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METTL14 suppresses the expression of YAP1 and the stemness of triple-negative breast cancer. METTL14 可抑制 YAP1 的表达和三阴性乳腺癌的干性。
IF 11.4 1区 医学 Q1 ONCOLOGY Pub Date : 2024-11-20 DOI: 10.1186/s13046-024-03225-2
Xupeng Bai, Jiarui Liu, Shujie Zhou, Lingzhi Wu, Xiaojie Feng, Pumin Zhang

Background: Triple-negative breast cancer (TNBC) has pronounced stemness that is associated with relapse. N6-methyladenosine (m6A) plays a crucial role in shaping cellular behavior by modulating transcript expression. However, the role of m6A in TNBC stemness, as well as the mechanisms governing its abundance, has yet to be elucidated.

Methods: We analyzed proteomic and transcriptomic data derived from breast cancer cohorts, with an emphasis on m6A regulators. To unravel the role of m6A in TNBC, we employed RNA sequencing, methylated RNA immunoprecipitation sequencing, RNA immunoprecipitation, chromatin immunoprecipitation, and luciferase reporter assays with mesenchymal stem-like (MSL) TNBC models. The clinical relevance was validated using human tissue microarrays and publicly accessible databases.

Results: Our findings indicate that the global level of m6A modification in MSL TNBC is downregulated primarily due to the loss of methyltransferase-like 14 (METTL14). The diminished m6A modification is crucial for the maintenance of TNBC stemness, as it increases the expression of yes-associated protein 1 (YAP1) by blocking YTH domain-containing family protein 2 (YTHDF2)-mediated transcript decay, thereby promoting the activation of Hippo-independent YAP1 signaling. YAP1 is essential for sustaining the stemness regulated by METTL14. Furthermore, we demonstrated that the loss of METTL14 expression results from lysine-specific demethylase 1 (LSD1)-mediated removal of histone H3 lysine 4 methylation at the promoter region, which is critical for LSD1-driven stemness in TNBC.

Conclusion: These findings present an epi-transcriptional mechanism that maintains Hippo-independent YAP1 signaling and plays a role in preserving the undifferentiated state of TNBC, which indicates the potential for targeting the LSD1-METTL14 axis to address TNBC stemness.

背景:三阴性乳腺癌(TNBC三阴性乳腺癌(TNBC)具有明显的干性,与复发有关。N6-甲基腺苷(m6A)通过调节转录本的表达,在塑造细胞行为方面发挥着至关重要的作用。然而,m6A在TNBC干性中的作用及其丰度调节机制仍有待阐明:我们分析了来自乳腺癌队列的蛋白质组和转录组数据,重点研究了m6A调控因子。为了揭示m6A在TNBC中的作用,我们采用了RNA测序、甲基化RNA免疫沉淀测序、RNA免疫沉淀、染色质免疫沉淀和荧光素酶报告实验,并使用间充质干样(MSL)TNBC模型。使用人体组织芯片和可公开访问的数据库验证了临床相关性:我们的研究结果表明,MSL TNBC 中 m6A 修饰的整体水平下调主要是由于甲基转移酶样 14(METTL14)的缺失。m6A修饰的减少对TNBC干性的维持至关重要,因为它通过阻断含YTH结构域的家族蛋白2(YTHDF2)介导的转录本衰减,增加了是相关蛋白1(YAP1)的表达,从而促进了独立于Hippo的YAP1信号的激活。YAP1对于维持由METTL14调控的干性至关重要。此外,我们还证明,METTL14表达的丧失是赖氨酸特异性去甲基化酶1(LSD1)介导的启动子区域组蛋白H3赖氨酸4甲基化清除的结果,这对LSD1驱动的TNBC干性至关重要:这些发现提出了一种外转录机制,它能维持独立于Hippo的YAP1信号传导,并在保持TNBC未分化状态方面发挥作用,这表明以LSD1-METTL14轴为靶点解决TNBC干性问题具有潜力。
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引用次数: 0
Transcriptional and post-transcriptional regulation of CARMN and its anti-tumor function in cervical cancer through autophagic flux blockade and MAPK cascade inhibition. CARMN的转录和转录后调控及其通过自噬通路阻断和MAPK级联抑制在宫颈癌中的抗肿瘤功能。
IF 11.4 1区 医学 Q1 ONCOLOGY Pub Date : 2024-11-19 DOI: 10.1186/s13046-024-03229-y
Xing Zhang, Wenjing Yan, Hua Jin, Bingjia Yu, Hao Zhang, Bo Ding, Xue Chen, Yan Zhang, Qianqian Xia, Dan Meng, Jing Hu, Haohan Liu, Yamei Nie, Fengying Liu, Yun Zheng, Yiran Lu, Juan Wang, Mulong Du, Meilin Wang, Evan Yi-Wen Yu, Xiuting Li, Shizhi Wang

Background: LncRNAs play essential roles in multiple tumors. However, research on genome-wide lncRNA alterations and their functions in cervical cancer (CC) is limited. This study aims to explore key lncRNAs in CC progression and uncover the molecular mechanisms involved in the development of CC.

Methods: In this study, we analyzed 30 tissues from CC, cervical intraepithelial neoplasia (CIN), and normal (NOR) using transcriptome sequencing and weighted gene co-expression network analysis to establish gene modules related to the NOR-CIN-CC transition. Machine learning diagnostic models were employed to investigate the role of lncRNAs in this transition. Molecular biological experiments were conducted to elucidate the potential mechanisms of CARMN in CC, with a particular focus on its transcriptional and post-transcriptional regulation of abnormal expression in CC.

