Translational Oncology最新文献_第5页

AVIL promotes osteosarcoma progression and cisplatin resistance via ARP2/3-mediated DNA damage repair AVIL通过arp2 /3介导的DNA损伤修复促进骨肉瘤进展和顺铂耐药。

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2026-02-01 Epub Date: 2026-01-06 DOI: 10.1016/j.tranon.2025.102654

Zhenyi Chen , Guozhu Tang , Xuan Lv , Guoqing Ding, Mingyang Huang, Zhe Chen, Shuo Dai, Huilin Liu, Sheng Zhang, Lin Cai

Osteosarcoma (OS) is the most common primary malignant tumor of bone that commonly occurs in adolescents with poor prognosis. Neoadjuvant chemotherapy with the MAP regimen (high-dose methotrexate (Methotrexate), doxorubicin, and cisplatin) is essential for the standardized OS therapeutic, the good response of which critically exceeds the patient survival. However, approximately 30–40 % of patients develop chemoresistance, leading to metastatic disease or recurrence. Understanding the molecular mechanisms underlying chemoresistance is crucial for improving clinical outcomes. In this study, AVIL was identified as a key gene correlated with OS progression and chemoresistance. AVIL overexpression was found to promote OS progression in vitro and in vivo by enhancing cell proliferation, migration, and invasion, while AVIL deficiency exerted the inverse phenotypes. In vivo experiments further confirmed that AVIL overexpression promotes tumor growth and suppresses apoptosis. Mechanistically, AVIL interacts with the ARP2/3 complex, a key regulator of DNA damage repair via actin polymerization and cytoskeletal dynamics. This interaction was confirmed to facilitate cisplatin resistance, with reduced DNA damage response and increased cell survival caused by AVIL overexpression. Furthermore, using patient-derived organoid (PDO) models, we demonstrated that CK666, an ARP2/3 inhibitor, enhanced the chemotherapy efficacy of cisplatin by increasing DNA damage response and reversing AVIL-mediated cisplatin resistance. These findings highlight AVIL as a potential therapeutic target and suggest that targeting the AVIL-ARP2/3 axis could serve as an alternative strategy to overcome chemoresistance during OS treatment.

骨肉瘤（Osteosarcoma， OS）是最常见的原发性骨恶性肿瘤，常见于青少年，预后较差。MAP方案（高剂量甲氨蝶呤、阿霉素和顺铂）的新辅助化疗对于标准化的OS治疗至关重要，其良好的反应严重超过了患者的生存期。然而，大约30- 40%的患者出现化疗耐药，导致转移性疾病或复发。了解化疗耐药的分子机制对改善临床结果至关重要。在本研究中，AVIL被确定为与OS进展和化疗耐药相关的关键基因。研究发现，在体外和体内，AVIL过表达可以通过增强细胞增殖、迁移和侵袭来促进OS的进展，而AVIL缺乏则会产生相反的表型。体内实验进一步证实，AVIL过表达可促进肿瘤生长，抑制细胞凋亡。在机制上，AVIL与ARP2/3复合物相互作用，ARP2/3复合物是通过肌动蛋白聚合和细胞骨架动力学进行DNA损伤修复的关键调节因子。这种相互作用被证实促进顺铂耐药，降低DNA损伤反应，增加AVIL过表达引起的细胞存活率。此外，通过患者源性类器官（PDO）模型，我们证明了ARP2/3抑制剂CK666通过增加DNA损伤反应和逆转avil介导的顺铂耐药来增强顺铂的化疗疗效。这些发现强调了AVIL作为一个潜在的治疗靶点，并表明靶向AVIL- arp2 /3轴可以作为在OS治疗期间克服化疗耐药的替代策略。

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引用次数: 0

First functional evidence that a rare germline TP53β variant drives senescence-associated immune suppression and impairs apoptosis and cell migration in breast cancer patients 在乳腺癌患者中，一种罕见的种系TP53β变异驱动衰老相关的免疫抑制并损害细胞凋亡和细胞迁移的第一个功能证据。

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2026-02-01 Epub Date: 2026-01-06 DOI: 10.1016/j.tranon.2025.102616

Claudia Christowitz , Daniel W Olivier , Nicole van der Merwe , Maritha J Kotze , Anna-Mart Engelbrecht

Introduction

Pathology-supported genetic testing (PSGT), a personalized medicine framework established in South Africa, led to the identification of a rare germline tumour suppressor protein 53 (TP53) beta-isoform (β) variant (NM_001126114.3, c.1018A>G, p.N340D) in a family with the Li-Fraumeni-like syndrome. While protein modeling predicted structural alterations consistent with impaired function, its pathogenicity remained unclear.

