Translational Oncology最新文献_第5页

CAV1 inhibits Xc- system through IFNGR1 to promote ferroptosis to inhibit stemness and improves anti-PD-1 efficacy in breast cancer CAV1 通过 IFNGR1 抑制 Xc- 系统，促进铁凋亡，从而抑制干细胞，提高乳腺癌的抗 PD-1 疗效

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2024-10-11 DOI: 10.1016/j.tranon.2024.102149

Wenhong Liu, Guanghua Luo

Breast cancer is the most prevalent malignancy among women worldwide, with breast cancer stem cells (BCSCs) being the primary drivers of metastasis and recurrence. Numerous studies have elucidated the relationship between ferroptosis and cellular stemness, identifying the Xc^- system as a key regulatory mechanism governing ferroptosis. However, the interplay between CAV1 and ferroptosis, along with its implications for stemness in breast cancer, remains inadequately understood. This gap in knowledge impedes advancements in targeted therapies for breast cancer. We employed immunohistochemistry and bioinformatics analyses to demonstrate the downregulation of CAV1 in breast cancer tissues. Additionally, we utilized CCK-8 assays, EDU staining, and Transwell assays to assess cell proliferation, migration, and invasion capabilities. Furthermore, we evaluated indicators associated with ferroptosis while examining markers related to stemness through sphere culture experiments and flow cytometry techniques. Our findings indicate that CAV1 expression can induce cell death via ferroptosis while simultaneously inhibiting both cell proliferation and features of stemness by upregulating IFNGR1 and promoting ferroptosis. Moreover, our in vivo experiments revealed that overexpression of CAV1 enhances the efficacy of anti-PD-1 therapy. In conclusion, our study elucidates the regulatory role of CAV1 on ferroptosis within breast cancer contexts; it suppresses BCSC characteristics while positioning CAV1 as a promising therapeutic target for combating this disease.

乳腺癌是全球女性中发病率最高的恶性肿瘤，乳腺癌干细胞（BCSCs）是导致转移和复发的主要因素。大量研究阐明了铁凋亡与细胞干性之间的关系，确定Xc-系统是管理铁凋亡的关键调控机制。然而，人们对CAV1和铁凋亡之间的相互作用及其对乳腺癌干性的影响仍然了解不足。这一知识空白阻碍了乳腺癌靶向疗法的发展。我们利用免疫组化和生物信息学分析证明了CAV1在乳腺癌组织中的下调。此外，我们还利用 CCK-8 检测法、EDU 染色法和 Transwell 检测法来评估细胞的增殖、迁移和侵袭能力。此外，我们还评估了与铁突变相关的指标，同时通过球培养实验和流式细胞术技术检查了与干性相关的标记物。我们的研究结果表明，CAV1的表达可通过铁中毒诱导细胞死亡，同时通过上调IFNGR1和促进铁中毒抑制细胞增殖和干性特征。此外，我们的体内实验还发现，CAV1的过表达能增强抗PD-1疗法的疗效。总之，我们的研究阐明了 CAV1 在乳腺癌中对铁凋亡的调控作用；它抑制了 BCSC 的特征，同时将 CAV1 定位为抗击这种疾病的一个有前景的治疗靶点。

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引用次数: 0

lncRNA WAC-AS1 promotes the progression of gastric cancer through miR-204-5p/HOXC8 axis lncRNA WAC-AS1通过miR-204-5p/HOXC8轴促进胃癌进展

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2024-10-11 DOI: 10.1016/j.tranon.2024.102139

Yan Liu , Kaixuan Li , Yongjian Gao , Ye Feng , Xiaoling Zhao , Ruizhi Hou

LncRNAs affect tumorigenesis, and although the genesis, regulation and physiological mechanism of lncRNAs in gastric cancer (GC) have been reported, the research of lncRNAs still have a lot of value. Through comprehensive bioinformatics analysis, we screened the candidate lncRNA WAC-AS1(WAC-AS1). We analyzed WAC-AS1 expression in GC related tissues and cells using qRT-PCR. WAC-AS1’s impact on GC growth and metastasis was investigated. LncRNA WC-AS-miR-204-5p-HOXC8 interaction was established through dual-luciferase reporter, FISH, RIP and RNA pull-down assay. We observed substantial upregulation in WAC-AS1 expression in cells and tissues of GC. WAC-AS1 through miR-204-5p/HOXC8 axis promoted GC proliferation, invasion, and migration. WAC-AS1 plays a cancer-promoting role for promoting the progression of GC.

