Translational Oncology最新文献_第10页

Identification of cuproptosis-related subtypes, construction of a prognosis model, and tumor microenvironment landscape in multiple myeloma 多发性骨髓瘤中铜质增生相关亚型的鉴定、预后模型的构建及肿瘤微环境景观

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2026-01-01 Epub Date: 2025-11-15 DOI: 10.1016/j.tranon.2025.102601

Li Xu , Hui Zhang , Kai Wang , Xuejie Gao , Wenxuan Bu , Dandan Yu , Ke Hu , Qikai Zhang , Guanli Wang , Xiaosong Wu , Xinyan Jia , Yu Peng , Dongliang Song , Hongfei Yi , Haiyan Cai , Jumei Shi , Qilin Feng

Multiple myeloma (MM) is a challenging hematologic malignancy with increasing incidence. Cuproptosis, a copper-dependent form of cell death associated with mitochondrial metabolism and protein lipoylation, remains unexplored in MM. This study aims to investigate this connection using transcriptome profiling and clinical data from the Gene Expression Omnibus database. Analysis of copper death-related genes (CRGs) revealed significant expression differences in 6 out of 12 CRGs, with GLS, ATP7B, PDHA1, MTF1, CDKN2A and DLAT showing notable correlations with survival of MM patients. Unsupervised clustering identified two cuproptosis molecular subtypes in MM patients, which exhibited significant associations with clinical features, prognosis, and immune cell infiltration. These subtypes identified 186 potential MM target genes, enriched in protein binding and intracellular/extracellular structure regulations. Five key biomarkers (CKS2, HGF, HSP90B1, PRIM1, and VCAM1) effectively stratified patients into high- and low-risk groups, strongly correlated with age, ISS stage, serum LDH content, and survival. Functional enrichment analysis revealed differential genes were involved in regulating cell membrane structure, protein binding, and metabolic pathways. High- and low-risk groups displayed distinct immune cell infiltration patterns and immune checkpoint expressions. In vitro experiments, the combination of elesclomol (a copper ion carrier) and bortezomib (Bortezomib) demonstrated a synergistic anti-myeloma effect through excessive intracellular reactive oxygen species generation. This study provides valuable insights into the role of CRGs in MM, potentially aiding in prognosis prediction and the development of effective, personalized therapeutic strategies.

多发性骨髓瘤（MM）是一种具有挑战性的血液系统恶性肿瘤，发病率越来越高。铜坏死是一种与线粒体代谢和蛋白质脂酰化相关的依赖铜的细胞死亡形式，在MM中仍未被发现。本研究旨在利用转录组分析和来自基因表达综合数据库的临床数据来研究这种联系。铜死亡相关基因（copper death-related genes, CRGs）分析显示，12个CRGs中有6个表达差异显著，其中GLS、ATP7B、PDHA1、MTF1、CDKN2A和DLAT与MM患者的生存有显著相关性。无监督聚类在MM患者中发现了两种cuprotosis分子亚型，它们与临床特征、预后和免疫细胞浸润有显著相关性。这些亚型鉴定出186个潜在的MM靶基因，这些基因在蛋白质结合和细胞内/细胞外结构调控中富集。5个关键生物标志物（CKS2、HGF、HSP90B1、PRIM1和VCAM1）有效地将患者分为高风险和低风险组，与年龄、ISS分期、血清LDH含量和生存率密切相关。功能富集分析显示，差异基因参与调节细胞膜结构、蛋白质结合和代谢途径。高危组和低危组表现出不同的免疫细胞浸润模式和免疫检查点表达。体外实验中，埃来氯莫尔（一种铜离子载体）与硼替佐米（硼替佐米）联合使用，通过细胞内活性氧的过量生成，显示出协同抗骨髓瘤的作用。这项研究为CRGs在MM中的作用提供了有价值的见解，可能有助于预测预后和制定有效的个性化治疗策略。

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引用次数: 0

Drug-tolerant persister cells in head and neck squamous cell carcinoma: Molecular mechanisms and therapeutic opportunities 头颈部鳞状细胞癌的耐药持续性细胞：分子机制和治疗机会。