Aim

To determine the functional impact of the TP53β N340D variant on cell proliferation, cell death, senescence, migration, and anti-tumour activity using a translational ex vivo model.

Methods

Peripheral blood mononuclear cells (PBMCs) were isolated from female controls and breast cancer patients, with or without the TP53β N340D variant. Lipopolysaccharide (LPS)- and phytohemagglutinin-L (PHA-L)-stimulated proliferation was evaluated by a water-soluble tetrazolium 1 (WST-1) assay. Doxorubicin (DXR)-induced cell death was assessed using a WST-1 assay, flow cytometry, and western blotting. A senescence-associated beta-galactosidase assay and western blotting determined senescence. Migration and anti-tumour activity were assessed using a Transwell assay and co-culturing PBMCs with BT-549 spheroids.

Results

The TP53β N340D variant impaired DXR-induced cell death (p < 0.001), supported by reduced late apoptosis and decreased CASP3 and PARP activation. TP53β N340D PBMCs exhibited increased senescence (p < 0.01), potentially contributing to chemoresistance. Reduced LPS- and PHA-L-stimulated proliferation was dependent on cancer status. The variant reduced PBMC migration (p < 0.01), suggesting altered immune recruitment. Although anti-tumour activity appeared reduced in TP53β N340D PBMCs, spheroid size remained unchanged.

Conclusions

This study provides supporting evidence for the pathogenicity of the TP53β N340D variant and highlights the importance of integrating functional genomics into PSGT to enhance medical decision-making.

病理学支持基因检测（PSGT）是南非建立的一种个性化医学框架，在一个li - fraumeni样综合征家庭中发现了一种罕见的种系肿瘤抑制蛋白53 (TP53) β -同型异构体（β）变异（NM_001126114.3, c.1018A>G, p.N340D）。虽然蛋白质模型预测结构改变与功能受损一致，但其致病性仍不清楚。目的：通过翻译离体模型确定TP53β N340D变异对细胞增殖、细胞死亡、衰老、迁移和抗肿瘤活性的功能影响。方法：从携带或不携带TP53β N340D变异的女性对照和乳腺癌患者中分离外周血单个核细胞（PBMCs）。脂多糖（LPS）和植物血凝素- l （PHA-L）刺激的增殖通过水溶性四氮唑1 （WST-1）试验进行评估。采用WST-1检测、流式细胞术和western blotting评估阿霉素（DXR）诱导的细胞死亡。衰老相关的-半乳糖苷酶测定和免疫印迹法测定衰老。通过Transwell实验和pbmc与BT-549球体共培养来评估迁移和抗肿瘤活性。结果：TP53β N340D变异体损害了dxr诱导的细胞死亡（p < 0.001），减少了晚期凋亡，降低了CASP3和PARP的激活。TP53β N340D pmcs衰老增加（p < 0.01），可能有助于化学耐药。LPS和pha - l刺激的增殖减少依赖于癌症状态。该变异降低了PBMC迁移（p < 0.01），提示免疫募集发生改变。虽然TP53β N340D pbmc的抗肿瘤活性降低，但球体大小保持不变。结论：本研究为TP53β N340D变异的致病性提供了支持证据，并强调了将功能基因组学整合到PSGT中以提高医疗决策的重要性。

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引用次数: 0

GATAD2B promotes ovarian cancer malignant progression via MYC/CD47 Axis GATAD2B通过MYC/CD47轴促进卵巢癌恶性进展

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2026-02-01 Epub Date: 2025-12-12 DOI: 10.1016/j.tranon.2025.102540

Ting Guo , Dengyun Nie , Jie Xu , Ruifang Zhou , Yunyao Ye , Yinxing Zhu , Mei Lin