LncRNAs影响肿瘤的发生，尽管lncRNAs在胃癌（GC）中的发生、调控和生理机制已有报道，但对lncRNAs的研究仍有很大价值。通过全面的生物信息学分析，我们筛选出了候选lncRNA WAC-AS1（WAC-AS1）。我们利用qRT-PCR技术分析了WAC-AS1在GC相关组织和细胞中的表达。研究了WAC-AS1对GC生长和转移的影响。通过双荧光素酶报告、FISH、RIP和RNA pull-down实验，确定了LncRNA WC-AS-miR-204-5p-HOXC8的相互作用。我们观察到 WAC-AS1 在 GC 细胞和组织中的表达大幅上调。WAC-AS1 通过 miR-204-5p/HOXC8 轴促进了 GC 的增殖、侵袭和迁移。WAC-AS1在促进GC进展方面起着促癌作用。

引用次数: 0

HSP90AA1 is an unfavorable prognostic factor for hepatocellular carcinoma and contributes to tumorigenesis and chemotherapy resistance HSP90AA1 是肝细胞癌的一个不利预后因素，并导致肿瘤发生和化疗耐药。

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2024-10-10 DOI: 10.1016/j.tranon.2024.102148

Zhaoying Wang , Longfei Fan , Heng Xu , Zhongqiang Qin , Ziyi Zhu , Di Wu , Yigang Zhang , Ruoyu Liu , Jianzhu Wei , Zhen Qian , Peipei Yang , Bo Xie , Mu Yuan , Jingyu Qian

Hepatocellular carcinoma (HCC) is still one of the leading causes of tumor-related deaths. Accumulating evidence indicates that immunogenic cell death (ICD) could occur in tumor cells. However, ICD-related studies are limited in HCC. This study collected HCC RNA sequencing data from the Cancer Genome Atlas, International Cancer Genome Consortium, and Gene Expression Omnibus databases. R software was used to analyze the expression of ICD in HCC and to screen essential genes with prognostic value. qRT-PCR and WB determined the mRNA and protein expressions of hub gene. Cell viability assay, Clonal formation assay, and Live/dead staining assay were employed to determine the gene functions. After cross-analysis of differentially expressed genes (DEGs) and ICD-related genes (ICDRGs), 7 differentially expressed ICDRGs were identified in HCC. Of them, HSP90AA1, with the most excellent prognostic value in HCC, was selected, whose expression was also validated in public cohorts, cell lines, and clinical tissue samples. High HSP90AA1 expression indicated an inferior prognosis of HCC, and HSP90AA1 knockdown significantly suppressed cell viability and chemotherapy resistance of HCC. ICD-related gene HSP90AA1 was an unfavorable factor for HCC, and high HSP90AA1 expression contributed to tumor cell survival and chemotherapy resistance.

肝细胞癌（HCC）仍然是导致肿瘤相关死亡的主要原因之一。越来越多的证据表明，免疫性细胞死亡（ICD）可能发生在肿瘤细胞中。然而，在 HCC 中与 ICD 相关的研究还很有限。本研究从癌症基因组图谱（Cancer Genome Atlas）、国际癌症基因组联盟（International Cancer Genome Consortium）和基因表达总库（Gene Expression Omnibus）数据库中收集了 HCC RNA 测序数据。使用 R 软件分析 ICD 在 HCC 中的表达，并筛选出具有预后价值的重要基因。采用细胞活力检测、克隆形成检测和活/死染色检测来确定基因的功能。在对差异表达基因（DEGs）和ICD相关基因（ICDRGs）进行交叉分析后，发现了7个在HCC中差异表达的ICDRGs。其中，HSP90AA1 在 HCC 中的预后价值最高，其表达也在公共队列、细胞系和临床组织样本中得到了验证。HSP90AA1 的高表达表明 HCC 的预后较差，而 HSP90AA1 的敲除能显著抑制 HCC 的细胞活力和化疗耐药性。ICD相关基因HSP90AA1是HCC的不利因素，HSP90AA1的高表达导致肿瘤细胞存活和化疗耐药。

