Drug Resistance Updates最新文献_第8页

ZNF207-driven PRDX1 lactylation and NRF2 activation in regorafenib resistance and ferroptosis evasion znf207驱动的PRDX1乳酸化和NRF2激活在瑞非尼耐药和铁中毒逃避中的作用

IF 15.8 1区医学 Q1 PHARMACOLOGY & PHARMACY

Drug Resistance Updates

Pub Date : 2025-09-01 Epub Date: 2025-07-12 DOI: 10.1016/j.drup.2025.101274

Tianfeng Yang , Suyu Zhang , Kun Nie , Cheng Cheng , Xiuhong Peng , Jian Huo , Yanmin Zhang

Regorafenib (RGF) is a critical second-line therapy for advanced hepatocellular carcinoma (HCC) following disease progression on sorafenib; however, the rapid onset of RGF resistance poses a significant barrier to enhancing patient outcomes. In this study, CRISPR/Cas9 screening in RGF-treated HCC cells identified Zinc Finger Protein 207 (ZNF207) as a primary driver of resistance. Further analysis revealed that ZNF207 promotes resistance by inducing antioxidant responses that inhibit ferroptosis, a form of iron-dependent cell death. Mechanistically, ZNF207 facilitates the lactylation of peroxiredoxin 1 (PRDX1) at lysine 67, enhancing nuclear translocation and activation of nuclear factor erythroid 2–related factor 2 (NRF2), a master regulator of antioxidant pathways. This ZNF207-PRDX1-NRF2 pathway creates a ferroptosis-resistant, pro-survival environment under RGF treatment, enabling HCC cells to evade cell death. Functional assays demonstrated that ZNF207 knockdown significantly enhances RGF sensitivity by restoring ferroptosis, with additional findings showing that disrupting PRDX1 lactylation or NRF2 activity similarly reverses resistance. Together, these findings establish a critical link between protein lactylation and RGF resistance, positioning the ZNF207-PRDX1-NRF2 axis as a promising therapeutic target to enhance treatment efficacy in HCC. The implications of this research extend beyond HCC, indicating that targeting ferroptosis-suppressive pathways may offer a broader approach to overcoming resistance in various cancers.

瑞非尼（Regorafenib， RGF）是索拉非尼治疗进展的晚期肝细胞癌（HCC）的关键二线治疗药物；然而，RGF耐药性的快速发作对提高患者预后构成了重大障碍。在这项研究中，CRISPR/Cas9筛选在rgf处理的HCC细胞中发现锌指蛋白207 （ZNF207）是耐药的主要驱动因素。进一步分析表明，ZNF207通过诱导抗氧化反应抑制铁凋亡（铁依赖性细胞死亡的一种形式）来促进耐药性。从机制上讲，ZNF207促进过氧化物还氧蛋白1 （PRDX1）在赖氨酸67处的乳酸化，增强核易位和核因子红细胞2相关因子2 （NRF2）的激活，NRF2是抗氧化途径的主要调节因子。这种ZNF207-PRDX1-NRF2通路在RGF治疗下创造了一种抗铁凋亡、促生存的环境，使HCC细胞逃避细胞死亡。功能分析表明，ZNF207基因敲低可通过恢复铁下沉显著增强RGF敏感性，其他研究结果表明，破坏PRDX1乳酸化或NRF2活性类似地逆转耐药性。总之，这些发现建立了蛋白乳酸化与RGF耐药之间的关键联系，将ZNF207-PRDX1-NRF2轴定位为提高HCC治疗疗效的有希望的治疗靶点。这项研究的意义超出了HCC，表明靶向铁细胞凋亡抑制途径可能为克服各种癌症的耐药提供更广泛的方法。

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引用次数: 0

The shadow of cancer therapeutic resistance: Unveiling the role of S-palmitoylation 癌症治疗耐药的阴影：揭示s -棕榈酰化的作用