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2026-01-01 Epub Date: 2025-10-29 DOI: 10.1016/j.tranon.2025.102579

Hang Huong Ling , Huei-Yu Huang , Chih-Ming Huang , Muhammad Yasir , Chun-Chen Ko , Vijesh Kumar Yadav , Kuang-Tai Kuo , Chi-Tai Yeh , Jo-Ting Tsai

Although treatments for HNSCC have improved, the cancer is still challenging because many patients tend to develop the disease again nearby and often have poor recovery. Since drug-tolerant persister (DTP) cells display a wide range of types and unique genetic characteristics, nonhormonal endocrine therapies, including chemotherapy, targeted therapy and immunotherapy, are ineffective in eliminating these cells. DTP cells evade elimination by entering a reversible dormant state characterized by altered metabolism, enhanced DNA repair capacity, and modified immune escape mechanisms, all of which promote the cells’ survival and treatment failure. Platinum-based chemotherapy, widely prescribed for HNSCC, reduces tumor size but fails to confer long-term benefits because of the strong treatment resistance of DTP cells. These cells also exhibit resistance to tyrosine kinase inhibitors by activating alternative signaling pathways. Alternative survival pathways are also activated in DTP cells when targeted therapies such as those using epidermal growth factor receptor inhibitors are used. Although programmed death 1/programmed death ligand 1 inhibitors are exciting new treatments, their effect is hampered by DTP cells that affect the immune system. This review examines the ways DTP cells make HNSCC tumor cells resistant to treatment by looking at metabolic reprogramming, DNA methylation alterations and the microenvironment of the tumor. This review further explores strategies for targeting metabolic dependencies, inhibiting DNA repair, and combining therapeutic approaches, all of which can mitigate DTP cell-mediated recurrence. Advancing strategies that specifically target DTP cells could enhance HNSCC management by reducing recurrence and improving overall prognosis.

尽管HNSCC的治疗方法已经有所改善，但这种癌症仍然具有挑战性，因为许多患者往往会在附近再次发病，而且往往很难康复。由于耐药持久性（DTP）细胞表现出广泛的类型和独特的遗传特征，非激素内分泌治疗，包括化疗、靶向治疗和免疫治疗，在消除这些细胞方面是无效的。DTP细胞通过进入可逆的休眠状态来逃避清除，其特征是代谢改变，DNA修复能力增强，免疫逃逸机制改变，所有这些都促进了细胞的生存和治疗失败。以铂为基础的化疗，广泛用于HNSCC，可减小肿瘤大小，但由于DTP细胞的强耐药性，不能带来长期的益处。这些细胞也通过激活替代信号通路表现出对酪氨酸激酶抑制剂的抗性。当使用靶向治疗（如使用表皮生长因子受体抑制剂）时，DTP细胞中的其他存活途径也被激活。尽管程序性死亡1/程序性死亡配体1抑制剂是令人兴奋的新治疗方法，但它们的效果受到影响免疫系统的DTP细胞的阻碍。本文通过观察代谢重编程、DNA甲基化改变和肿瘤微环境，探讨了DTP细胞使HNSCC肿瘤细胞抵抗治疗的途径。这篇综述进一步探讨了针对代谢依赖性、抑制DNA修复和结合治疗方法的策略，所有这些都可以减轻DTP细胞介导的复发。推进特异性靶向DTP细胞的策略可以通过减少复发和改善整体预后来加强HNSCC的管理。

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引用次数: 0

B2M regulates ELANE in pyroptosis to affect pancreatic cancer progression B2M调节ELANE在胰腺癌焦亡中的作用

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2026-01-01 Epub Date: 2025-11-21 DOI: 10.1016/j.tranon.2025.102613