Results: CARMN was identified as a hub gene in two modules significantly associated with the NOR-CIN-CC transition. Analysis using ten machine learning models confirmed its critical role in this progression. The results of RNA-seq, qPCR and RNAScope performed in another cohort of 83 cervical tissues all showed that CARMN was significantly downregulated in CC. CARMN significantly enhanced the interaction between Keap1 and Nrf2, leading to increased ROS levels. The elevated ROS levels suppressed the Akt/mTOR signaling pathway, leading to autophagy arrest via autophagic flux blockade. Additionally, CARMN interacted with TFAP2α to repress MAPK13 transcription, further inhibiting the MAPK cascade. A promoter SNP (rs12517403) was found to increase CC risk (OR = 1.34, 95% CI = 1.11-1.61) and reduce CARMN expression by decreasing SP1 binding. Furthermore, the RNA binding proteins that could modulate CARMN RNA stability were also determined using RNA-pulldown assay. The results demonstrated that YBX1, a component of the coding region instability determinant (CRD)-mediated mRNA stabilization complex, promoted CARMN RNA stability. DHX9, another component of complex, acted as a scaffold to bridge YBX1 and CARMN.

Conclusions: CARMN exerts an anti-cancer effect in CC progression by inhibiting the Akt-mTOR and MAPK signaling pathways. rs12517403 and the YBX1/DHX9 complex are key mechanisms influencing its transcription and stability in CC cells. CARMN represents a promising biomarker for CC diagnosis and therapeutic target.

背景:LncRNA在多种肿瘤中发挥着重要作用。然而,有关全基因组lncRNA改变及其在宫颈癌(CC)中功能的研究还很有限。本研究旨在探索CC进展过程中的关键lncRNA,并揭示参与CC发展的分子机制:在这项研究中,我们利用转录组测序和加权基因共表达网络分析技术分析了30例CC、宫颈上皮内瘤变(CIN)和正常(NOR)组织,以建立与NOR-CIN-CC转变相关的基因模块。利用机器学习诊断模型研究了lncRNA在这一转变中的作用。进行了分子生物学实验,以阐明CARMN在CC中的潜在机制,尤其关注其对CC中异常表达的转录和转录后调控:结果:CARMN被确定为与NOR-CIN-CC转变显著相关的两个模块中的枢纽基因。使用十个机器学习模型进行的分析证实了CARMN在这一进展中的关键作用。在另一批 83 例宫颈组织中进行的 RNA-seq、qPCR 和 RNAScope 结果均显示,CARMN 在 CC 中明显下调。CARMN 明显增强了 Keap1 和 Nrf2 之间的相互作用,导致 ROS 水平升高。ROS 水平的升高抑制了 Akt/mTOR 信号通路,通过自噬通路阻断导致自噬停止。此外,CARMN 与 TFAP2α 相互作用,抑制了 MAPK13 的转录,进一步抑制了 MAPK 级联。研究发现,一个启动子 SNP(rs12517403)会增加 CC 风险(OR = 1.34,95% CI = 1.11-1.61),并通过减少 SP1 结合来降低 CARMN 的表达。此外,还利用 RNA-pulldown 试验确定了可调节 CARMN RNA 稳定性的 RNA 结合蛋白。结果表明,编码区不稳定性决定因子(CRD)介导的mRNA稳定复合物的一个成分YBX1促进了CARMN RNA的稳定性。DHX9是复合物的另一个成分,它是连接YBX1和CARMN的支架:rs12517403和YBX1/DHX9复合物是影响CARMN在CC细胞中转录和稳定性的关键机制。CARMN是一种很有前景的CC诊断生物标志物和治疗靶标。
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引用次数: 0
The prognostic role of ACSL4 in postoperative adjuvant TACE-treated HCC: implications for therapeutic response and mechanistic insights. ACSL4 在术后辅助 TACE 治疗的 HCC 中的预后作用:对治疗反应的影响和机理认识。
IF 11.4 1区 医学 Q1 ONCOLOGY Pub Date : 2024-11-19 DOI: 10.1186/s13046-024-03222-5
Ji Feng, Jin-Lian Bin, Xi-Wen Liao, Yong Wu, Yue Tang, Pei-Zhi Lu, Guang-Zhi Zhu, Qian-Ru Cui, Yock Young Dan, Guo-Huan Yang, Li-Xin Li, Jing-Huan Deng, Tao Peng, Shing Chuan Hooi, Jing Zhou, Guo-Dong Lu

Background: The response of hepatocellular carcinoma (HCC) to transarterial chemoembolization (TACE) treatment and its underlying mechanisms remain elusive. This study investigates the role of enzymes involved in fatty acid activation, specifically Acyl-CoA synthetase long chain 4 (ACSL4), in HCC patients treated with postoperative adjuvant TACE (PA-TACE) and in nutrient-deprived HCC cells.

Methods: We examined the expression of ACSL4 and its family members in HCC clinical samples and cell lines. The clinical significance of ACSL4, particularly regarding the prognosis of patients treated with PA-TACE, was assessed using two independent HCC cohorts. We further explored the role of ACSL4 in glucose starvation-induced cell death in HCC cells and xenograft mouse models.

Results: Among the family members, ACSL4 is the most up-regulated enzyme, associated with poor survival in HCC patients, particularly in post-recurrent TACE-treated patients in a Singapore cohort. ACSL4 is essential for HCC cell survival in response to glucose starvation, rather than to hypoxia or to the combination of hypoxia with doxorubicin or cisplatin. ACSL4-mediated arachidonic acid (AA) metabolism supports mitochondrial β-oxidation and energy production. CCAAT/enhancer binding protein α (CEBPA) transcriptionally regulates ACSL4 by binding 3 motifs (-623 to -613, -1197 to -1187 and -1745 to -1735) of ACSL4 upstream promoter region, enhancing its pro-survival effects. Furthermore, canagliflozin (Cana), a clinical-approved drug for type 2 diabetes, mimics glucose starvation and inhibits the growth of ACSL4-low xenograft tumors. Moreover, high ACSL4 or CEBPA expressions correlate with increased recurrence susceptibility after PA-TACE in the China-Guangxi HCC cohort.

Conclusions: The CEBPA-ACSL4 pathway is critical in protecting HCC cells from glucose starvation-induced cell death, suggesting that ACSL4 and CEBPA could serve as valuable prognostic indicators and potential therapeutic targets in the context of PA-TACE treatment for HCC.