IF 15.8 1区医学 Q1 PHARMACOLOGY & PHARMACY

Drug Resistance Updates

Pub Date : 2025-09-01 Epub Date: 2025-06-02 DOI: 10.1016/j.drup.2025.101264

Xue Yang , Mengke Xu , Zhiqin Deng, Bo Xu

Cancer therapeutic resistance remains a formidable challenge due to its diverse underlying mechanisms. S-palmitoylation (or called S-acylation), a reversible post-translational modification involving the attachment of long-chain fatty acids to cysteine residues, has emerged as a critical regulator of cancer progression and treatment response. This review offers a comprehensive analysis of recent advancements in understanding the role of S-palmitoylation in cancer therapeutic resistance. We examine the intricate relationship between S-palmitoylation and major oncogenic pathways, with particular focus on its distinct contributions to resistance mechanisms in molecularly-targeted therapy, immunotherapy, chemotherapy, radiotherapy, and endocrine therapy. Additionally, we highlight the progress in the proteomic identification and characterization of S-palmitoylated proteins, as well as the development of selective inhibitors targeting protein acyltransferases (PATs) and acyl-protein thioesterases (APTs). Furthermore, we discuss the further directions for developing S-palmitoylation-targeted strategies, providing insights into potential avenues for overcoming cancer treatment resistance.

由于其潜在机制的多样性，癌症治疗耐药性仍然是一个艰巨的挑战。s -棕榈酰化（或称为s -酰化）是一种可逆的翻译后修饰，涉及长链脂肪酸与半胱氨酸残基的附着，已成为癌症进展和治疗反应的关键调节因子。本文综述了最近在理解s -棕榈酰化在癌症治疗耐药中的作用方面的进展。我们研究了s -棕榈酰化与主要致癌途径之间的复杂关系，特别关注其在分子靶向治疗、免疫治疗、化疗、放疗和内分泌治疗中对耐药性机制的独特贡献。此外，我们还重点介绍了s -棕榈酰化蛋白的蛋白质组学鉴定和表征，以及针对蛋白酰基转移酶（PATs）和酰基蛋白硫酯酶（APTs）的选择性抑制剂的开发。此外，我们还讨论了开发s -棕榈酰化靶向策略的进一步方向，为克服癌症治疗耐药性提供了潜在途径。

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引用次数: 0

Corrigendum to “NDRG1 overcomes resistance to immunotherapy of pancreatic ductal adenocarcinoma through inhibiting ATG9A-dependent degradation of MHC-I” [Drug Resist. Updates 73 (2024) 101040] “NDRG1通过抑制atg9a依赖性MHC-I降解来克服对胰腺导管腺癌免疫治疗的耐药性”[耐药]的更正。更新73 (2024)101040]

IF 15.8 1区医学 Q1 PHARMACOLOGY & PHARMACY

Drug Resistance Updates

Pub Date : 2025-09-01 Epub Date: 2025-06-13 DOI: 10.1016/j.drup.2025.101269

Zhiheng Zhang , Bojiao Song , Haowei Wei , Yang Liu , Wenjie Zhang , Yuhong Yang , Beicheng Sun

引用次数: 0

The multifaceted contributions of cancer-associated fibroblasts to drug resistance in primary and metastatic tumors 癌症相关成纤维细胞对原发性和转移性肿瘤耐药的多方面贡献

IF 15.8 1区医学 Q1 PHARMACOLOGY & PHARMACY

Drug Resistance Updates

Pub Date : 2025-09-01 Epub Date: 2025-07-01 DOI: 10.1016/j.drup.2025.101273

Xinhao Zhang , Yuhang Wang , Wenming Cui , Danyang Li , Junmin Song , Zhen Li , Ying Liu , Shuaixi Yang