Hui xie , Xiaonan Hu , Yongde Cai , Sheng Zhu , Zuliang Deng

The role of pyroptosis in pancreatic cancer remains controversial. Using two-sample Mendelian randomization (MR) integrating GWAS data from FinnGen (314,193 controls, 731 cases), pQTL data from Iceland, and the UK Biobank, we systematically investigated causal links between pyroptosis genes and pancreatic cancer. We found that Beta-2-microglobulin (B2M) indirectly increases pancreatic cancer risk by upregulating Neutrophil Elastase (ELANE)—to our knowledge, this is the first study to establish a causal, mediation-based genetic link between B2M and ELANE in the context of pancreatic cancer. Mediation analysis revealed ELANE accounts for 20.572 % [15.32%–25.81 %] of this effect. Sensitivity analyses confirmed robustness without significant pleiotropy, and bioinformatics validation supported our MR findings. Drug sensitivity analysis further identified potential therapeutic agents. The findings support B2M as a diagnostic biomarker for pancreatic cancer, given its significant overexpression in tumors and high diagnostic accuracy (AUC = 0.976, 95 % CI: 0.958–0.993), and highlight the B2M–ELANE axis—identified through a data-driven MR mediation framework—as a promising therapeutic target.

焦亡在胰腺癌中的作用仍有争议。采用两样本孟德尔随机化（MR），结合FinnGen的GWAS数据（314,193例对照，731例病例）、冰岛的pQTL数据和UK Biobank的pQTL数据，我们系统地研究了热亡基因与胰腺癌之间的因果关系。我们发现β -2微球蛋白（B2M）通过上调中性粒细胞弹性酶（ELANE）间接增加胰腺癌风险，据我们所知，这是第一个在胰腺癌背景下建立B2M和ELANE之间因果、基于介导的遗传联系的研究。中介分析显示，ELANE占20.572%[15.32% - 25.81%]。敏感性分析证实了鲁棒性，没有显著的多效性，生物信息学验证支持我们的MR发现。药物敏感性分析进一步确定了潜在的治疗药物。鉴于B2M在肿瘤中的显著过表达和高诊断准确性（AUC = 0.976, 95% CI: 0.958-0.993），该研究结果支持B2M作为胰腺癌的诊断生物标志物，并强调B2M - elane轴（通过数据驱动的MR中介框架确定）是一个有希望的治疗靶点。

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引用次数: 0

Poly-ADP-ribosylation modulated by poly(ADP-ribose) polymerase 1 is associated with glucose metabolism in colorectal cancer cells poly（adp -核糖）聚合酶1调控的poly - adp核糖基化与结直肠癌细胞的糖代谢有关。

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2026-01-01 Epub Date: 2025-12-03 DOI: 10.1016/j.tranon.2025.102623

Chenxuan Zhang , Peng Wang , Jia Yu , Jianhui Yuan , Lilong Zhang , Man Li

The preference of cancer cells to generate energy from glycolysis for rapid cell proliferation is called the Warburg effect. Poly(ADP-ribose) polymerase 1 (PARP1) performs various cellular functions, including poly-ADP-ribosylation and DNA repair. In the present study, we investigated the novel effects and mechanisms of PARP1 inhibition on glucose metabolism in colorectal cancer cells under hypoxia. We subjected Caco-2 and LoVo cancer cell lines to a concentration gradient of PARP1 inhibitor in a hypoxic environment induced with a tri-gas incubator (5 % CO₂, 1 % O₂, 94 % N₂). Inhibiting PARP1 activation attenuated Poly-ADP-ribosylation, increasing the NAD⁺/NADH ratio. High concentrations of PARP1 significantly reduced the glucose consumption rate of the treated cells, while PARP1 inhibition depressed cell progression in a concentration-dependent manner. The expression of hypoxia-inducible factor-1α (HIF-1α), hexokinase 2 (HK2), and glucose transporter 1 (GLUT-1), critical for the Warburg effect and glucose metabolism, was considerably reduced after the inhibitor treatments. Moreover, inhibiting PARP1 activation reduced phosphorylated AKT (p-AKT) and mTOR (p-mTOR) levels. In conclusion, our study revealed that PARP1 inhibition decelerates the Warburg effect in colorectal cancer cells, likely through the AKT/mTOR/HIF-1α pathway.