背景:肝细胞癌(HCC)对经动脉化疗栓塞(TACE)治疗的反应及其内在机制仍不明确。本研究探讨了参与脂肪酸活化的酶,特别是酰基-CoA合成酶长链4(ACSL4),在接受术后辅助TACE(PA-TACE)治疗的HCC患者和营养缺乏的HCC细胞中的作用:我们检测了ACSL4及其家族成员在HCC临床样本和细胞系中的表达。方法:我们检测了 ACSL4 及其家族成员在 HCC 临床样本和细胞系中的表达情况,并利用两个独立的 HCC 队列评估了 ACSL4 的临床意义,尤其是与接受 PA-TACE 治疗的患者的预后有关的意义。我们进一步探讨了 ACSL4 在葡萄糖饥饿诱导的 HCC 细胞和异种移植小鼠模型中的作用:结果:在家族成员中,ACSL4是上调幅度最大的酶,与HCC患者的不良生存率有关,尤其是在新加坡队列中接受TACE治疗后的患者中。ACSL4是HCC细胞在葡萄糖饥饿条件下存活的必要条件,而不是在缺氧或缺氧与多柔比星或顺铂结合的条件下。ACSL4介导的花生四烯酸(AA)代谢支持线粒体β氧化和能量生成。CCAAT/增强子结合蛋白α(CEBPA)通过结合ACSL4上游启动子区的3个基序(-623至-613、-1197至-1187和-1745至-1735)转录调控ACSL4,增强其促生存作用。此外,临床批准的 2 型糖尿病药物卡格列净(Cana)可模拟葡萄糖饥饿,抑制低 ACSL4 异种移植肿瘤的生长。此外,在中国-广西HCC队列中,ACSL4或CEBPA高表达与PA-TACE后复发易感性增加相关:结论:CEBPA-ACSL4通路在保护HCC细胞免受葡萄糖饥饿诱导的细胞死亡方面至关重要,这表明ACSL4和CEBPA可作为有价值的预后指标和PA-TACE治疗HCC的潜在治疗靶点。
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引用次数: 0
The KLF16/MYC feedback loop is a therapeutic target in bladder cancer. KLF16/MYC 反馈环是膀胱癌的治疗靶点。
IF 11.4 1区 医学 Q1 ONCOLOGY Pub Date : 2024-11-18 DOI: 10.1186/s13046-024-03224-3
Lisi Zheng, Jingxuan Wang, Shan Han, Li Zhong, Zefu Liu, Bin Li, Ruhua Zhang, Liwen Zhou, Xianchong Zheng, Zhenhua Liu, Cuiling Zeng, Ruonan Li, Yezi Zou, Liqin Wang, Yuanzhong Wu, Tiebang Kang

Background: Bladder cancer (BLCA) is a common malignancy characterized by dysregulated transcription and a lack of effective therapeutic targets. In this study, we aimed to identify and evaluate novel targets with clinical potential essential for tumor growth in BLCA.

Methods: CRISPR-Cas9 screening was used to identify transcription factors essential for bladder cancer cell viability. The biological functions of KLF16 in bladder cancer were investigated both in vitro and in vivo. The regulatory mechanism between KLF16 and MYC was elucidated through a series of analyses, including RNA sequencing, quantitative polymerase chain reaction (qPCR), RNA immunoprecipitation, Western blotting, Mass spectrometry, Dual-luciferase reporter assays, Cleavage Under Targets and Tagmentation (CUT&Tag) sequencing, OptoDroplets assays, and RNA stability assay. The clinical relevance of KLF16 and MYC in bladder cancer was evaluated through analyses of public databases and immunohistochemistry.

Results: Krüppel-like factor 16 (KLF16) was essential for BLCA cell viability. Elevated expression of KLF16 was observed in bladder cancer tissues, and higher expression levels of KLF16 were correlated with poor progression-free survival (PFS) and cancer-specific survival (CSS) probabilities in BLCA patients. Mechanistically, KLF16 mRNA competed with the mRNA of dual-specificity phosphatase 16 (DUSP16) for binding to the RNA-binding protein, WW domain binding protein 11 (WBP11), resulting in destabilization of the DUSP16 mRNA. This, in turn, led to activation of ERK1/2, which stabilized the MYC protein. Furthermore, KLF16 interacted with MYC to form nuclear condensates, thereby enhancing MYC's transcriptional activity. Additionally, MYC transcriptionally upregulated KLF16, creating a positive feedback loop between KLF16 and MYC that amplified their oncogenic functions. Targeting this loop with bromodomain inhibitors, such as OTX015 and ABBV-744, suppressed the transcription of both KLF16 and MYC, resulting in reduced BLCA cell viability and tumor growth, as well as increased sensitivity to chemotherapy.

Conclusions: Our study revealed the crucial role of the KLF16/MYC regulatory axis in modulating tumor growth and chemotherapy sensitivity in BLCA, suggesting that combining bromodomain inhibitors, such as OTX015 or ABBV-744, with DDP or gemcitabine could be a promising therapeutic intervention for BLCA patients.