Drug resistance remains a formidable barrier in modern oncology, undermining the efficacy of the current therapeutic regimens. As pivotal stromal constituents within tumor ecosystems, cancer-associated fibroblasts (CAFs) have emerged as critical mediators of treatment resistance through multifaceted mechanisms. In this review, we summarize the historical progression of research on CAFs and drug resistance, and highlight the recent discoveries related to CAF biomarkers and their functions associated with drug resistance. Furthermore, we discuss the relationship between CAF heterogeneity, secretion, autophagy, and senescence and their contributions to the evolution of drug resistance. Additionally, we provide a detailed explanation of how CAFs contribute to the development of drug resistance in primary tumors, including mechanisms such as immune suppression and evasion, promotion of tumor stemness, angiogenesis, extracellular matrix remodeling, and metabolic reprogramming. We also explored the role of CAFs in metastatic tumors and their association with drug resistance at various metastatic sites, including lymph nodes, brain, lungs, peritoneum, bone, and liver. Finally, we summarize the advancements in clinical trials targeting CAFs, the emerging research on potential therapeutic targets, and anticipating future trends in this area.

耐药性仍然是现代肿瘤学的一个巨大障碍，破坏了当前治疗方案的有效性。作为肿瘤生态系统中关键的基质成分，癌症相关成纤维细胞（CAFs）已通过多方面机制成为治疗耐药的关键介质。本文综述了CAF与耐药研究的历史进展，重点介绍了CAF生物标志物及其与耐药相关功能的最新发现。此外，我们还讨论了CAF异质性、分泌、自噬和衰老之间的关系及其对耐药性进化的贡献。此外，我们还详细解释了CAFs如何促进原发肿瘤耐药的发展，包括免疫抑制和逃避、促进肿瘤干细胞、血管生成、细胞外基质重塑和代谢重编程等机制。我们还探讨了CAFs在转移性肿瘤中的作用及其与各种转移部位耐药的关系，包括淋巴结、脑、肺、腹膜、骨和肝脏。最后，我们总结了针对CAFs的临床试验进展，潜在治疗靶点的新兴研究，并展望了该领域的未来趋势。

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引用次数: 0

Global, regional, and national disease burden of multidrug-resistant tuberculosis without extensive drug resistance, 1990–2021: Findings from the Global Burden of Disease Study 2021 1990-2021年无广泛耐药的耐多药结核病的全球、区域和国家疾病负担：《2021年全球疾病负担研究》的结果

IF 15.8 1区医学 Q1 PHARMACOLOGY & PHARMACY

Drug Resistance Updates

Pub Date : 2025-09-01 Epub Date: 2025-06-02 DOI: 10.1016/j.drup.2025.101265

Xinyue Wang , Anquan Shang , Haowei Chen , Jing Li , Yuan Jiang , Lili Wang , Shuai Qiu , Fenyong Sun , Chaoyan Yue

Objective

Utilizing Global Burden of Disease Study (GBD 2021) data, this study aims to illustrate trends and spatiotemporal patterns of multidrug-resistant tuberculosis (MDR-TB) burden from 1990 to 2021, and explore their potential mechanisms.

Methods

This research extracted core indicators including incidence, mortality, prevalence, and disability-adjusted life years (DALYs), with their age-standardized rate (ASR). Joinpoint regression, age-period-cohort analysis, inequality analysis, and frontier analysis were applied to describe the temporal and spatial trends of the disease burden. Decomposition analysis and risk factor analysis were performed to explore factors associated with MDR-TB burden fluctuation. Bayesian Age-Period-Cohort (BAPC) model was used to project the disease burden till 2050.

Results

Global MDR-TB cases and ASRs of all indicators rose from 1990 to 2021, with heavier burden in older populations and lower socioeconomic regions. Cross-country inequality widened over time. Frontier analysis identified countries including India and Russia with considerable potential for improvement in disease control. Decomposition analysis uncovered epidemiological changes as the main driver of the growing burden globally. Risk factors of MDR-TB in different regions and age groups were heterogeneous. The numbers and ASRs of all indicators are predicted to increase by 2050.

Conclusions

This study revealed that the global disease burden of MDR-TB increased from 1990 to 2021 and is predicted to grow till 2050. Disparities among different social-demographic regions were remarkable and extended over time. Epidemiological changes contributed most to the escalated disease burden. Targeted public health strategies should be adopted for patients in specific regions and age groups.