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引用次数: 0

Oncolytic vaccinia virus armed with 4–1BBL elicits potent and safe antitumor immunity and enhances the therapeutic efficiency of PD-1/PD-L1 blockade in a pancreatic cancer model 在胰腺癌模型中，以4-1BBL为载体的肿瘤溶解性疫苗病毒可激发强效、安全的抗肿瘤免疫，并提高PD-1/PD-L1阻断的治疗效率。

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2024-10-09 DOI: 10.1016/j.tranon.2024.102151

Yushi Ju , Feiyu Dai , Yirong Wang , Zhenyu Ye , Yang Li , Songguang Ju , Yan Ge , Wei Chen

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease with a poor prognosis. Mono-immunotherapy, such as blockade of the PD-1/PD-L1 pathway, for PDAC has proven to be less effective. The systemic exertion of 4–1BB signaling enhanced antitumor immunity accompanied by hepatotoxicity, which is an obstacle for its clinical application. Our study exploits an oncolytic virus armed with 4–1BBL (VV-ΔTK-4L) to locally express 4–1BBL in the tumor microenvironment (TME), thus avoiding hepatotoxicity. VV-ΔTK-4L prolonged the survival time of a pancreatic tumor mouse model and modified the immune status of the TME and spleen. In the TME, the quantities of CD45⁺ cells, NK1.1⁺ cells, CD11c⁺ DCs, CD3⁺ T, CD4⁺ T, and CD8⁺ T cells increased. Compared to VV-ΔTK treatment, VV-ΔTK-4L further increases the number of CD8⁺ T cells with effector phenotypes, and downregulates exhaustion-related molecules on CD8⁺ T cells, and does not increase the proportion of Foxp3⁺ T cells. Thus, the TME of pancreatic cancer was converted from “cold” to “hot” by VV-ΔTK-4L. Blockade of the PD-1/PD-L1 pathway combined with VV-ΔTK-4L further significantly improves the survival ratio of a tumor-bearing mouse model. This study provides a systemic therapeutic strategy and approach for PDAC immunotherapy.

胰腺导管腺癌（PDAC）是一种致死率极高、预后极差的疾病。针对 PDAC 的单一免疫疗法，如阻断 PD-1/PD-L1 通路，已被证明效果不佳。4-1BB信号的全身作用增强了抗肿瘤免疫力，但同时也带来了肝脏毒性，这是临床应用的一个障碍。我们的研究利用带有4-1BBL的溶瘤病毒（VV-ΔTK-4L）在肿瘤微环境（TME）中局部表达4-1BBL，从而避免了肝毒性。VV-ΔTK-4L 延长了胰腺肿瘤小鼠模型的存活时间，并改变了肿瘤微环境和脾脏的免疫状态。在TME中，CD45+细胞、NK1.1+细胞、CD11c+ DCs、CD3+T、CD4+T和CD8+T细胞的数量均有所增加。与 VV-ΔTK 处理相比，VV-ΔTK-4L 进一步增加了具有效应表型的 CD8+T 细胞的数量，并下调了 CD8+T 细胞上的衰竭相关分子，但没有增加 Foxp3+T 细胞的比例。因此，VV-ΔTK-4L 将胰腺癌的 TME 从 "冷 "转化为 "热"。结合 VV-ΔTK-4L 阻断 PD-1/PD-L1 通路还能进一步显著提高肿瘤小鼠模型的生存率。这项研究为PDAC免疫疗法提供了一种系统治疗策略和方法。

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引用次数: 0

MicroRNA-450b-5p modulated RPLP0 promotes hepatocellular carcinoma progression via activating JAK/STAT3 pathway 微RNA-450b-5p调节的RPLP0通过激活JAK/STAT3通路促进肝细胞癌的进展。

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2024-10-08 DOI: 10.1016/j.tranon.2024.102150

Yanqiu Meng , Xianbin Huang , Guangxin Zhang , Sansan Fu , Youhua Li , Jielong Song , Yizi Zhu , Xinping Xu , Xiaodong Peng