背景:膀胱癌(BLCA)是一种常见的恶性肿瘤,其特点是转录失调和缺乏有效的治疗靶点。在这项研究中,我们旨在鉴定和评估对 BLCA 肿瘤生长至关重要的、具有临床潜力的新靶点:方法:采用CRISPR-Cas9筛选技术鉴定膀胱癌细胞存活所必需的转录因子。方法:采用 CRISPR-Cas9 技术筛选出对膀胱癌细胞活力至关重要的转录因子,并在体外和体内研究了 KLF16 在膀胱癌中的生物学功能。通过一系列分析,包括RNA测序、定量聚合酶链反应(qPCR)、RNA免疫沉淀、Western印迹、质谱分析、双荧光素酶报告实验、靶标下裂解和标记(CUT&Tag)测序、OptoDroplets实验和RNA稳定性实验,阐明了KLF16和MYC之间的调控机制。通过分析公共数据库和免疫组化,评估了KLF16和MYC在膀胱癌中的临床意义:结果:Krüppel样因子16(KLF16)对膀胱癌细胞的活力至关重要。在膀胱癌组织中观察到 KLF16 的高表达,KLF16 的高表达水平与 BLCA 患者的无进展生存期(PFS)和癌症特异性生存期(CSS)相关。从机理上讲,KLF16 mRNA 与双特异性磷酸酶 16(DUSP16)的 mRNA 竞争结合 RNA 结合蛋白 WW 结构域结合蛋白 11(WBP11),导致 DUSP16 mRNA 失稳。这反过来又导致ERK1/2被激活,从而稳定了MYC蛋白。此外,KLF16 与 MYC 相互作用形成核凝聚物,从而增强了 MYC 的转录活性。此外,MYC 转录上调 KLF16,在 KLF16 和 MYC 之间形成了一个正反馈环,扩大了它们的致癌功能。用溴域抑制剂(如OTX015和ABBV-744)靶向这一环路,可抑制KLF16和MYC的转录,从而降低BLCA细胞的活力和肿瘤的生长,并提高对化疗的敏感性:我们的研究揭示了KLF16/MYC调控轴在调控BLCA肿瘤生长和化疗敏感性中的关键作用,这表明将OTX015或ABBV-744等溴域抑制剂与DDP或吉西他滨联合使用可能是治疗BLCA患者的一种很有前景的干预措施。
{"title":"The KLF16/MYC feedback loop is a therapeutic target in bladder cancer.","authors":"Lisi Zheng, Jingxuan Wang, Shan Han, Li Zhong, Zefu Liu, Bin Li, Ruhua Zhang, Liwen Zhou, Xianchong Zheng, Zhenhua Liu, Cuiling Zeng, Ruonan Li, Yezi Zou, Liqin Wang, Yuanzhong Wu, Tiebang Kang","doi":"10.1186/s13046-024-03224-3","DOIUrl":"10.1186/s13046-024-03224-3","url":null,"abstract":"<p><strong>Background: </strong>Bladder cancer (BLCA) is a common malignancy characterized by dysregulated transcription and a lack of effective therapeutic targets. In this study, we aimed to identify and evaluate novel targets with clinical potential essential for tumor growth in BLCA.</p><p><strong>Methods: </strong>CRISPR-Cas9 screening was used to identify transcription factors essential for bladder cancer cell viability. The biological functions of KLF16 in bladder cancer were investigated both in vitro and in vivo. The regulatory mechanism between KLF16 and MYC was elucidated through a series of analyses, including RNA sequencing, quantitative polymerase chain reaction (qPCR), RNA immunoprecipitation, Western blotting, Mass spectrometry, Dual-luciferase reporter assays, Cleavage Under Targets and Tagmentation (CUT&Tag) sequencing, OptoDroplets assays, and RNA stability assay. The clinical relevance of KLF16 and MYC in bladder cancer was evaluated through analyses of public databases and immunohistochemistry.</p><p><strong>Results: </strong>Krüppel-like factor 16 (KLF16) was essential for BLCA cell viability. Elevated expression of KLF16 was observed in bladder cancer tissues, and higher expression levels of KLF16 were correlated with poor progression-free survival (PFS) and cancer-specific survival (CSS) probabilities in BLCA patients. Mechanistically, KLF16 mRNA competed with the mRNA of dual-specificity phosphatase 16 (DUSP16) for binding to the RNA-binding protein, WW domain binding protein 11 (WBP11), resulting in destabilization of the DUSP16 mRNA. This, in turn, led to activation of ERK1/2, which stabilized the MYC protein. Furthermore, KLF16 interacted with MYC to form nuclear condensates, thereby enhancing MYC's transcriptional activity. Additionally, MYC transcriptionally upregulated KLF16, creating a positive feedback loop between KLF16 and MYC that amplified their oncogenic functions. Targeting this loop with bromodomain inhibitors, such as OTX015 and ABBV-744, suppressed the transcription of both KLF16 and MYC, resulting in reduced BLCA cell viability and tumor growth, as well as increased sensitivity to chemotherapy.</p><p><strong>Conclusions: </strong>Our study revealed the crucial role of the KLF16/MYC regulatory axis in modulating tumor growth and chemotherapy sensitivity in BLCA, suggesting that combining bromodomain inhibitors, such as OTX015 or ABBV-744, with DDP or gemcitabine could be a promising therapeutic intervention for BLCA patients.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"43 1","pages":"303"},"PeriodicalIF":11.4,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11571712/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142649425","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
S1PR1 suppresses lung adenocarcinoma progression through p-STAT1/miR-30c-5 p/FOXA1 pathway. S1PR1 通过 p-STAT1/miR-30c-5 p/FOXA1 通路抑制肺腺癌的进展。
IF 11.4 1区 医学 Q1 ONCOLOGY Pub Date : 2024-11-18 DOI: 10.1186/s13046-024-03230-5
Yanfei Chai, Hong Xiang, Yuchao Ma, Wei Feng, Zhibin Jiang, Qianjun Zhu, Yingji Chen, Quanjun Liu, Jing Zhang, Jie Ouyang, Peng Gao, Xiao Zhang, Shuhua Chen, Longyu Jin, Hongwei Lu

Background: Sphingosine-1-phosphate receptor 1 (S1PR1) is considered to be closely related to a variety of malignant tumors, but the role and mechanism of S1PR1 in lung adenocarcinoma are not fully understood. In this study, we aim to explore the role and downstream signaling pathways of S1PR1 in the malignant biological functions of lung adenocarcinoma (LUAD).