癌细胞倾向于通过糖酵解产生能量，以促进细胞快速增殖，这种现象被称为Warburg效应。聚（adp -核糖）聚合酶1 （PARP1）具有多种细胞功能，包括聚adp -核糖基化和DNA修复。在本研究中，我们研究了缺氧条件下PARP1抑制结直肠癌细胞糖代谢的新作用和机制。我们在三气培养箱（5% CO2, 1% O2, 94% N2）诱导的缺氧环境中，将Caco-2和LoVo癌细胞置于PARP1抑制剂的浓度梯度中。抑制PARP1激活可减弱poly - adp核糖基化，增加NAD+/NADH比值。高浓度的PARP1显著降低了处理细胞的葡萄糖消耗率，而PARP1抑制以浓度依赖的方式抑制细胞进展。低氧诱导因子-1α (HIF-1α)、己糖激酶2 （HK2）和葡萄糖转运蛋白1 （GLUT-1）的表达在抑制剂处理后显著降低，这对Warburg效应和葡萄糖代谢至关重要。此外，抑制PARP1激活可降低磷酸化AKT （p-AKT）和mTOR （p-mTOR）水平。总之，我们的研究表明，PARP1抑制可能通过AKT/mTOR/HIF-1α途径减缓结直肠癌细胞中的Warburg效应。

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引用次数: 0

The PI3K pathway is a downstream effector of NRF2 activation in the esophagus PI3K通路是NRF2在食道中激活的下游效应。

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2026-01-01 Epub Date: 2025-12-03 DOI: 10.1016/j.tranon.2025.102629

Boopathi Subramaniyan , Yahui Li , Zhaohui Xiong , Chorlada Paiboonrungruang , Candice Bui-Linh , Francis Spitz , Xiaoxin Chen

Mutations in nuclear factor erythroid 2–related factor 2 (NFE2L2 or NRF2) occur in 10–22 % of esophageal squamous cell carcinoma (ESCC) cases and result in NRF2 activation, promoting tumor progression, and therapeutic resistance. Although previous studies suggested a link between NRF2 and kinases, specific kinases responsive to NRF2 activation remain to be fully identified. Using protein phosphorylation profiling and kinase activity profiling, we identified phosphatidylinositol 3-kinase (PI3K) pathway as a downstream effector in NRF2^W24C-KYSE70 cells compared to isogenic NRF2^null-KYSE70 cells. AREG, pEGFR, PIK3CA, pAKT, p-S6, and p-PTEN were downregulated in NRF2 deficient cells. Notably, NRF2 deficiency sensitized ESCC cells to EGFR, PIK3CA, and AKT inhibitors. Co-treatment with Alpelisib (a PIK3CA inhibitor) and Pyrimethamine (an NRF2 inhibitor) synergistically suppressed the growth of NRF2^W24C-KYSE70 and NRF2^D77V-KYSE180 cells. In vivo, NRF2 activation in the esophageal epithelium of Keap1^-/- and Sox2CreER;LSL-Nrf2^E79Q/+ mice resulted in upregulation of pAKT, p-mTOR, and pS6. In human ESCC tissues, expression of pNRF2 (an active form of NRF2) was positively associated with that of pAKT and p-mTOR. Furthermore, co-treatment with Pyrimethamine and Alpelisib significantly inhibited hyperproliferation and hyperkeratinization in the esophageal epithelium of Sox2CreER;LSL-Nrf2^E79Q/+mice. Together, our data demonstrates the PI3K pathway as a downstream effector of NRF2 activation in the esophagus, and co-targeting of NRF2 and the PI3K pathway may offer a promising therapeutic strategy for NRF2^Mut ESCC.

10- 22%的食管鳞状细胞癌（ESCC）病例发生核因子红系2相关因子2 （NFE2L2或NRF2）突变，导致NRF2激活，促进肿瘤进展和治疗耐药。尽管先前的研究表明NRF2与激酶之间存在联系，但对NRF2激活有反应的特定激酶仍有待完全确定。通过蛋白磷酸化分析和激酶活性分析，我们发现与等基因NRF2W24C-KYSE70细胞相比，NRF2W24C-KYSE70细胞中的PI3K通路是下游效应物。AREG、pEGFR、PIK3CA、pAKT、p-S6和p-PTEN在NRF2缺陷细胞中下调。值得注意的是，NRF2缺乏使ESCC细胞对EGFR、PIK3CA和AKT抑制剂敏感。Alpelisib（一种PIK3CA抑制剂）和Pyrimethamine（一种NRF2抑制剂）协同抑制NRF2W24C-KYSE70和NRF2D77V-KYSE180细胞的生长。在体内，NRF2在Keap1-/-和Sox2CreER的食管上皮中活化；LSL-Nrf2E79Q/+小鼠导致pAKT、p-mTOR和pS6的上调。在人ESCC组织中，pNRF2 （NRF2的一种活性形式）的表达与pAKT和p-mTOR的表达呈正相关。此外，乙胺嘧啶和Alpelisib联合治疗可显著抑制Sox2CreER；LSL-Nrf2E79Q/+小鼠食管上皮的过度增生和角化过度。综上所述，我们的数据表明PI3K通路是NRF2在食管中激活的下游效应物，同时靶向NRF2和PI3K通路可能为NRF2Mut ESCC提供一种有希望的治疗策略。