Hepatocellular carcinoma (HCC) is distinguished by its insidious onset, difficult treatment, and poor prognosis. Ribosomal Protein Lateral Stalk Subunit P0 (RPLP0) is implicated in numerous tumor progression processes. Nevertheless, the regulatory mechanism of RPLP0 in HCC progression remains unclear. Our study suggested that RPLP0 exhibits high expression levels in HCC and possesses promising diagnostic capabilities, as indicated by its area under the curve (AUC) of 0.908. Further analysis showed that RPLP0 was a significant independent prognostic factor, and elevated expression levels of RPLP0 were linked with poorer overall survival (OS) and progression-free interval (PFI) outcomes. Additionally, reducing RPLP0 levels led to a decrease in HCC cell proliferation, clonality, invasion, migration, and xenograft tumor growth, as well as an increase in apoptosis. Furthermore, our findings indicated that microRNA(miR)-450b-5p induced downregulation of RPLP0, leading to the suppression of the JAK/STAT3 pathway and consequently hindering the advancement of HCC. The study indicates that RPLP0 plays a role as a carcinogenic factor in HCC and carries important diagnostic and prognostic implications. Targeting the miR-450b-5p/RPLP0/JAK/STAT3 axis has potential clinical value in treating HCC.

肝细胞癌（HCC）以起病隐匿、治疗困难和预后不良而闻名。核糖体蛋白侧柄亚基 P0（RPLP0）与许多肿瘤进展过程有关。然而，RPLP0在HCC进展中的调控机制仍不清楚。我们的研究表明，RPLP0 在 HCC 中呈现高表达水平，其曲线下面积（AUC）为 0.908，具有良好的诊断能力。进一步的分析表明，RPLP0 是一个重要的独立预后因素，RPLP0 表达水平的升高与较差的总生存期（OS）和无进展间期（PFI）结果有关。此外，降低 RPLP0 水平可减少 HCC 细胞的增殖、克隆性、侵袭、迁移和异种移植肿瘤的生长，并增加细胞凋亡。此外，我们的研究结果表明，microRNA（miR）-450b-5p 可诱导 RPLP0 下调，从而抑制 JAK/STAT3 通路，进而阻碍 HCC 的发展。该研究表明，RPLP0 在 HCC 中扮演着致癌因子的角色，具有重要的诊断和预后意义。针对 miR-450b-5p/RPLP0/JAK/STAT3 轴治疗 HCC 具有潜在的临床价值。

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引用次数: 0

Unraveling the mechanisms of RECQL4-mediated cervical cancer progression through the PI3K/AKT pathway 揭示 RECQL4 通过 PI3K/AKT 通路介导宫颈癌进展的机制。

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2024-10-07 DOI: 10.1016/j.tranon.2024.102146

Wen Huo , Yiheng Huang , Baoqinq Tian , Xiaozheng Chen , Jie Lu , Xinyi Huang , Meng Wu , Jinming Yu , Dawei Chen , Ruozheng Wang

Background

RECQL4 is a member of the DNA helicase family and is critical for DNA replication, DNA damage repair, and tumor progression. However, its specific role in cervical cancer remains uncertain.

Methods

In this study, we aimed to investigate the impact of RECQL4 on cervical cancer prognosis using clinical specimens from The Cancer Genome Atlas. We evaluated the malignant effects of RECQL4 through various experimental assays including cell Cell Counting Kit-8, EdU, colony formation, cell cycle analysis, cell apoptosis, scratch, and Transwell assays. We explored the mechanisms of RECQL4-regulated malignancy using analyses of bioinformatics, RNA sequencing data, polymerase chain reaction (PCR), western blotting, and cell immunofluorescence experiments. Furthermore, we validated the effects of RECQL4 knockdown on tumor growth using subcutaneous tumor models in nude mice.

Results

RECQL4 was upregulated in cervical cancer and correlated with prognosis, demonstrating a positive relationship with tumor mutational burden. Knockdown of RECQL4 inhibits cervical cancer cell proliferation, migration, and invasion, suppresses epithelial-mesenchymal transition status, induces cell cycle arrest, and promotes apoptosis. Mechanistically, RECQL4 mediated malignancy through the PI3K/AKT pathway and reduced nuclear β-catenin expression. In vivo studies further confirmed that RECQL4 knockout significantly inhibited tumor growth.