Methods: Bioinformatics analysis, RT-qPCR, western blot and immunohistochemistry (IHC) were was used to investigate the expression of S1PR1 in LUAD. The prognosis of S1PR1 was also analyzed. CCK-8 assay, colony formation assay, scratch assay, transwell migration and invasion assay, cell adhesion assay were performed to examine the effect of S1PR1 on LUAD. RNA sequencing was employed to analyze the DEGs in LUAD cells overexpressing S1PR1. Enrichment pathway analysis using KEGG, GO, and GSEA was conducted to predict potential signaling pathways and downstream targets. chromatin immunoprecipitation (ChIP) and dual luciferase reporter assay were performed to verify the direct regulation between FOXA1 and the target genes. Then FOXA1 overexpression were performed to functional rescue experiments. miRNA-30c-5p was identified as a microRNA regulating FOXA1 by dual luciferase reporter assay. The downstream signaling pathways of S1PR1 was detected to clarify the specific pathways to regulates miR-30c-5p.

Results: S1PR1 is significantly decreased in LUAD and is positively correlated with the prognosis. Overexpression of S1PR1 inhibits the proliferation, migration, invasion and adhesion function of LUAD cells by suppressing the expression of COL5A1, MMP1, and SERPINE1. FOXA1 is a key transcription factor regulating the expression of MMP1, COL5A1 and SERPINE1. S1PR1 inhibits the expression of FOXA1 through p-STAT1/miR-30c-5p, thereby suppressing the malignant function of LUAD cells.

Conclusions: The expression of S1PR1 is downregulated in LUAD, which is positively correlated with prognosis. S1PR1 regulates the malignant function of LUAD cells by inhibiting the expression of COL5A1, MMP1 and SERPINE1 through the p-STAT1/miR-30c-5p/FOXA1 signaling pathway.

背景:两性鞘氨醇-1-磷酸受体1(S1PR1)被认为与多种恶性肿瘤密切相关,但S1PR1在肺腺癌中的作用和机制尚不完全清楚。本研究旨在探讨 S1PR1 在肺腺癌(LUAD)恶性生物学功能中的作用及下游信号通路:方法:采用生物信息学分析、RT-qPCR、western blot和免疫组织化学(IHC)等方法研究S1PR1在LUAD中的表达。同时还分析了 S1PR1 的预后。为研究 S1PR1 对 LUAD 的影响,进行了 CCK-8 试验、集落形成试验、划痕试验、Transwell 迁移和侵袭试验以及细胞粘附试验。采用 RNA 测序分析了过表达 S1PR1 的 LUAD 细胞中的 DEGs。染色质免疫沉淀(ChIP)和双荧光素酶报告实验验证了 FOXA1 与靶基因之间的直接调控。通过双荧光素酶报告实验确定了miRNA-30c-5p是调控FOXA1的微RNA。检测了S1PR1的下游信号通路,以明确调控miRNA-30c-5p的特定通路:结果:S1PR1在LUAD中明显减少,并与预后呈正相关。过表达 S1PR1 可抑制 COL5A1、MMP1 和 SERPINE1 的表达,从而抑制 LUAD 细胞的增殖、迁移、侵袭和粘附功能。FOXA1 是调节 MMP1、COL5A1 和 SERPINE1 表达的关键转录因子。S1PR1通过p-STAT1/miR-30c-5p抑制FOXA1的表达,从而抑制LUAD细胞的恶性功能:结论:S1PR1在LUAD中表达下调,与预后呈正相关。S1PR1通过p-STAT1/miR-30c-5p/FOXA1信号通路抑制COL5A1、MMP1和SERPINE1的表达,从而调节LUAD细胞的恶性功能。
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引用次数: 0
MDM2 drives resistance to Osimertinib by contextually disrupting FBW7-mediated destruction of MCL-1 protein in EGFR mutant NSCLC. 在表皮生长因子受体突变的 NSCLC 中,MDM2 通过干扰 FBW7 介导的 MCL-1 蛋白破坏来驱动奥希替尼的抗药性。
IF 11.4 1区 医学 Q1 ONCOLOGY Pub Date : 2024-11-15 DOI: 10.1186/s13046-024-03220-7
Jiaxin Liu, Lingyun Wei, Qing Miao, Sutong Zhan, Peilin Chen, Wei Liu, Liang Cao, Dong Wang, Hongbing Liu, Jie Yin, Yong Song, Mingxiang Ye, Tangfeng Lv

Background: Overcoming resistance to Osimertinib in epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) is clinically challenging because the underlying mechanisms are not fully understood. The murine double minute 2 (MDM2) has been extensively described as a tumor promotor in various malignancies, mainly through a negative regulatory machinery on the p53 tumor suppressor. However, the significance of MDM2 on the sensitivity to Osimertinib has not been described.

Methods: Osimertinib resistant cells were generated by standard dose escalation strategy and individual resistant clones were isolated for MDM2 testing. The MDM2 and its mutant constructs (ΔPBD, ΔRING, C464A) were introduced into PC-9, HCC827 and H1975 cells and evaluated for the sensitivity to Osimertinib by MTT assay, colony formation, EdU assay and TUNEL assay. MDM2 expression in resistant cells was manipulated by pharmacological and molecular approaches, respectively. Proteins that were implicated in PI3K/Akt, MAPK/Erk and apoptosis signaling were measured by Western blot analysis. Candidate proteins that interacted with MDM2 were captured by immunoprecipitation and probed with indicated antibodies.

Results: In comparison with parental PC-9 cells, the PC-9 OR resistant cells expressed high level of MDM2. Ectopic expression of MDM2 in PC-9, HCC827 and H1975 sensitive cells generated an Osimertinib resistant phenotype, regardless of p53 status. MDM2 promoted resistance to Osimertinib through a PI3K/Akt and MAPK/Erk-independent machinery, in contrast, MDM2 selectively stabilized MCL-1 protein to arrest Osimertinib-induced cancer cell apoptosis. Mechanistically, MDM2 acted as a E3 ligase to ubiquitinate FBW7, a well-established E3 ligase for MCL-1, at Lys412 residue, which resulted in FBW7 destruction and MCL-1 stabilization. Targeting MDM2 to augment MCL-1 protein breakdown overcame resistance to Osimertinib in vitro and in vivo. Finally, the clinical relevance of MDM2-FBW7-MCL-1 regulatory axis was validated in mouse xenograft tumor model and in NSCLC specimen.