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引用次数: 0

Biomarker analysis from a Phase 1/1b study of tusamitamab ravtansine in patients with advanced non-small cell lung cancer tusamitamab ravtansine在晚期非小细胞肺癌患者中的1/1b期研究的生物标志物分析。

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2026-01-01 Epub Date: 2025-12-03 DOI: 10.1016/j.tranon.2025.102615

Anas Gazzah , Nils Ternès , Joon Sang Lee , Emma Wang , Dimitri Carene , Hong Wang , Nina Masson , Eric Boitier , Aude Lartigau , Nathalie Mace , Mustapha Chadjaa , Colette Dib , Manoel Nunes , Gaëlle Muzard , Sandrine Longuemaux-Valence , Anne-Laure Bauchet

Background

Tusamitamab ravtansine demonstrated antitumor activity in the Phase 1/1b study of advanced non-squamous non-small cell lung cancer with high (HE, ≥2+ intensity in ≥50 % of tumor cells) or moderate (ME, ≥2+ intensity in ≥1 % to <50 % of tumor cells) carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) expression. Tumor CEACAM5 expression, biomarker associations and whether biomarkers predict objective response rate (ORR) were explored.

Methods

We assessed CEACAM5, circulating CEACAM5 (cCEACAM5) and CEA (cCEA). Enrollment was according to immunohistochemistry (IHC) CEACAM5 membrane expression: HE (n=64) and ME (n=28). Patients received tusamitamab ravtansine 100 mg/m² intravenously every 2 weeks.

Results

cCEA and cCEACAM5 were strongly associated (Spearman ρ, 0.99), with moderate associations between IHC CEACAM5 and cCEA or cCEACAM5 (Spearman ρ, 0.43 and 0.38). In patients with baseline cCEA data, 40.3 % (25/62) of HE and 25 % (7/28) of ME had cCEA ≥100 µg/L (median: 71.6 µg/L [1–8809] versus 12.4 µg/L [0.5–684]). Among response-evaluable patients in HE, ORR for high cCEA (≥100 µg/L) was 41.7 % (10/24) versus 8.1 % (3/37) for low cCEA, and in ME, ORR was 0/7 versus 10 % (2/20). Elevated CEACAM5 mRNA was observed in HE versus ME (P = 0.0027). EGFR and KRAS alterations were present in 44.8 % and 65.5 % of HE and in 21.4 % and 78.6 % of ME patients, respectively.

Conclusions

In CEACAM5 HE, the ORR was greater with high versus low cCEA. Associations were observed between cCEA and cCEACAM5; IHC CEACAM5, cCEA, and cCEACAM5; IHC CEACAM5 and CEACAM5 mRNA, but not between IHC CEACAM5 and oncogenic drivers.