This study elucidates the biological function of GADAT2B and its underlying mechanism in ovarian cancer.The results of our experiment showed that GATAD2B highly expressed in OC tissues, which was associated with a poor prognosis. METTL3 regulated the expression of GATAD2B in OC cells via m6A methylation. And it was unveiled that up-regulation of GATAD2B significantly promoted OC growth, invasion, migration of and suppressed the tumor cell apoptosis. After transfected with sh-GATAD2B, the OC cells were just the reverse in behavior. Additionally, GATAD2B played a crucial role in regulating CD47 expression via the MYC-mediated pathway, and the further experiments showed that GATAD2B and MYC were co-localized on tumor cell membrane. The in vivo and in vitro experiments showed an important role of GATAD2B in OC growth and metastasis, as confirmed by the inhibited tumor growth and the enhanced M1 macrophage infiltration.GATAD2B m6A methylation mediated by METTL3 can promote malignant progress. And GATAD2B can promote immune escape by MYC/CD47 pathway in OC, providing a promising anti-OC therapeutic target.

本研究阐明了GADAT2B在卵巢癌中的生物学功能及其潜在机制。我们的实验结果表明，GATAD2B在OC组织中高表达，与预后不良相关。METTL3通过m6A甲基化调控OC细胞中GATAD2B的表达。发现上调GATAD2B可显著促进OC的生长、侵袭、迁移，抑制肿瘤细胞凋亡。转染sh-GATAD2B后，OC细胞的行为正好相反。此外，GATAD2B通过MYC介导的途径在调节CD47的表达中发挥了至关重要的作用，进一步的实验表明GATAD2B和MYC在肿瘤细胞膜上共定位。体内和体外实验表明，GATAD2B在OC的生长和转移中发挥重要作用，抑制肿瘤生长，增强M1巨噬细胞浸润。METTL3介导的GATAD2B m6A甲基化可促进恶性进展。GATAD2B可通过MYC/CD47通路促进OC的免疫逃逸，为抗OC提供了一个有希望的治疗靶点。

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引用次数: 0

Serial proteomic analysis identifies small extracellular vesicle-MASP2 as an early biomarker of chemotherapy response in advanced pancreatic cancer 序列蛋白质组学分析确定小细胞外囊泡- masp2是晚期胰腺癌化疗反应的早期生物标志物

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2026-02-01 Epub Date: 2025-12-12 DOI: 10.1016/j.tranon.2025.102636

Shatovisha Dey , Deep Pandya , Tammy Lo , Ryan Narbutas , Bhavna Khandpur , Pramila Krumholtz , Mohammadreza Shervinrad , Kiyoe Sullivan , Deborah August , Sarah Evans , Saraswathi Nair , Nader Okby , Gregory Niland , Richard C Frank

Background

The average survival of advanced pancreatic cancer (APC) is 6–12 months with first-line chemotherapy. Only one-third receive second-line treatment. No early biomarker exists to guide chemotherapy efficacy before tumor progression occurs. Circulating small extracellular vesicles (sEVs) are a potential source of biomarker discovery.

Methods

Longitudinally collected sEVs from chemotherapy treated APC patients at pre-treatment, remission and relapse underwent proteomic profiling by mass spectrometry (MS). GO and KEGG analyses assessed differential protein characteristics, while protein-protein interactions and upstream analyses explored potential mechanisms. A candidate biomarker was validated by ELISA in larger patient cohorts of responders and non-responders. Gene knock-down and overexpression studies and tumor immunohistochemistry (IHC) evaluated potential function and localization.

Results

MS identified 34 proteins unique to remission, 132 unique to treatment resistance, and 9 differential across both phases. Complement cascade alterations best reflected response to treatment. Lectin pathway component MASP2 (Mannose-Binding Lectin-Associated Serine Protease 2) emerged as a predictive biomarker: >20 % decline in sEV-MASP2 levels at month 2 (M2) of chemotherapy predicted response in 72 % of responders, whereas >20 % increase predicted treatment resistance in 73 % of non-responders. sEV-MASP2 at M2 was prognostic for survival (11 vs. 8 months; p = 0.0037), unlike CA 19–9 (11 vs. 12 months) and retained significance when CA 19–9 was unevaluable. Functional data indicated that sEV-MASP2 alterations largely reflect systemic rather than tumor site-specific activity.