目的利用全球疾病负担研究（GBD 2021）数据，分析1990 - 2021年全球耐多药结核病（MDR-TB）负担趋势和时空格局，并探讨其可能机制。方法本研究提取核心指标包括发病率、死亡率、患病率和残疾调整生命年（DALYs）及其年龄标准化率（ASR）。采用连接点回归、年龄-时期-队列分析、不平等分析和前沿分析来描述疾病负担的时空变化趋势。进行分解分析和危险因素分析，探讨影响耐多药结核病负担波动的相关因素。采用贝叶斯年龄-时期-队列（BAPC）模型预测到2050年的疾病负担。结果从1990年到2021年，全球耐多药结核病病例和所有指标的asr均有所上升，年龄较大的人群和社会经济水平较低的地区负担更重。跨国不平等随着时间的推移而扩大。前沿分析指出，包括印度和俄罗斯在内的国家在疾病控制方面具有相当大的改善潜力。分解分析发现，流行病学变化是全球负担日益加重的主要驱动因素。不同地区和年龄组耐多药结核病危险因素存在异质性。预计到2050年，所有指标的数量和asr都将增加。结论本研究表明，从1990年到2021年，全球耐多药结核病疾病负担有所增加，预计到2050年将继续增长。不同社会人口区域之间的差距是显著的，并随着时间的推移而扩大。流行病学变化是造成疾病负担升级的主要原因。应针对特定区域和年龄组的患者采取有针对性的公共卫生战略。

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引用次数: 0

Metabolic reprogramming of tumor-associated macrophages via adenosine-A2AR signaling drives cross-resistance in non-small cell lung cancer 肿瘤相关巨噬细胞通过腺苷- a2ar信号的代谢重编程驱动非小细胞肺癌的交叉耐药

IF 15.8 1区医学 Q1 PHARMACOLOGY & PHARMACY

Drug Resistance Updates

Pub Date : 2025-09-01 Epub Date: 2025-06-30 DOI: 10.1016/j.drup.2025.101272

Wen Ding , Jianshan Mo , Yingxue Su , Qiyi Zhang , Danyuan Sun , Xiangchao Yao , Guopin Liu , Jiangling Ye , Yanle Wu , Menghan Xue , Peibin Yue , Jinjian Lu , Jian Zhang , Yanyu Shi , Wenhao Hu , Kai Zhu , Yandong Wang , Xiaolei Zhang

Immunosuppression within the tumor microenvironment (TME) is frequently associated with chemoresistance. However, the mechanisms by which chemoresistance promotes immune evasion and impairs subsequent immunotherapy remain poorly understood, underscoring the urgent need for novel therapeutic strategies to counteract these effects. In this study, we observed that tumors exhibit cross-resistance to immunotherapy following chemoresistance in a non-small cell lung cancer (NSCLC) mouse model. The aberrant accumulation of tumor-associated macrophages (TAMs) and extracellular adenosine (Ado) were identified as mediators of immunosuppression, fostering cross-resistance to immunotherapy in the context of chemoresistance. Mechanistically, selective activation of the Ado/A_2AR signaling pathway induced metabolic reprogramming of TAMs, thereby creating an immunosuppressive niche in cross-resistant NSCLC. Based on these findings, we designed a novel selective A_2AR inhibitor DL082 and explored its therapeutic potential for treating cross-resistant NSCLC. The combination of DL082 with an anti-PD-L1 antibody significantly enhanced immune activation and inhibited tumor progression in cross-resistant NSCLC. These findings elucidate the specific mechanisms underlying cross-resistance between chemotherapy and immunotherapy in NSCLC and propose targeting the Ado-TAM axis as a potential strategy for overcoming resistance in NSCLC therapy.