Conclusions

Our findings provide novel insights into the mechanism behind RECQL4-mediated cervical cancer progression through the PI3K/AKT pathway. Furthermore, our study suggests potential therapeutic strategies for targeting RECQL4 in cervical cancer treatment.

背景RECQL4是DNA螺旋酶家族的成员，对DNA复制、DNA损伤修复和肿瘤进展至关重要。然而，它在宫颈癌中的具体作用仍不确定：本研究旨在利用癌症基因组图谱（The Cancer Genome Atlas）中的临床标本，研究 RECQL4 对宫颈癌预后的影响。我们通过细胞计数试剂盒-8、EdU、集落形成、细胞周期分析、细胞凋亡、划痕和 Transwell 试验等多种实验方法评估了 RECQL4 的恶性影响。我们通过生物信息学分析、RNA 测序数据、聚合酶链反应（PCR）、Western 印迹和细胞免疫荧光实验，探索了 RECQL4 调控恶性肿瘤的机制。此外，我们还利用裸鼠皮下肿瘤模型验证了 RECQL4 基因敲除对肿瘤生长的影响：结果：RECQL4在宫颈癌中上调，并与预后相关，与肿瘤突变负荷呈正相关。敲除 RECQL4 可抑制宫颈癌细胞的增殖、迁移和侵袭，抑制上皮-间质转化状态，诱导细胞周期停滞，促进细胞凋亡。从机理上讲，RECQL4通过PI3K/AKT途径介导恶性程度，并减少核β-catenin的表达。体内研究进一步证实，RECQL4敲除可显著抑制肿瘤生长：我们的研究结果为了解 RECQL4 通过 PI3K/AKT 通路介导宫颈癌进展的机制提供了新见解。此外，我们的研究还提出了在宫颈癌治疗中靶向 RECQL4 的潜在治疗策略。

{"title":"Unraveling the mechanisms of RECQL4-mediated cervical cancer progression through the PI3K/AKT pathway","authors":"Wen Huo , Yiheng Huang , Baoqinq Tian , Xiaozheng Chen , Jie Lu , Xinyi Huang , Meng Wu , Jinming Yu , Dawei Chen , Ruozheng Wang","doi":"10.1016/j.tranon.2024.102146","DOIUrl":"10.1016/j.tranon.2024.102146","url":null,"abstract":"<div><h3>Background</h3><div>RECQL4 is a member of the DNA helicase family and is critical for DNA replication, DNA damage repair, and tumor progression. However, its specific role in cervical cancer remains uncertain.</div></div><div><h3>Methods</h3><div>In this study, we aimed to investigate the impact of RECQL4 on cervical cancer prognosis using clinical specimens from The Cancer Genome Atlas. We evaluated the malignant effects of RECQL4 through various experimental assays including cell Cell Counting Kit-8, EdU, colony formation, cell cycle analysis, cell apoptosis, scratch, and Transwell assays. We explored the mechanisms of RECQL4-regulated malignancy using analyses of bioinformatics, RNA sequencing data, polymerase chain reaction (PCR), western blotting, and cell immunofluorescence experiments. Furthermore, we validated the effects of RECQL4 knockdown on tumor growth using subcutaneous tumor models in nude mice.</div></div><div><h3>Results</h3><div>RECQL4 was upregulated in cervical cancer and correlated with prognosis, demonstrating a positive relationship with tumor mutational burden. Knockdown of RECQL4 inhibits cervical cancer cell proliferation, migration, and invasion, suppresses epithelial-mesenchymal transition status, induces cell cycle arrest, and promotes apoptosis. Mechanistically, RECQL4 mediated malignancy through the PI3K/AKT pathway and reduced nuclear β-catenin expression. In vivo studies further confirmed that RECQL4 knockout significantly inhibited tumor growth.</div></div><div><h3>Conclusions</h3><div>Our findings provide novel insights into the mechanism behind RECQL4-mediated cervical cancer progression through the PI3K/AKT pathway. Furthermore, our study suggests potential therapeutic strategies for targeting RECQL4 in cervical cancer treatment.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"50 ","pages":"Article 102146"},"PeriodicalIF":5.0,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142393559","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The PIK3CA gene and its pivotal role in tumor tropism of triple-negative breast cancer PIK3CA 基因及其在三阴性乳腺癌肿瘤滋养过程中的关键作用。