Clinical Trial Registration: NCT02187848

背景：Tusamitamab ravtansine在晚期非鳞状非小细胞肺癌的1/1b期研究中显示出高（HE，≥50%肿瘤细胞≥2+强度）或中等（ME，≥1%肿瘤细胞≥2+强度）的抗肿瘤活性。方法：我们评估了CEACAM5、循环CEACAM5 （cCEACAM5）和CEA （cCEA）。根据免疫组化（IHC） CEACAM5膜表达入组：HE （n=64）和ME （n=28）。患者静脉注射tusamitamab ravtansine 100mg /m2，每2周一次。结果：cCEA与cCEACAM5呈正相关（Spearman ρ, 0.99）， IHC CEACAM5与cCEA或cCEACAM5呈正相关（Spearman ρ， 0.43和0.38）。在基线cCEA数据的患者中，40.3%（25/62）的HE和25%（7/28）的ME的cCEA≥100µg/L（中位数：71.6µg/L [1-8809] vs 12.4µg/L[0.5-684]）。在HE组反应可评估的患者中，高cCEA（≥100µg/L）的ORR为41.7%(10/24)，而低cCEA的ORR为8.1%(3/37)，在ME组，ORR为0/7，而10%（2/20）。HE组与ME组CEACAM5 mRNA升高（P = 0.0027）。EGFR和KRAS的改变在HE患者中分别为44.8%和65.5%，在ME患者中分别为21.4%和78.6%。结论：在CEACAM5 HE中，高cCEA比低cCEA的ORR更大。cCEA与cCEACAM5存在相关性；IHC CEACAM5、cCEA和cCEACAM5；IHC CEACAM5和CEACAM5 mRNA，但在IHC CEACAM5和致癌驱动因子之间不存在差异。临床试验注册：NCT02187848。

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引用次数: 0

Unveiling shared PANoptosis mechanisms in LUAD and osteoarthritis via bioinformatics and machine learning 通过生物信息学和机器学习揭示LUAD和骨关节炎的共同泛光机制

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2026-01-01 Epub Date: 2025-11-08 DOI: 10.1016/j.tranon.2025.102586

Hailin Xiong , Junjie Liu , Shuyi Zhang , Xuli Guo

Lung adenocarcinoma (LUAD) and osteoarthritis (OA) pose significant therapeutic challenges due to their invasive heterogeneity and limited treatment options. This study investigates PANoptosis-related genes in LUAD and OA to develop a prognostic risk model using bioinformatics and machine learning. We obtained gene expression data from TCGA, GEO, and MSigDB, then applied consensus clustering to stratify LUAD samples and identified PANoptosis-associated differentially expressed genes (DEGs). For OA, ssGSEA and WGCNA were used to pinpoint hub genes linked to PANoptosis. Functional enrichment analyses (GO/KEGG) revealed key pathways in both diseases. By intersecting LUAD DEGs and OA hub genes, we refined candidate genes using LASSO and Random Forest algorithms, ultimately selecting five key genes (S100A3, PFN2, DEFB1, TSPO, and KMO) for model construction. The prognostic model demonstrated robust predictive performance. Additionally, immune infiltration and mutational profiling in LUAD provided mechanistic insights for potential therapeutic strategies. Our findings highlight shared PANoptosis-related pathways in LUAD and OA, offering a novel framework for risk stratification and targeted therapy.

肺腺癌（LUAD）和骨关节炎（OA）由于其侵袭性异质性和有限的治疗选择，给治疗带来了重大挑战。本研究利用生物信息学和机器学习技术研究LUAD和OA中panoposis相关基因，建立预后风险模型。我们获得了来自TCGA、GEO和MSigDB的基因表达数据，然后应用共识聚类对LUAD样本进行分层，并鉴定出panopsis相关的差异表达基因（DEGs）。对于OA， ssGSEA和WGCNA用于定位与泛视症相关的中枢基因。功能富集分析（GO/KEGG）揭示了这两种疾病的关键途径。通过交叉LUAD DEGs和OA枢纽基因，我们使用LASSO和Random Forest算法对候选基因进行了细化，最终选择了5个关键基因（S100A3、PFN2、DEFB1、TSPO和KMO）进行模型构建。该预测模型显示了稳健的预测性能。此外，LUAD的免疫浸润和突变分析为潜在的治疗策略提供了机制见解。我们的研究结果强调了LUAD和OA中共享的panopatos相关途径，为风险分层和靶向治疗提供了新的框架。

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引用次数: 0

Clinical and molecular variations in Burkitt lymphoma 伯基特淋巴瘤的临床和分子变异

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2026-01-01 Epub Date: 2025-11-25 DOI: 10.1016/j.tranon.2025.102611

Eoghan O’Connor , Patricia Scanlan , Owen Patrick Smith , Melinda Halasz

Burkitt lymphoma (BL) is an aggressive B-cell non-Hodgkin lymphoma, historically classified into three subtypes; endemic, sporadic and immunodeficiency associated BL. Accumulating evidence suggests that Epstein-Barr virus (EBV)-positive and EBV-negative BL represent biologically distinct entities. In this review, we aim to compare the clinicopathological and molecular differences in BL in the context of EBV status and chronic malaria infection.