肿瘤微环境（TME）内的免疫抑制通常与化疗耐药有关。然而，化疗耐药促进免疫逃避和损害后续免疫治疗的机制仍然知之甚少，强调迫切需要新的治疗策略来抵消这些影响。在这项研究中，我们在非小细胞肺癌（NSCLC）小鼠模型中观察到肿瘤在化疗耐药后对免疫治疗表现出交叉耐药。肿瘤相关巨噬细胞（tam）和细胞外腺苷（Ado）的异常积累被认为是免疫抑制的介质，在化疗耐药的背景下促进对免疫治疗的交叉耐药。从机制上讲，Ado/A2AR信号通路的选择性激活诱导了tam的代谢重编程，从而在交叉耐药NSCLC中创建了免疫抑制生态位。基于这些发现，我们设计了一种新的选择性A2AR抑制剂DL082，并探索其治疗交叉耐药NSCLC的治疗潜力。DL082联合抗pd - l1抗体可显著增强交叉耐药NSCLC的免疫激活并抑制肿瘤进展。这些发现阐明了非小细胞肺癌化疗和免疫治疗交叉耐药的具体机制，并提出靶向Ado-TAM轴作为克服非小细胞肺癌治疗耐药的潜在策略。

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引用次数: 0

Corrigendum to “A novel platinum(IV) prodrug, gramine-Pt(IV) enhances chemoimmunotherapy by activating cGAS-STING and modulating TGF-β-MHC-I axis” [Drug Resist. Updates 81 (2025) 101252] “一种新型铂（IV）前药，gramine-Pt（IV）通过激活cGAS-STING和调节TGF-β-MHC-I轴来增强化学免疫治疗”的勘误表。更新81 (2025)101252]

IF 15.8 1区医学 Q1 PHARMACOLOGY & PHARMACY

Drug Resistance Updates

Pub Date : 2025-09-01 Epub Date: 2025-06-13 DOI: 10.1016/j.drup.2025.101268

Bowen Ding , Xiaomeng Liu , Zhe Li , Xinru Xie , Jiaqi Li , Jiaqian Wang , Shouyi Li , Pengyu Wang , Yongjie Xie , Xiaoqing Ma , Hongwei Wang , Chengzhi Xie , Xin Qiao , Yumin Wang , Jingyuan Xu , Yukuan Feng , Jihui Hao

引用次数: 0

Molecular mechanisms of acquired resistance to EGFR tyrosine kinase inhibitors in non-small cell lung cancer 非小细胞肺癌对EGFR酪氨酸激酶抑制剂获得性耐药的分子机制

IF 15.8 1区医学 Q1 PHARMACOLOGY & PHARMACY

Drug Resistance Updates

Pub Date : 2025-09-01 Epub Date: 2025-06-09 DOI: 10.1016/j.drup.2025.101266

Zhenfang Du , Hongfei Kan , Jinghan Sun , Yue Liu , Jiahui Gu , Shugela Akemujiang , Yudi Zou , Lufan Jiang , Qinzhuo Wang , Chen Li , Lei Luo , Yunkai Zhang , Hong Fan , Pengfei Luo , Bo Wang

Tyrosine kinase inhibitors (TKIs) have revolutionized the management of epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). Despite the initially favorable outcomes, these patients inevitably acquire resistance to EGFR-TKIs. The molecular mechanism of the acquired resistance is highly complex and heterogeneous, and can be generalized as three categories, including EGFR pathway reactivation (re-engagement of EGFR downstream), EGFR pathway bypass (adoption of a parallel pathway to re-engage the downstream transcriptional oncogenic output of the original EGFR), and EGFR pathway indifference (acquirement of a cellular state alternate to the original EGFR-driven output). This review summarizes the recent progress on the identification and understanding of the acquired resistance mechanisms to EGFR-TKIs in patients with NSCLC. The potential strategies to delay or overcome the acquired resistance are also discussed.

酪氨酸激酶抑制剂（TKIs）已经彻底改变了表皮生长因子受体（EGFR）突变的非小细胞肺癌（NSCLC）的治疗。尽管最初结果良好，但这些患者不可避免地对EGFR-TKIs产生耐药性。获得性耐药的分子机制是高度复杂和异质性的，可以概括为三类，包括EGFR途径再激活（EGFR下游重新参与），EGFR途径旁路（采用平行途径重新参与原始EGFR的下游转录致癌输出），以及EGFR途径无差异（获得替代原始EGFR驱动输出的细胞状态）。本文综述了近年来对NSCLC患者EGFR-TKIs获得性耐药机制的研究进展。本文还讨论了延迟或克服获得性耐药性的潜在策略。