Conclusions

Complement pathway activity tracks with chemotherapy response and resistance in PC. Changes in sEV-MASP2 may serve as an early predictive/prognostic biomarker, helping to improve decision making in this lethal malignancy.

晚期胰腺癌（APC）一线化疗的平均生存期为6-12个月。只有三分之一的患者接受二线治疗。在肿瘤发生进展之前，没有早期的生物标志物来指导化疗的疗效。循环小细胞外囊泡（sev）是发现生物标志物的潜在来源。方法采用质谱法（MS）对接受化疗的APC患者在治疗前、缓解期和复发期的sev进行纵向采集。GO和KEGG分析评估了蛋白质的差异特征，而蛋白质相互作用和上游分析探索了潜在的机制。候选生物标志物通过ELISA在更大的应答者和无应答者患者队列中进行验证。基因敲除和过表达研究以及肿瘤免疫组化（IHC）评估了潜在的功能和定位。结果ms鉴定出缓解期特有的34个蛋白，治疗耐药期特有的132个蛋白，两个阶段之间的9个差异蛋白。补体级联改变最能反映对治疗的反应。凝集素途径组分MASP2（甘露糖结合凝集素相关丝氨酸蛋白酶2）成为一种预测性生物标志物：在化疗的第2个月（M2）， sEV-MASP2水平下降20%，预测72%的缓解者有反应，而73%的无反应者有20%的预测耐药。与CA 19-9（11个月vs. 12个月）不同，M2时sEV-MASP2对生存有预后作用（11个月vs. 8个月；p = 0.0037），当CA 19-9无法评估时，sEV-MASP2仍具有重要意义。功能数据表明sEV-MASP2的改变在很大程度上反映了全身而非肿瘤部位特异性活性。结论补体通路活性与前列腺癌化疗反应和耐药密切相关。sEV-MASP2的变化可能作为早期预测/预后的生物标志物，有助于改善这种致命恶性肿瘤的决策。

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引用次数: 0

Unraveling the anti-cancer potential of procyanidin B2 from grape seeds in gastric cancer through a multi-omics approach with emphasis on ROS and ferroptosis 通过多组学方法揭示葡萄籽原花青素B2在胃癌中的抗癌潜力，重点是ROS和铁下垂。

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2026-02-01 Epub Date: 2025-12-15 DOI: 10.1016/j.tranon.2025.102642

Zhejin Li , Nannan Song , Yawen Deng , Qingqing Zhang , Fanglong Hu , Yanfang Lu , Jinting Chen , Pengfei Xiao , Ao Yan , Jianheng Li , Zongjin Guo , Chengyan Zhou

Some flavonoids have been reported to enhance metal-catalyzed Fenton reactions, leading to excessive reactive oxygen species (ROS) and oxidative stress. Procyanidin B2 (PB2) is a plant-derived flavonoid whose anticancer activity has been attributed to inhibition of tumorigenesis-related signaling pathways in previous studies. However, the role of oxidative stress in the therapeutic activity of PB2 against gastric cancer remains unexplored. Beyond evaluating the anticancer potential of PB2 in proliferation, migration, cell death, and immune cell recruitment, we concentrated on alterations in intracellular redox state following PB2 treatment in gastric cancer cells. Through metabolomic and transcriptomic screening, we identified pathways altered by PB2 in gastric cancer cells, focusing on oxidative stress related biological functions, which were further confirmed through in vitro and in vivo validation. The heightened oxidative levels resulting from PB2 treatment induce endoplasmic reticulum stress and promote apoptosis. Furthermore, PB2 enhances autophagic flux to increase cellular free iron and promote ferroptosis. All in all, our research provides a comprehensive perspective on the therapeutic potential of PB2 in treating gastric cancer, demonstrating its capacity to inhibit growth signals and induce oxidative stress-related cell death.