From our review, clinical features of BL vary by both EBV status and geographical region, reflecting underlying epidemiological differences. The cell of origin may also differ between EBV-positive and EBV-negative cases. At a molecular level, differences based on EBV status include variations in the immunoglobulin (IG)::MYC translocation breakpoints, mutations in the inhibitor of DNA binding 3 (ID3)/ transcription factor 3 (TCF3)/ cyclin D3 (CCND3) signalling axis, the anti-apoptotic effects of EBV latency gene products, differences in the alternative reading frame (ARF)/ mouse double minute 2 (MDM2)/p53 and ataxia-telangiectasia mutated (ATM)/ ATM and RAD3-related (ATR) pathways, and deregulation of B-cell leukemia/lymphoma 2 (BCL-2) family proteins. We further discuss the theory that aberrant activation-induced cytidine deaminase (AID) expression, in the setting of EBV infection and chronic malaria exposure, is the most likely aetiology of endemic BL.

This review provides a comprehensive summary of key molecular differences between EBV-positive and EBV-negative BL, that may guide the development of future targeted therapeutic strategies.

伯基特淋巴瘤（BL）是一种侵袭性b细胞非霍奇金淋巴瘤，历史上分为三个亚型；越来越多的证据表明EBV阳性和EBV阴性的BL在生物学上是不同的实体。在这篇综述中，我们旨在比较EBV状态和慢性疟疾感染背景下BL的临床病理和分子差异。从我们的综述来看，EBV状态和地理区域不同，BL的临床特征也不同，反映了潜在的流行病学差异。在ebv阳性和ebv阴性病例中，起源细胞也可能不同。在分子水平上，基于EBV状态的差异包括免疫球蛋白（IG）： MYC易位断点的变化，DNA结合3 (ID3)/转录因子3 (TCF3)/细胞周期蛋白D3 （CCND3）信号轴的突变，EBV潜伏期基因产物的抗凋亡作用，替代阅读框(ARF)/小鼠双分钟2 (MDM2)/p53和失调性毛细血管扩张突变(ATM)/ ATM和rad3相关（ATR）途径的差异，b细胞白血病/淋巴瘤2 （BCL-2）家族蛋白的失调。我们进一步讨论了在EBV感染和慢性疟疾暴露的情况下，激活诱导的胞苷脱氨酶（AID）表达异常是最可能的地方流行BL病因的理论。本文综述了EBV阳性和EBV阴性BL之间的关键分子差异，这可能指导未来靶向治疗策略的发展。

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引用次数: 0

HERC4 downregulates KRT19 to promote lung adenocarcinoma, migration, invasion and EMT HERC4下调KRT19促进肺腺癌、迁移、侵袭和EMT。

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2026-01-01 Epub Date: 2025-11-04 DOI: 10.1016/j.tranon.2025.102593

Hao-Jia Sun , Ming-Hui Peng , Zi-Yang Feng , Hua Fu , Xue-Wen Liu

Background

Metastasis is a major cause of treatment failure and poor prognosis in lung adenocarcinoma (LUAD). Epithelial-mesenchymal transition (EMT) plays a crucial role in promoting LUAD metastasis. Pulmonary sarcomatoid carcinoma (PSC), a highly aggressive non-small cell lung cancer subtype, contains both carcinomatous component (CaC) and sarcomatous component (SaC) with strong metastatic potential. Previous studies have shown that EMT contributes to the formation of Sac in PSC.

Methods

The differential expression of KRT19 between SaC and CaC in PSC was screened and validated using immunohistochemistry. GO, KEGG analysis were conducted to investigate the potential mechanism of KRT19. The CCK-8, wound healing, transwell assay and mouse model were used to confirm the impact of KRT19 on cell proliferation, migration and invasion in LUAD. The upstream regulatory molecules of KRT19 were identified and validated through CO-IP, GST Pull-down Assay and ubiquitination experiments.