Conclusion: Overexpression of MDM2 is a novel resistant mechanism to Osimertinib in EGFR mutant NSCLC. MDM2 utilizes its E3 ligase activity to provoke FBW7 destruction and sequentially leads to MCL-1 stabilization. Cancer cells with aberrant MDM2 state are refractory to apoptosis induction and elicit a resistant phenotype to Osimertinib. Therefore, targeting MDM2 would be a feasible approach to overcome resistance to Osimertinib in EGFR mutant NSCLC.

背景:克服表皮生长因子受体(EGFR)突变非小细胞肺癌(NSCLC)对奥希莫替尼(Osimertinib)的耐药性在临床上具有挑战性,因为其潜在机制尚未完全明了。小鼠双分化 2(MDM2)已被广泛描述为各种恶性肿瘤中的肿瘤促进因子,主要通过对 p53 肿瘤抑制因子的负调控机制发挥作用。然而,MDM2对奥希替尼敏感性的意义尚未得到描述:方法:通过标准剂量递增策略产生奥希替尼耐药细胞,并分离出单个耐药克隆进行MDM2检测。将 MDM2 及其突变构建体(ΔPBD、ΔRING、C464A)导入 PC-9、HCC827 和 H1975 细胞,并通过 MTT 检测、菌落形成、EdU 检测和 TUNEL 检测评估其对奥希替尼的敏感性。耐药细胞中 MDM2 的表达分别通过药理和分子方法进行了处理。通过 Western 印迹分析检测了与 PI3K/Akt、MAPK/Erk 和细胞凋亡信号转导有关的蛋白质。通过免疫沉淀捕获与MDM2相互作用的候选蛋白,并用指定的抗体进行检测:结果:与亲代PC-9细胞相比,PC-9 OR耐药细胞表达了高水平的MDM2。在PC-9、HCC827和H1975敏感细胞中异位表达MDM2会产生奥希替尼耐药表型,与p53状态无关。MDM2通过PI3K/Akt和MAPK/Erk依赖机制促进对奥希替尼的耐药性,相反,MDM2选择性地稳定MCL-1蛋白,阻止奥希替尼诱导的癌细胞凋亡。从机理上讲,MDM2作为E3连接酶在Lys412残基上泛素化MCL-1的E3连接酶FBW7,从而导致FBW7破坏和MCL-1稳定。以MDM2为靶点增强MCL-1蛋白的分解,克服了体外和体内对奥希替尼的耐药性。最后,在小鼠异种移植肿瘤模型和NSCLC标本中验证了MDM2-FBW7-MCL-1调控轴的临床相关性:结论:MDM2的过表达是表皮生长因子受体突变型NSCLC对奥希替尼的一种新型耐药机制。MDM2利用其E3连接酶活性引发FBW7破坏,进而导致MCL-1稳定。MDM2状态异常的癌细胞对凋亡诱导具有耐受性,并对奥希替尼产生耐药表型。因此,靶向 MDM2 将是克服表皮生长因子受体突变 NSCLC 对奥希替尼耐药性的可行方法。
{"title":"MDM2 drives resistance to Osimertinib by contextually disrupting FBW7-mediated destruction of MCL-1 protein in EGFR mutant NSCLC.","authors":"Jiaxin Liu, Lingyun Wei, Qing Miao, Sutong Zhan, Peilin Chen, Wei Liu, Liang Cao, Dong Wang, Hongbing Liu, Jie Yin, Yong Song, Mingxiang Ye, Tangfeng Lv","doi":"10.1186/s13046-024-03220-7","DOIUrl":"10.1186/s13046-024-03220-7","url":null,"abstract":"<p><strong>Background: </strong>Overcoming resistance to Osimertinib in epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) is clinically challenging because the underlying mechanisms are not fully understood. The murine double minute 2 (MDM2) has been extensively described as a tumor promotor in various malignancies, mainly through a negative regulatory machinery on the p53 tumor suppressor. However, the significance of MDM2 on the sensitivity to Osimertinib has not been described.</p><p><strong>Methods: </strong>Osimertinib resistant cells were generated by standard dose escalation strategy and individual resistant clones were isolated for MDM2 testing. The MDM2 and its mutant constructs (ΔPBD, ΔRING, C464A) were introduced into PC-9, HCC827 and H1975 cells and evaluated for the sensitivity to Osimertinib by MTT assay, colony formation, EdU assay and TUNEL assay. MDM2 expression in resistant cells was manipulated by pharmacological and molecular approaches, respectively. Proteins that were implicated in PI3K/Akt, MAPK/Erk and apoptosis signaling were measured by Western blot analysis. Candidate proteins that interacted with MDM2 were captured by immunoprecipitation and probed with indicated antibodies.</p><p><strong>Results: </strong>In comparison with parental PC-9 cells, the PC-9 OR resistant cells expressed high level of MDM2. Ectopic expression of MDM2 in PC-9, HCC827 and H1975 sensitive cells generated an Osimertinib resistant phenotype, regardless of p53 status. MDM2 promoted resistance to Osimertinib through a PI3K/Akt and MAPK/Erk-independent machinery, in contrast, MDM2 selectively stabilized MCL-1 protein to arrest Osimertinib-induced cancer cell apoptosis. Mechanistically, MDM2 acted as a E3 ligase to ubiquitinate FBW7, a well-established E3 ligase for MCL-1, at Lys412 residue, which resulted in FBW7 destruction and MCL-1 stabilization. Targeting MDM2 to augment MCL-1 protein breakdown overcame resistance to Osimertinib in vitro and in vivo. Finally, the clinical relevance of MDM2-FBW7-MCL-1 regulatory axis was validated in mouse xenograft tumor model and in NSCLC specimen.</p><p><strong>Conclusion: </strong>Overexpression of MDM2 is a novel resistant mechanism to Osimertinib in EGFR mutant NSCLC. MDM2 utilizes its E3 ligase activity to provoke FBW7 destruction and sequentially leads to MCL-1 stabilization. Cancer cells with aberrant MDM2 state are refractory to apoptosis induction and elicit a resistant phenotype to Osimertinib. Therefore, targeting MDM2 would be a feasible approach to overcome resistance to Osimertinib in EGFR mutant NSCLC.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"43 1","pages":"302"},"PeriodicalIF":11.4,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11566350/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142631821","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Correction: HERC2 promotes inflammation-driven cancer stemness and immune evasion in hepatocellular carcinoma by activating STAT3 pathway. 更正:HERC2通过激活STAT3通路促进肝细胞癌中炎症驱动的癌症干性和免疫逃避。
IF 11.4 1区 医学 Q1 ONCOLOGY Pub Date : 2024-11-13 DOI: 10.1186/s13046-024-03223-4
Yunzhi Liu, Qishan Xu, Fan Deng, Zhuojun Zheng, Jialiang Luo, Ping Wang, Jia Zhou, Xiao Lu, Liyun Zhang, Zhengliang Chen, Qifan Zhang, Qingyun Chen, Daming Zuo
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引用次数: 0
Correction: ISG15 and ISGylation modulates cancer stem cell-like characteristics in promoting tumor growth of anaplastic thyroid carcinoma. 更正:ISG15和ISGylation在促进无性甲状腺癌肿瘤生长的过程中调节癌症干细胞样特征。
IF 11.4 1区 医学 Q1 ONCOLOGY Pub Date : 2024-11-13 DOI: 10.1186/s13046-024-03226-1
Tong Xu, Chaozhuang Zhu, Jinming Chen, Feifeng Song, Xinxin Ren, Shanshan Wang, Xiaofen Yi, Yiwen Zhang, Wanli Zhang, Qing Hu, Hui Qin, Yujia Liu, Song Zhang, Zhuo Tan, Zongfu Pan, Ping Huang, Minghua Ge
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引用次数: 0
Drug prioritization identifies panobinostat as a tailored treatment element for patients with metastatic hepatoblastoma. 药物优先排序将帕诺比诺司他确定为转移性肝母细胞瘤患者的定制治疗要素。
IF 11.4 1区 医学 Q1 ONCOLOGY Pub Date : 2024-11-12 DOI: 10.1186/s13046-024-03221-6
Salih Demir, Alina Hotes, Tanja Schmid, Stefano Cairo, Emilie Indersie, Claudio Pisano, Eiso Hiyama, Tomoro Hishiki, Christian Vokuhl, Sophie Branchereau, Penelope Brock, Irene Schmid, József Zsiros, Roland Kappler