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引用次数: 0

Exosome-derived lnc-FAM72D-3 promotes lenvatinib resistance by remodeling hepatocellular carcinoma cytoskeleton via MBNL1/FAK axis 外泌体衍生的lnc-FAM72D-3通过MBNL1/FAK轴重塑肝癌细胞骨架，促进lenvatinib耐药

IF 15.8 1区医学 Q1 PHARMACOLOGY & PHARMACY

Drug Resistance Updates

Pub Date : 2025-09-01 Epub Date: 2025-06-07 DOI: 10.1016/j.drup.2025.101271

Mingbo Cao , Yuxuan Li , Xiaorui Su , Yongchang Tang , Yupeng Ren , Jing Luo , Feng Yuan , Gaoyuan Yang , Zhiwei He , Zheng Shi , Ziyi Hu , Guirong Liang , Qi Zhang , Meihai Deng , Zhicheng Yao , Nan Lin

Lenvatinib resistance (LR) profoundly exacerbates the prognosis of patients afflicted with advanced hepatocellular carcinoma (HCC). As pivotal mediators of intercellular communication, exosomes have been implicated in the development of LR. Nonetheless, the precise contributions of exosome-derived long non-coding RNAs (lncRNAs) to this phenomenon remain inadequately elucidated. Our prior investigations identified that lnc-FAM72D-3 is markedly up-regulated in the serum exosomes of HCC patients, yet its specific functions and underlying mechanisms remain only partially defined. In this study, we established lenvatinib-resistant HCC cell lines and organoids and demonstrated, through rigorous in vitro and in vivo experiments, that exosome-derived lnc-FAM72D-3 facilitates HCC progression and contributes to the phenomenon of LR. Mechanistically, lnc-FAM72D-3 augments the affinity of the E3 ubiquitin ligase HECTD3 for MBNL1, inciting lysine 48-linked ubiquitination and subsequent degradation of MBNL1. This degradation diminishes the interaction between MBNL1 and focal adhesion kinase (FAK), precipitating the de-nucleation of FAK and its activation by phosphorylation. The activated FAK subsequently reorganizes the cytoskeleton, markedly enhancing the proliferation, invasion, and stemness of HCC cells, thereby fostering LR. In summary, this investigation offers novel mechanistic insights into the regulatory role of exosomal lncRNAs in LR and posits a potential therapeutic strategy aimed at mitigating LR in patients with HCC.

Lenvatinib耐药（LR）严重恶化了晚期肝细胞癌（HCC）患者的预后。作为细胞间通讯的关键介质，外泌体参与了LR的发展。尽管如此，外泌体衍生的长链非编码rna （lncRNAs）在这一现象中的确切作用仍未得到充分阐明。我们之前的研究发现，lnc-FAM72D-3在HCC患者的血清外泌体中明显上调，但其具体功能和潜在机制仅部分确定。在本研究中，我们建立了lenvatinib耐药HCC细胞系和类器官，并通过严格的体外和体内实验证明，外泌体衍生的lnc-FAM72D-3促进了HCC的进展，并促进了LR现象。从机制上讲，lnc-FAM72D-3增强了E3泛素连接酶het3对MBNL1的亲和力，刺激赖氨酸48连接的泛素化和随后的MBNL1降解。这种降解减少了MBNL1和focal adhesion kinase （FAK）之间的相互作用，促使FAK去核并通过磷酸化激活FAK。激活的FAK随后重组细胞骨架，显著增强HCC细胞的增殖、侵袭和干性，从而促进LR。总之，这项研究为外泌体lncRNAs在LR中的调节作用提供了新的机制见解，并提出了一种旨在减轻HCC患者LR的潜在治疗策略。

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引用次数: 0

Hypoxia-induced upregulation of HIF1A-AS3 promotes MSC transition to cancer-associated fibroblasts and confers drug resistance in gastric cancer 缺氧诱导的HIF1A-AS3上调可促进间充质干细胞向癌症相关成纤维细胞转化，并在胃癌中产生耐药性