据报道，一些类黄酮可以增强金属催化的Fenton反应，导致活性氧（ROS）过多和氧化应激。原花青素B2 （Procyanidin B2, PB2）是一种植物来源的类黄酮，其抗癌活性在先前的研究中被认为是抑制肿瘤发生相关的信号通路。然而，氧化应激在PB2抗胃癌治疗活性中的作用仍未被探索。除了评估PB2在增殖、迁移、细胞死亡和免疫细胞募集方面的抗癌潜力外，我们还关注了PB2治疗胃癌细胞后细胞内氧化还原状态的改变。通过代谢组学和转录组学筛选，我们在胃癌细胞中发现了PB2改变的通路，重点关注氧化应激相关的生物学功能，并通过体外和体内验证进一步证实。PB2处理引起的氧化水平升高诱导内质网应激并促进细胞凋亡。此外，PB2增强自噬通量，增加细胞游离铁，促进铁凋亡。总之，我们的研究为PB2治疗胃癌的治疗潜力提供了一个全面的视角，证明了其抑制生长信号和诱导氧化应激相关细胞死亡的能力。

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引用次数: 0

Radiomics as a visual tool with potential clinical implications: A comment on the implementation of habitat radiomics in a liver cancer series 放射组学作为一种具有潜在临床意义的视觉工具：对生境放射组学在肝癌系列中的实施的评论。

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2026-02-01 Epub Date: 2025-12-15 DOI: 10.1016/j.tranon.2025.102640

Francesco Fiz , Angela Ammirabile , Luca Viganò

引用次数: 0

Scutellarin regulates MAPK/ERK signalling in nasopharyngeal cancer via the apoptotic and ROS induced DNA damage 黄芩苷通过凋亡和ROS诱导的DNA损伤调控鼻咽癌中MAPK/ERK信号通路。

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2026-02-01 Epub Date: 2026-01-06 DOI: 10.1016/j.tranon.2025.102635

Jingda Xu , Guanzheng Wu , Lu Wang , Qingfeng Zhang , Periyannan Velu , Annamalai Vijayalakshmi , Gang Chen

Nasopharyngeal carcinoma (NPC) occurs frequently, and NPC poses a significant risk to public health in areas where it is endemic. Better care is needed because NPC is associated with considerable morbidity and mortality. A natural anticancer substance called scutellarin fights cancer by acting on a variety of signalling pathways. Nevertheless, little is known about the underlying apoptotic and anti-proliferative actions of scutellarin. The current study aimed to determine the molecular effects of in vitro scutellarin on CNE1 human NPC cells through mechanisms such as cell proliferation, anti-inflammatory, and anti-apoptotic effects. NPC cells were exposed to scutellarin (20 and 30 μM/ml), and their proliferation and apoptosis were evaluated using the MTT assay, AO/EB, Rh-123, DCFH-DA, DAPI, and PI staining, cell adhesion, cell migration, and western blot analysis. We evaluated putative molecular pathways, MAPKs/NF-κB signaling, MMP, and intracellular ROS, cell proliferation regulatory proteins. By generating intracellular ROS, causing MMP loss and inducing apoptosis via the signalling pathways of TNF-α, COX-2, iNOS, and IL-6, pRB, cyclin-D1, CDK4/CDK6, and MAPKs/NF-κB, it has been found that scutellarin may reduce the proliferative, inflammatory, migratory, and invasive capacity of NPC cells. Our research supports the MAPKs/NF-κB pathway as a therapeutic target and suggests that it may play a key role in mediating the scutellarin actions against nasopharyngeal cancer malignancy. In summary, scutellarin may be an effective conventional therapeutic drug in preventing the progression of NPC.