Background: Patients with metastatic hepatoblastoma are treated with severely toxic first-line chemotherapies in combination with surgery. Yet, inadequate response of lung metastases to neo-adjuvant chemotherapy still compromises patient outcomes making new treatment strategies, tailored to more efficient lung clearance, mandatory.

Methods: We harnessed a comprehensive patient-derived xenograft platform and a variety of in vitro and in vivo assays to establish the preclinical and biological rationale for a new drug for patients with metastatic hepatoblastoma.

Results: The testing of a library of established drugs on patient-derived xenografts identified histone deacetylase inhibitors, most notably panobinostat, to be highly efficacious on hepatoblastoma cells, as compared to non-cancerous cells. Molecularly, the anti-tumor effect of panobinostat is mediated by posttranslational obstruction of the MYC oncoprotein as a result of dual specificity phosphatase 1 upregulation, thereby leading to growth inhibition and programmed cell death. Of clinical importance, upregulation of the MYC target gene nucleophosmin 1 is indicative of response to panobinostat and associated with metastatic disease in patients with hepatoblastoma. The combination of panobinostat with the current SIOPEL 4 induction protocol, consisting of cisplatin and doxorubicin, revealed high synergies already at low nanomolar levels. The simulation of a clinical trial, with this combination therapy, in patient-derived xenograft models, and ultimately heterotypic lung metastasis mimics clearly underscored the potency of this approach.

Conclusion: Integrated studies define MYC inhibition by panobinostat as a novel treatment element to be introduced into the therapeutic strategy for patients with metastatic hepatoblastoma.

背景:转移性肝母细胞瘤患者接受毒性严重的一线化疗,并结合手术治疗。然而,肺转移灶对新辅助化疗的反应不充分仍然影响着患者的预后,因此必须采取新的治疗策略,以更有效地清除肺转移灶:我们利用一个全面的患者来源异种移植平台以及各种体外和体内试验,为治疗转移性肝母细胞瘤患者的新药建立临床前和生物学依据:结果:在患者来源的异种移植物上测试现有药物库后发现,组蛋白去乙酰化酶抑制剂,尤其是帕诺比诺司他,与非癌细胞相比,对肝母细胞瘤细胞具有很高的疗效。从分子角度看,帕诺比诺司他的抗肿瘤作用是通过双特异性磷酸酶 1 上调导致 MYC 癌症蛋白翻译后阻断,从而导致生长抑制和细胞程序性死亡。具有临床意义的是,MYC靶基因nucleophosmin 1的上调表明肝母细胞瘤患者对帕诺比诺司他(panobinostat)的反应,并与转移性疾病相关。将帕诺比诺司特与目前由顺铂和多柔比星组成的SIOPEL 4诱导方案相结合,发现在低纳摩尔水平时就能产生很高的协同作用。在病人异种移植模型以及最终的异型肺转移仿制模型中模拟使用这种联合疗法进行临床试验,明确强调了这种方法的有效性:综合研究将帕诺比诺司他对 MYC 的抑制作用定义为一种新型治疗元素,可引入转移性肝母细胞瘤患者的治疗策略中。
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引用次数: 0
Soluble and EV-bound CD27 act as antagonistic biomarkers in patients with solid tumors undergoing immunotherapy. 在接受免疫疗法的实体瘤患者中,可溶性和与 EV 结合的 CD27 可作为拮抗生物标记物。
IF 11.4 1区 医学 Q1 ONCOLOGY Pub Date : 2024-11-08 DOI: 10.1186/s13046-024-03215-4
Joao Gorgulho, Sven H Loosen, Ramsha Masood, Franziska Giehren, Francesca Pagani, Gustav Buescher, Lorenz Kocheise, Vincent Joerg, Constantin Schmidt, Kornelius Schulze, Christoph Roderburg, Eva Kinkel, Britta Fritzsche, Simon Wehmeyer, Benjamin Schmidt, Paul Kachel, Christina Rolling, Julian Götze, Alina Busch, Marianne Sinn, Thais Pereira-Veiga, Harriet Wikman, Maria Geffken, Sven Peine, Urte Matschl, Markus Altfeld, Samuel Huber, Ansgar W Lohse, Fabian Beier, Tim H Brümmendorf, Carsten Bokemeyer, Tom Luedde, Johann von Felden