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2024-10-05 DOI: 10.1016/j.tranon.2024.102140

Sumit Mallick , Asim K Duttaroy , Suman Dutta

The PIK3CA gene is a linchpin in the intricate molecular network governing triple-negative breast cancer (TNBC) tumor tropism, serving as a focal point for understanding this aggressive disease. Anchored within the PI3K/AKT/mTOR signaling axis, PIK3CA mutations exert substantial influence, driving cellular processes that highlight the unique biology of TNBC. This review meticulously highlights the association between PIK3CA mutations and distinct TNBC subtypes, elucidating the gene's multifaceted contributions to tumor tropism. Molecular dissection reveals how PIK3CA mutations dynamically modulate chemokine responses, growth factor signaling, and extracellular matrix interactions, orchestrating the complex migratory behaviour characteristic of TNBC cells. A detailed exploration of PIK3CA-targeted strategies in the therapeutic arena is presented, outlining the current landscape of clinical trials and precision medicine approaches. As the scientific narrative converges, this review underscores the critical role of PIK3CA in shaping the molecular intricacies of TNBC tumor tropism and illuminates pathways toward tailored interventions, promising a paradigm shift in the clinical management of TNBC.

PIK3CA 基因是支配三阴性乳腺癌（TNBC）肿瘤趋向的复杂分子网络中的关键，是了解这种侵袭性疾病的焦点。PIK3CA 基因突变锚定在 PI3K/AKT/mTOR 信号转导轴上，对 TNBC 的细胞过程产生了重大影响，凸显了 TNBC 独特的生物学特性。这篇综述细致地强调了PIK3CA突变与不同TNBC亚型之间的关联，阐明了该基因对肿瘤滋养的多方面贡献。分子剖析揭示了PIK3CA突变如何动态调节趋化因子反应、生长因子信号转导和细胞外基质相互作用，从而协调TNBC细胞特有的复杂迁移行为。本文详细探讨了治疗领域的 PIK3CA 靶向策略，概述了当前的临床试验和精准医疗方法。随着科学叙事的汇聚，这篇综述强调了 PIK3CA 在形成 TNBC 肿瘤向性错综复杂的分子过程中的关键作用，并阐明了实现定制干预的途径，有望实现 TNBC 临床管理模式的转变。

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引用次数: 0

Dronedarone hydrochloride inhibits gastric cancer proliferation in vitro and in vivo by targeting SRC 盐酸决奈达隆通过靶向 SRC 在体外和体内抑制胃癌增殖。

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2024-10-05 DOI: 10.1016/j.tranon.2024.102136

Xuebo Lu , Weizhe Zhang , Xiaoxiao Yang , Xiao Yan , Zubair Hussain , Qiong Wu , Jinmin Zhao , Baoyin Yuan , Ke Yao , Zigang Dong , Kangdong Liu , Yanan Jiang

Background

Gastric cancer (GC) is a significant global concern, ranking as the fifth most prevalent cancer. Unfortunately, the five-year survival rate is less than 30 %. Additionally, approximately 50 % of patients experience a recurrence or metastasis. As a result, finding new drugs to prevent relapse is of utmost importance.

Methods

The inhibitory effect of Dronedarone hydrochloride (DH) on gastric cancer cells was examined using proliferation assays and anchorage-dependent assays. The binding of DH with SRC was detected by molecular docking, pull-down assays, and cellular thermal shift assays (CETSA). DH's inhibition of Src kinase activity was confirmed through in vitro kinase assays. The SRC knockout cells, established using the CRISPR-Cas9 system, were used to verify Src's role in GC cell proliferation. Patient-derived xenograft (PDX) models were employed to elucidate that DH suppressed tumor growth in vivo.

Results

Our research discovered DH inhibited GC cell proliferation in vitro and in vivo. DH bound to the SRC protein to inhibit the SRC/AKT1 signaling pathway in gastric cancer. Additionally, we observed a decrease in the sensitivity of gastric cancer cells to DH upon down-regulation of SRC. Notably, we demonstrated DH's anti-tumor effects were similar to those of Dasatinib, a well-known SRC inhibitor, in GC patient-derived xenograft models.