鼻咽癌发生频繁，在鼻咽癌流行地区对公共卫生构成重大威胁。需要更好的护理，因为鼻咽癌与相当高的发病率和死亡率有关。一种叫做黄芩素的天然抗癌物质通过作用于多种信号通路来对抗癌症。然而，对黄芩苷潜在的凋亡和抗增殖作用知之甚少。本研究旨在通过细胞增殖、抗炎、抗凋亡等机制，确定体外黄芩苷对CNE1人鼻咽癌细胞的分子作用。采用MTT法、AO/EB、Rh-123、DCFH-DA、DAPI和PI染色、细胞粘附、细胞迁移和western blot分析鼻咽癌细胞的增殖和凋亡情况。我们评估了可能的分子途径，MAPKs/NF-κB信号，MMP和细胞内ROS，细胞增殖调节蛋白。研究发现，黄芩苷通过TNF-α、COX-2、iNOS、IL-6、pRB、cyclin-D1、CDK4/CDK6、MAPKs/NF-κB等信号通路产生细胞内ROS，导致MMP丢失，诱导细胞凋亡，从而降低鼻咽癌细胞的增殖、炎症、迁移和侵袭能力。我们的研究支持MAPKs/NF-κB通路作为治疗靶点，并提示其可能在介导黄芩素抗鼻咽癌的作用中发挥关键作用。综上所述，黄芩苷可能是一种有效的预防鼻咽癌进展的常规治疗药物。

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引用次数: 0

Induction chemotherapy with nedaplatin, docetaxel and 5-fluorouracil followed by concurrent nedaplatin and radiotherapy in locoregionally advanced nasopharyngeal carcinoma: A single arm, open label, phase II clinical trial 局部进展期鼻咽癌诱导化疗奈达铂、多西紫杉醇和5-氟尿嘧啶并发奈达铂和放疗：单臂、开放标签、II期临床试验

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2026-02-01 Epub Date: 2026-01-06 DOI: 10.1016/j.tranon.2025.102634

Fang-Zheng Chen , Ying Deng , Wen-Jing Yin , Meng-Yao Wang , Fang Yang , Zhi-Huan Yang , Li-Ping Zhou , Si-Da Chen , Jie-Ling Chen , Xi-Zhen Jiang , Ao-Xiong Zhou , Yu-Meng Ou , Jin-Quan Liu , Dong-Ping Chen , Bin Qi

Purpose

To evaluate the efficacy of nedaplatin in induction chemotherapy and concurrent chemoradiotherapy for locoregionally advanced nasopharyngeal carcinoma.

Methods

In this prospective, single-arm, open-label phase II trial, patients with newly diagnosed stage III-IVa (except T3–4N0) nasopharyngeal carcinoma were enrolled. Participants received three cycles of induction chemotherapy with docetaxel (60 mg/m² IV on days 1, 22, and 43), nedaplatin (60 mg/m² IV on days 1, 22, and 43), and fluorouracil (600 mg/m²/day as a continuous 120 h infusion on days 1–5, 22–26, and 43–47). This was followed by intensity-modulated radiotherapy with concurrent nedaplatin (100 mg/m² IV on days 1, 22, and/or 43) for two or three cycles. The primary endpoint was the objective response rate (ORR). Secondary endpoints included overall survival (OS), progression-free survival (PFS), and toxicity profile.

Results

From March 2020 to November 2021, 32 patients were enrolled. With a median follow-up of 42.4 months (IQR, 35.4–45.2), 32 patients (100 %) achieved ORR at 12 weeks post-treatment. The 36-month PFS was 87.5 % (95 % CI, 76.1 %-98.8 %), and the 36-month OS was 100 %. The most common grade 3 or 4 adverse events during induction chemotherapy were neutropenia (9.4 %), diarrhea (9.4 %), leukopenia (6.2 %), fatigue (3.1 %) and hepatotoxicity (3.1 %). Mucositis (9.4 %) was the most common adverse events during concurrent chemoradiotherapy, followed by leukopenia (3.1 %), neutropenia (3.1 %), and thrombocytopenia (3.1 %). All adverse events were manageable.

Conclusion

Induction chemotherapy with nedaplatin, docetaxel, and 5-fluorouracil, followed by concurrent nedaplatin with intensity-modulated radiotherapy, demonstrated promising antitumor activity and manageable toxicities in locoregionally advanced nasopharyngeal carcinoma patients.

Trial registration

This trial was registered with ClinicalTrials.gov identifier: NCT04834206.