Background: The major breakthrough in cancer therapy with immune checkpoint inhibitors (ICIs) has highlighted the important role of immune checkpoints in antitumoral immunity. However, most patients do not achieve durable responses, making biomarker research in this setting essential. CD27 is a well known costimulatory molecule, however the impact of its soluble form in ICI is poorly investigated. Therefore, we aimed at testing circulating concentrations of soluble CD27 (sCD27) and CD27 bound to extracellular vesicles (EVs) as potential biomarkers to predict response and overall survival (OS) in patients undergoing ICI.

Methods: Serum and plasma levels of sCD27 were assessed by immunoassay in three patient cohorts (n = 187) with advanced solid malignancies including longitudinal samples (n = 126): a training (n = 84, 210 specimens, Aachen ICI) and validation cohort (n = 70, 70 specimens, Hamburg ICI), both treated with ICI therapy, and a second independent validation cohort (n = 33, 33 specimens, Hamburg non-ICI) undergoing systemic therapy without any ICI. In a subset (n = 36, 36 baseline and 108 longitudinal specimens), EV-bound CD27 from serum was measured, while EV characterization studies were conducted on a fourth cohort (n = 45).

Results: In the Aachen and Hamburg ICI cohorts, patients with lower circulating sCD27 levels before and during ICI therapy had a significantly longer progression-free survival (PFS) and OS compared to patients with higher levels, a finding that was confirmed by multivariate analysis (MVA) (Aachen ICI: pPFS = 0.012, pOS = 0.001; Hamburg ICI: pPFS = 0.040, pOS = 0.004) and after randomly splitting both cohorts into training and validation. This phenomenon was not observed in the Hamburg non-ICI cohort, providing a rationale for the predictive biomarker role of sCD27 in immune checkpoint blockade. Remarkably, EV-bound CD27 baseline levels and dynamics during ICI therapy also emerged as potent predictive biomarkers, acting however antagonistically to soluble sCD27, i.e. higher levels were associated with PFS and OS benefit. Combining both molecules ("multi-CD27" score) enhanced the predictive ability (HRPFS: 17.21 with p < 0.001, HROS: 6.47 with p = 0.011).

Conclusion: Soluble and EV-bound CD27 appear to have opposing immunomodulatory functions and may represent easily measurable, non-invasive prognostic markers to predict response and survival in patients undergoing ICI therapy.

背景:免疫检查点抑制剂(ICIs)在癌症治疗中的重大突破凸显了免疫检查点在抗肿瘤免疫中的重要作用。然而,大多数患者并不能获得持久的反应,因此在这种情况下进行生物标志物研究至关重要。CD27 是一种众所周知的成本刺激分子,但其可溶性形式在 ICI 中的影响却鲜有研究。因此,我们旨在检测可溶性CD27(sCD27)和与细胞外囊泡(EVs)结合的CD27的循环浓度,以此作为潜在的生物标志物,预测接受ICI治疗的患者的反应和总生存率(OS):通过免疫测定评估了三个晚期实体恶性肿瘤患者队列(n = 187)的血清和血浆sCD27水平,包括纵向样本(n = 126):一个训练队列(n = 84,210份标本,亚琛ICI)和一个验证队列(n = 70,70份标本,汉堡ICI),两个队列均接受了ICI治疗,以及第二个独立的验证队列(n = 33,33份标本,汉堡非ICI),该队列接受了全身治疗,但未接受任何ICI治疗。在一个子集(n = 36,36 份基线标本和 108 份纵向标本)中,测量了血清中与 EV 结合的 CD27,同时对第四个队列(n = 45)进行了 EV 特征研究:在亚琛和汉堡的ICI队列中,在ICI治疗前和治疗期间循环sCD27水平较低的患者的无进展生存期(PFS)和OS明显长于水平较高的患者,这一结果在多变量分析(MVA)中得到了证实(亚琛ICI:pPFS = 0.012,pOS = 0.001;汉堡ICI:pPFS = 0.040,pOS = 0.004),并且在将两个队列随机分为训练组和验证组后也得到了证实。汉堡非 ICI 队列中没有观察到这种现象,这为 sCD27 在免疫检查点阻断中的预测性生物标志物作用提供了依据。值得注意的是,EV结合的CD27基线水平和ICI治疗期间的动态变化也是有效的预测性生物标志物,但与可溶性sCD27的作用是拮抗的,即较高的水平与PFS和OS获益相关。结合这两种分子("multi-CD27 "评分)可增强预测能力(HRPFS:17.21,p OS:6.47,p = 0.011):结论:可溶性 CD27 和与 EV 结合的 CD27 似乎具有相反的免疫调节功能,可能是预测接受 ICI 治疗患者的反应和生存期的易测、非侵入性预后标志物。
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引用次数: 0
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