Conclusion

Our research has revealed that Dronedarone hydrochloride, an FDA-approved drug, is an SRC inhibitor that can suppress the growth of GC cells by blocking the SRC/AKT1 signaling pathway. It provides a scientific basis for use in the clinical treatment of GC.

背景：胃癌（GC）是全球关注的一个重大问题，是发病率排名第五的癌症。不幸的是，五年生存率不到 30%。此外，约 50% 的患者会出现复发或转移。因此，寻找预防复发的新药至关重要：方法：使用增殖试验和锚定依赖性试验研究了盐酸决奈达隆（DH）对胃癌细胞的抑制作用。通过分子对接、牵引试验和细胞热转移试验（CETSA）检测了 DH 与 SRC 的结合。体外激酶试验证实了 DH 对 Src 激酶活性的抑制作用。利用 CRISPR-Cas9 系统建立的 SRC 基因敲除细胞被用来验证 Src 在 GC 细胞增殖中的作用。我们还利用患者衍生异种移植（PDX）模型来阐明 DH 能抑制肿瘤在体内的生长：结果：我们的研究发现 DH 可抑制 GC 细胞在体外和体内的增殖。DH与SRC蛋白结合，抑制了胃癌中的SRC/AKT1信号通路。此外，我们观察到下调 SRC 后，胃癌细胞对 DH 的敏感性降低。值得注意的是，在胃癌患者衍生异种移植模型中，我们发现DH的抗肿瘤效果与著名的SRC抑制剂达沙替尼相似：我们的研究揭示了盐酸决奈达隆是一种SRC抑制剂，可以通过阻断SRC/AKT1信号通路抑制GC细胞的生长。这为用于临床治疗 GC 提供了科学依据。

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引用次数: 0

Spatial heterogeneity of infiltrating immune cells in the tumor microenvironment of non-small cell lung cancer 非小细胞肺癌肿瘤微环境中浸润免疫细胞的空间异质性。

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2024-10-03 DOI: 10.1016/j.tranon.2024.102143

Xinyue Liu , Yan Kong , Youwen Qian , Haoyue Guo , Lishu Zhao , Hao Wang , Kandi Xu , Li Ye , Yujin Liu , Hui Lu , Yayi He

Tumor-infiltrating lymphocytes (TILs) are essential components of the tumor microenvironment (TME) of non-small cell lung cancer (NSCLC). Still, it is difficult to describe due to their heterogeneity. In this study, five cell markers from NSCLC patients were analyzed. We segmented tumor cells (TCs) and TILs using Efficientnet-B3 and explored their quantitative information and spatial distribution. After that, we simulated multiplex immunohistochemistry (mIHC) by overlapping continuous single chromogenic IHCs slices. As a result, the proportion and the density of programmed cell death-ligand 1 (PD-L1)-positive TCs were the highest in the core. CD8+ T cells were the closest to the tumor (median distance: 41.71 μm), while PD-1+T cells were the most distant (median distance: 62.2μm), and our study found that most lymphocytes clustered together within the peritumoral range of 10-30 μm where cross-talk with TCs could be achieved. We also found that the classification of TME could be achieved using CD8+ T-cell density, which is correlated with the prognosis of patients. In addition, we achieved single chromogenic IHC slices overlap based on CD4-stained IHC slices. We explored the number and spatial distribution of cells in heterogeneous TME of NSCLC patients and achieved TME classification. We also found a way to show the co-expression of multiple molecules economically.