目的：评价奈达铂在局部进展期鼻咽癌诱导化疗和同步放化疗中的疗效。方法：在这项前瞻性、单臂、开放标签的II期试验中，纳入了新诊断的III-IVa期（T3-4N0期除外）鼻咽癌患者。参与者接受了三个周期的诱导化疗，包括多西紫杉醇（60mg /m²IV，第1、22和43天）、奈达铂（60mg /m²IV，第1、22和43天）和氟尿嘧啶（600mg /m²/天，连续输注120小时，第1-5、22-26和43-47天）。随后进行调强放疗，同时使用奈达铂（100mg /m²IV，在第1、22和/或43天）进行2或3个周期。主要终点为客观缓解率（ORR）。次要终点包括总生存期（OS）、无进展生存期（PFS）和毒性特征。结果：从2020年3月到2021年11月，32例患者入组。中位随访42.4个月（IQR, 35.4-45.2）， 32例（100%）患者在治疗后12周达到ORR。36个月的PFS为87.5% (95% CI, 76.1% - 98.8%)， 36个月的OS为100%。诱导化疗期间最常见的3级或4级不良事件是中性粒细胞减少（9.4%）、腹泻（9.4%）、白细胞减少（6.2%）、疲劳（3.1%）和肝毒性（3.1%）。粘膜炎（9.4%）是同步放化疗期间最常见的不良事件，其次是白细胞减少（3.1%）、中性粒细胞减少（3.1%）和血小板减少（3.1%）。所有不良事件均在可控范围内。结论：奈达铂、多西紫杉醇和5-氟尿嘧啶诱导化疗，随后奈达铂联合调强放疗，在局部进展期鼻咽癌患者中显示出良好的抗肿瘤活性和可控的毒性。试验注册：该试验在ClinicalTrials.gov注册，注册号：NCT04834206。

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引用次数: 0

Zeaxanthin targets TOP2A to regulate autophagy and suppress lung cancer progression via the MAPK/ERK pathway 玉米黄质通过MAPK/ERK通路靶向TOP2A调节自噬，抑制肺癌进展。

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2026-02-01 Epub Date: 2026-01-06 DOI: 10.1016/j.tranon.2025.102658

Jinxi He , Bo Yu , Xuyang Song , Tong Zhang, Zhixiong Qiao, Jing Li

Lung cancer (LC) remains a significant global health challenge, characterized by rapid progression and limited therapeutic options. Zeaxanthin (Zea), a natural carotenoid, exhibits promising antioxidant, anti-inflammatory, and anti-tumor activities; however, its precise mechanisms in LC are largely unexplored. Here, we demonstrate that Zea and DNA topoisomerase II A (TOP2A) significantly suppresses the viability, proliferation, and migration of LC cells while promoting apoptosis in vitro. Mechanistically, transcriptome analysis identified TOP2A as a critical downstream target. Molecular docking and cellular thermal shift assays further confirmed a direct interaction between Zea and TOP2A, suggesting Zea enhances TOP2A protein stability. We found that Zea inhibits TOP2A expression, which subsequently disrupts MAPK/ERK signaling and enhances autophagic activity, evidenced by increased autophagosome and autolysosome formation. Western blot and immunofluorescence analyses corroborated the modulation of key autophagy-related proteins. In vivo studies using an orthotopic LC model revealed that Zea treatment markedly reduced tumor growth, accompanied by decreased TOP2A and Ki67 expression. Collectively, our findings establish Zea as a potent LC therapeutic agent that suppresses tumor progression by targeting TOP2A, inhibiting the MAPK/ERK pathway, and ultimately modulating autophagy.

肺癌（LC）仍然是一个重大的全球健康挑战，其特点是快速进展和有限的治疗选择。玉米黄质（Zea）是一种天然类胡萝卜素，具有良好的抗氧化、抗炎和抗肿瘤活性；然而，其在LC中的确切机制在很大程度上尚未被探索。在这里，我们证明了玉米和DNA拓扑异构酶II A （TOP2A）在体外显著抑制LC细胞的活力、增殖和迁移，同时促进细胞凋亡。从机制上讲，转录组分析确定TOP2A是一个关键的下游靶标。分子对接和细胞热移实验进一步证实了Zea与TOP2A之间的直接相互作用，表明Zea增强了TOP2A蛋白的稳定性。我们发现，Zea抑制TOP2A的表达，进而破坏MAPK/ERK信号通路，增强自噬活性，自噬体和自噬酶体的形成增加。Western blot和免疫荧光分析证实了关键自噬相关蛋白的调节。原位LC模型的体内研究显示，Zea处理显著降低肿瘤生长，同时降低TOP2A和Ki67的表达。总的来说，我们的研究结果表明Zea是一种有效的LC治疗剂，通过靶向TOP2A，抑制MAPK/ERK通路，最终调节自噬来抑制肿瘤进展。

