）的化疗耐药性中起着重要作用。铁突变是一种新发现的细胞程序性死亡形式，铁突变诱导剂在一些癌症中显示出良好的治疗效果。然而，NPC细胞在缺氧微环境下对铁突变的敏感性仍不清楚，本研究旨在澄清这一点：将经依拉斯汀处理的鼻咽癌细胞置于37℃的常氧或缺氧环境（5% CO2、94% N2和1% O2）中24小时。从 TCGA 数据库下载了头颈部鳞状细胞癌（HNSCC）组织的基因表达谱，以筛选构建分子。筛选出了 BAP1，并通过敲除 BAP1 检测了其在麦拉宁诱导的鼻咽癌细胞铁突变中的功能。通过荧光素酶报告实验和co-IP实验来探索其分子机制。最后，应用肿瘤异种移植模型在体内进一步验证了这些结果：结果：CCK8测定显示，在缺氧条件下，用依拉斯汀处理的鼻咽癌细胞的IC50明显低于正常缺氧条件下的IC50。结果：CCK8测定显示，缺氧条件下，厄拉斯汀处理的鼻咽癌细胞的IC50明显低于正常缺氧条件下的IC50。基于TCGA数据库，构建并验证了包含6个铁蛋白沉积相关基因的HNSCC预后风险模型。BAP1在缺氧条件下明显上调，荧光素酶报告实验表明HIF-1α是BAP1的上游转录调控因子。在鼻咽癌细胞中敲除 BAP1 能明显提高厄拉斯汀在缺氧条件下的 IC50 值，并在脂质 ROS、MDA 含量和 GSH 方面明显改善厄拉斯汀在缺氧条件下诱导的铁变态反应。Co-IP 结果显示，BAP1 介导了 H2A 的去泛素化，并降低了 SLC7A11 的表达。最后，在肿瘤异种移植模型中，敲除 BAP1 可降低对厄拉斯汀诱导的铁变态反应的敏感性。结论：缺氧诱导的BAP1在肿瘤异种移植模型中降低了对依拉斯汀诱导的铁突变的敏感性：缺氧诱导的BAP1通过稳定H2A增强了厄拉斯汀诱导的鼻咽癌铁变态反应。

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引用次数: 0