肿瘤浸润淋巴细胞（TILs）是非小细胞肺癌（NSCLC）肿瘤微环境（TME）的重要组成部分。然而，由于其异质性，很难对其进行描述。本研究分析了非小细胞肺癌患者的五种细胞标记物。我们使用 Efficientnet-B3 对肿瘤细胞（TCs）和 TILs 进行了分割，并探索了它们的定量信息和空间分布。然后，我们通过重叠连续的单色原 IHC 切片来模拟多重免疫组化（mIHC）。结果显示，程序性细胞死亡配体 1（PD-L1）阳性 TC 的比例和密度在核心区最高。CD8+T细胞距离肿瘤最近（中位距离：41.71 μm），而PD-1+T细胞距离肿瘤最远（中位距离：62.2 μm），我们的研究发现，大多数淋巴细胞聚集在瘤周10-30 μm的范围内，可与TC发生交叉对话。我们还发现，通过 CD8+ T 细胞密度可对 TME 进行分类，而 CD8+ T 细胞密度与患者的预后相关。此外，我们还在 CD4 染色 IHC 切片的基础上实现了单一色原 IHC 切片的重叠。我们探索了 NSCLC 患者异质性 TME 中细胞的数量和空间分布，并实现了 TME 分类。我们还找到了一种经济地显示多种分子共同表达的方法。

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引用次数: 0

Near-infrared photoimmunotherapy for osteosarcoma targeting epidermal growth factor receptor 针对表皮生长因子受体的骨肉瘤近红外光免疫疗法

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2024-10-01 DOI: 10.1016/j.tranon.2024.102132

Motofumi Suzuki , Hisataka Kobayashi , Hirofumi Hanaoka

Osteosarcoma is the most common bone tumor, and it possesses high metastatic propensity. Although systemic chemotherapy has improved its prognosis, improvements in survival rates have stalled in recent years. Moreover, the prognosis of patients with metastatic osteosarcoma remains poor. Near-infrared photoimmunotherapy (NIR-PIT) is a highly selective cancer therapy that induces immunogenic cell death (ICD), and the therapeutic effects spread to distant metastatic sites. Therefore, NIR-PIT could be useful in both primary and metastatic osteosarcoma treatment. In this study, we investigated the efficacy of NIR-PIT targeting epidermal growth factor receptor (EGFR) in osteosarcoma. The cytotoxic effects of NIR-PIT in osteosarcoma cell lines with different EGFR expression levels (MG63; high, Saos-2; low) were evaluated. NIR-PIT–induced cell death was dependent on the EGFR expression level. After NIR-PIT, swelling and bleb formation, the characteristic morphological changes induced by NIR-PIT associated with necrosis caused by the influx of extracellular fluid, were observed. In addition, the release of the ICD markers lactate dehydrogenase and ATP was detected after NIT-PIT. NIR-PIT significantly suppressed tumor growth in tumor-bearing mice. This study revealed that NIR-PIT targeting EGFR has therapeutic effects and induces ICD in osteosarcoma; thus, it is potentially a novel therapeutic strategy for primary and metastatic osteosarcoma.

骨肉瘤是最常见的骨肿瘤，具有高度转移倾向。虽然全身化疗改善了骨肉瘤的预后，但近年来其生存率的改善却停滞不前。此外，转移性骨肉瘤患者的预后仍然很差。近红外光免疫疗法（NIR-PIT）是一种高度选择性的癌症疗法，可诱导免疫性细胞死亡（ICD），治疗效果可扩散到远处的转移部位。因此，NIR-PIT 可用于原发性和转移性骨肉瘤的治疗。在这项研究中，我们探讨了以表皮生长因子受体（EGFR）为靶点的近红外-PIT在骨肉瘤中的疗效。我们评估了 NIR-PIT 在不同表皮生长因子受体表达水平（MG63；高；Saos-2；低）的骨肉瘤细胞系中的细胞毒性作用。NIR-PIT 诱导的细胞死亡取决于表皮生长因子受体的表达水平。近红外-PIT诱导细胞死亡与表皮生长因子受体表达水平有关。近红外-PIT诱导细胞死亡后，可观察到肿胀和出血点的形成，这是近红外-PIT诱导细胞死亡的特征性形态变化，与细胞外液流入导致细胞坏死有关。此外，NIT-PIT 还能检测到 ICD 标志物乳酸脱氢酶和 ATP 的释放。NIR-PIT 能明显抑制肿瘤小鼠的肿瘤生长。这项研究揭示了以表皮生长因子受体为靶点的 NIR-PIT 对骨肉瘤具有治疗作用，并能诱导 ICD，因此它有可能成为治疗原发性和转移性骨肉瘤的一种新型治疗策略。

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引用次数: 0