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引用次数: 0

The HYAL1 paradox in cancer: From complex tumor biology to novel therapeutic strategies 癌症中的HYAL1悖论：从复杂的肿瘤生物学到新的治疗策略

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2026-02-01 Epub Date: 2025-12-19 DOI: 10.1016/j.tranon.2025.102649

Yun Jin, Tongyu Wang, Junyan Ma, Jiao Quan, Ning Zhou

Hyaluronidase 1 (HYAL1), a key enzyme in hyaluronic acid (HA) metabolism, exhibits a perplexing paradoxical character in tumor biology. This review systematically delineates the dual roles of HYAL1 in cancer: on one hand, by degrading HA to generate low-molecular-weight fragments with pro-angiogenic and immunomodulatory activities, HYAL1 promotes tumor progression and metastasis in various malignancies, including prostate cancer, esophageal carcinoma, and osteosarcoma; on the other hand, it demonstrates tumor-suppressive properties in specific contexts such as colorectal cancer models. This functional contradiction underscores the context-dependent nature of HYAL1, whose activity and effects are profoundly influenced by tumor type, microenvironmental features, and epigenetic regulation.

Mechanistically, HYAL1 functions not only through the classical HA-CD44 signaling axis but also by regulating the MMPs/TIMPs balance, integrin activation, and cytoskeletal reorganization. Recent studies reveal that HYAL1 expression is directly controlled by epigenetic regulators like BRD2, while its activity can be monitored in real-time using novel bioluminescent probes, providing powerful tools for investigating its dynamic functions. Notably, HYAL1-based therapeutic strategies have shown considerable promise, particularly in oncolytic virotherapy, where HYAL1-expressing recombinant viruses significantly enhance the penetration and efficacy of chemotherapeutic agents and immune cells within tumors.

Key challenges persist, including HA metabolic complexity, functional redundancy among hyaluronidases, and HA fragment instability. Future research must decipher HYAL1′s context-specific roles within tumor heterogeneity, elucidate its epigenetic regulation, and develop targeted strategies. A deeper understanding of this HYAL1 paradox is essential to leverage its potential for precision cancer therapies targeting HA metabolism.

透明质酸酶1 （HYAL1）是透明质酸（HA）代谢的关键酶，在肿瘤生物学中表现出令人困惑的矛盾特征。本综述系统地描述了HYAL1在癌症中的双重作用：一方面，通过降解透明质酸生成具有促血管生成和免疫调节活性的低分子量片段，HYAL1促进各种恶性肿瘤的肿瘤进展和转移，包括前列腺癌、食管癌和骨肉瘤；另一方面，它在特定情况下如结直肠癌模型中显示出肿瘤抑制特性。这种功能矛盾强调了HYAL1的环境依赖性，其活性和作用受到肿瘤类型、微环境特征和表观遗传调控的深刻影响。从机制上讲，HYAL1不仅通过经典的HA-CD44信号轴发挥作用，还通过调节MMPs/TIMPs平衡、整合素激活和细胞骨架重组发挥作用。最近的研究表明，HYAL1的表达受BRD2等表观遗传调控因子的直接控制，而利用新型生物发光探针可以实时监测其活性，为研究其动态功能提供了有力的工具。值得注意的是，基于hyal1的治疗策略已经显示出相当大的前景，特别是在溶瘤病毒治疗中，表达hyal1的重组病毒显著提高了化疗药物和肿瘤内免疫细胞的渗透和功效。关键的挑战仍然存在，包括透明质酸代谢的复杂性，透明质酸酶之间的功能冗余，以及HA片段的不稳定性。未来的研究必须破译HYAL1在肿瘤异质性中的环境特异性作用，阐明其表观遗传调控，并制定有针对性的策略。更深入地了解这种HYAL1悖论对于利用其针对血凝素代谢的精确癌症治疗的潜力至关重要。

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