Results

KRT19 was found to be downregulated in SaC compared to CaC and LUAD. Knock down of KRT19 in A549 and PC-9 cells led to EMT, decreased adhesion, and increased proliferation and metastasis. HERC4 was identified as a potential upstream regulator of KRT19, with its expression negatively correlated with KRT19 levels. HERC4 promoted KRT19 ubiquitination, leading to its downregulation.

Conclusion

KRT19 downregulation promoted LUAD cell EMT, enhancing metastatic potential. HERC4 functioned as an upstream regulator that suppresses KRT19 expression by promoting its ubiquitination.

背景：转移是肺腺癌（LUAD）治疗失败和预后不良的主要原因。上皮-间质转化（Epithelial-mesenchymal transition， EMT）在促进LUAD转移中起着至关重要的作用。肺肉瘤样癌（PSC）是一种高度侵袭性的非小细胞肺癌亚型，包含癌性成分（CaC）和肉瘤性成分（SaC），具有很强的转移潜力。先前的研究表明，EMT有助于PSC中Sac的形成。方法：采用免疫组化方法筛选PSC中SaC与CaC之间KRT19的差异表达并进行验证。通过GO、KEGG分析探讨KRT19的潜在机制。通过CCK-8、创面愈合、transwell实验和小鼠模型验证KRT19对LUAD细胞增殖、迁移和侵袭的影响。通过CO-IP、GST Pull-down Assay和泛素化实验对KRT19的上游调控分子进行鉴定和验证。结果：与CaC和LUAD相比，KRT19在SaC中下调。在A549和PC-9细胞中敲低KRT19可导致EMT，减少粘附，增加增殖和转移。HERC4被认为是KRT19的潜在上游调控因子，其表达与KRT19水平呈负相关。HERC4促进KRT19泛素化，导致其下调。结论：KRT19下调可促进LUAD细胞EMT，增强转移潜能。HERC4作为上游调控因子，通过促进KRT19泛素化抑制其表达。

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Integrative multi-omics of matched primary and liver metastatic colorectal cancer organoids identifies putative molecular targets 匹配原发性和肝转移性结直肠癌类器官的整合多组学确定了假定的分子靶点。

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2026-01-01 Epub Date: 2025-11-04 DOI: 10.1016/j.tranon.2025.102592

Chae-Young Kim , Soon-Chan Kim , Rumi Shin , Min Jung Kim , Seung-Yong Jeong , Ji Won Park , Ja-Lok Ku

Hepatic metastasis from colorectal cancer (CRC) mainly accounts for the dismal prognosis of advanced CRC. Metastasized tumor cells exhibit strong resistance to commonly used systemic chemotherapy, which causes the high mortality of colorectal liver metastasis (CLM) patients. Although previous studies using biological resources have suggested multiple metastatic factors, molecular integration into chemotherapeutic responses is seldom studied.

In this study, we established five pairs of CLM organoids, which were subjected to a multi-omics approach including genetic, transcriptional, exosomal miRNA and pharmacological analyses. These multi-omics layers were interlinked through machine learning analysis to construct a drug response prediction model.

Our approach not only recapitulated druggable molecular targets that were specifically dysregulated in LM organoids but also potentially revealed a statistical connection to systemic therapy regimens.

结直肠癌晚期预后不佳的主要原因是肝转移。转移性肿瘤细胞对常用的全身化疗具有很强的耐药性，导致结直肠癌肝转移（CLM）患者的高死亡率。尽管先前利用生物资源的研究表明了多种转移因素，但很少研究分子整合到化疗反应中。在这项研究中，我们建立了5对CLM类器官，并对其进行了多组学分析，包括遗传、转录、外泌体miRNA和药理学分析。这些多组学层通过机器学习分析相互关联，构建药物反应预测模型。我们的方法不仅概括了LM类器官中特异性失调的可药物分子靶点，而且还潜在地揭示了与全身治疗方案的统计学联系。

引用次数: 0