IF 15.8 1区医学 Q1 PHARMACOLOGY & PHARMACY

Drug Resistance Updates

Pub Date : 2025-09-01 Epub Date: 2025-07-14 DOI: 10.1016/j.drup.2025.101275

Jiajin Xu , Shuo Fang , Xiaotong Dong , Chengdong Liang , Ruoyu Yang , Yang Zhao , Hailong Gu , Min Fu , Jiahui Zhang , Xiaoxin Zhang , Xu Zhang , Runbi Ji

Chemotherapy resistance is a major cause of poor prognosis in gastric cancer patients and tumor microenvironment plays a critical role in conferring chemotherapy resistance. As a dominant source of tumor stromal cells, mesenchymal stem cells (MSCs) exert pro-oncogenic activities when reprogrammed to a cancer-associated fibroblast (CAF) phenotype. The precise mechanisms for MSC reprogramming and their subsequent role in chemotherapy resistance have not been fully understood. Herein, we reported that HIF1A-AS3, a lncRNA that was highly expressed in tumor-promoting MSCs, was upregulated in tumor tissues and serum of gastric cancer patients and associated with poor prognosis. The upregulation of HIF1A-AS3 reprogramed MSCs to acquire the CAF phenotype, which consequently enhanced the resistance of gastric cancer cells to oxaliplatin. Mechanistically, hypoxia related transcription factor HIF-1α induced high expression of HIF1A-AS3 in MSCs. Then, HIF1A-AS3 competitively sponged miR-142–3p and miR-24–3p, leading to the upregulation of PROX1 (prospero-related homeobox protein 1) gene expression. This further promoted the nuclear translocation of β-catenin and the activation of β-catenin signaling pathway in MSCs, which critically regulated their transition to CAFs. Finally, targeted inhibition of HIF1A-AS3 in hypoxia-MSCs through exosome-mediated siRNA delivery significantly suppressed gastric cancer growth and improved chemosensitivity in mouse tumor models. Conclusively, hypoxia-induced HIF1A-AS3 upregulation reprograms MSCs to CAFs through the miR-142–3p/miR-24–3p/PROX1/β-catenin axis, thereby promoting chemotherapy resistance in gastric cancer, which uncovers a new molecular mechanism for MSCs transition to CAFs in gastric cancer and provides a new target for the diagnosis and targeted therapy of gastric cancer.

化疗耐药是胃癌患者预后不良的主要原因，肿瘤微环境在化疗耐药的形成中起着至关重要的作用。作为肿瘤基质细胞的主要来源，间充质干细胞（MSCs）在重编程为癌症相关成纤维细胞（CAF）表型时发挥促癌活性。MSC重编程的确切机制及其在化疗耐药中的后续作用尚未完全了解。本文中，我们报道了在促肿瘤MSCs中高表达的lncRNA HIF1A-AS3在胃癌患者的肿瘤组织和血清中表达上调，并与不良预后相关。HIF1A-AS3的上调使MSCs重编程获得CAF表型，从而增强胃癌细胞对奥沙利铂的抗性。机制上，缺氧相关转录因子HIF-1α诱导MSCs中高表达HIF1A-AS3。然后，HIF1A-AS3竞争性地海绵化miR-142-3p和miR-24-3p，导致PROX1 （prospero-related homobox protein 1）基因表达上调。这进一步促进了β-catenin的核易位和β-catenin信号通路的激活，这对MSCs向CAFs的转变起着关键的调节作用。最后，在小鼠肿瘤模型中，通过外泌体介导的siRNA递送靶向抑制HIF1A-AS3在缺氧间充质干细胞中显著抑制胃癌生长并改善化疗敏感性。总之，缺氧诱导的HIF1A-AS3上调通过miR-142-3p/miR-24-3p/PROX1/β-catenin轴将MSCs重编程为CAFs，从而促进胃癌的化疗耐药，揭示了胃癌中MSCs向CAFs转变的新的分子机制，为胃癌的诊断和靶向治疗提供了新的靶点。

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引用次数: 0