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GDF15 induces chemoresistance to oxaliplatin by forming a reciprocal feedback loop with Nrf2 to maintain redox homeostasis in colorectal cancer GDF15 通过与 Nrf2 形成互惠反馈环路来维持结直肠癌的氧化还原平衡,从而诱导对奥沙利铂的化疗耐药性
IF 6.6 2区 医学 Q1 Medicine Pub Date : 2024-02-22 DOI: 10.1007/s13402-024-00918-w
Haiping Lin, Yang Luo, Tingyue Gong, Hongsheng Fang, Hao Li, Guangyao Ye, Yan Zhang, Ming Zhong

Purpose

Growth differentiating Factor 15 (GDF15) is linked to several cancers, but its effect on chemoresistance in colorectal cancer (CRC) remains unclear. Here, we investigated the role of GDF15 in the chemotherapeutic response of CRC patients to oxaliplatin (L-OHP).

Methods

GDF15 levels in serum and tumour tissues were detected in CRC patients have received L-OHP-based neoadjuvant chemotherapy. The effects of GDF15 neutralization or GDF15 knockdown on cell proliferation, apoptosis and intracellular reactive oxygen species (ROS) levels were analysed in vitro and in vivo. Co-immunoprecipitation (Co-IP), Chromatin Immunoprecipitation (ChIP) and luciferase reporter assays were used to explore the interaction between GDF15 and Nrf2.

Results

In this study, we found that GDF15 alleviates oxidative stress to induce chemoresistance of L-OHP in CRC. Mechanically, GDF15 posttranscriptionally regulates protein stability of Nrf2 through the canonical PI3K/AKT/GSK3β signaling pathway, and in turn, Nrf2 acts as a transcription factor to regulate GDF15 expression to form a positive feedback loop, resulting in the maintenance of redox homeostasis balance in CRC. Furthermore, a positive correlation between GDF15 and Nrf2 was observed in clinical CRC samples, and simultaneous overexpression of both GDF15 and Nrf2 was associated with poor prognosis in CRC patients treated with L-OHP. Simultaneous inhibition of both GDF15 and Nrf2 significantly increases the response to L-OHP in an L-OHP-resistant colorectal cancer cells-derived mouse xenograft model.

Conclusion

This study identified a novel GDF15-Nrf2 positive feedback loop that drives L-OHP resistance and suggested that the GDF15-Nrf2 axis is a potential therapeutic target for the treatment of L-OHP-resistant CRC.

Graphical Abstract

目的 生长分化因子15(GDF15)与多种癌症有关,但它对结直肠癌(CRC)化疗耐药性的影响仍不清楚。方法 在接受了以奥沙利铂(L-OHP)为基础的新辅助化疗的 CRC 患者中检测血清和肿瘤组织中的 GDF15 水平。在体外和体内分析了GDF15中和或GDF15敲除对细胞增殖、凋亡和细胞内活性氧(ROS)水平的影响。结果在这项研究中,我们发现GDF15能减轻氧化应激,从而诱导CRC对L-OHP的化疗抵抗。从机理上讲,GDF15通过典型的PI3K/AKT/GSK3β信号通路转录后调节Nrf2的蛋白稳定性,而Nrf2又作为转录因子调节GDF15的表达,形成正反馈环,从而维持CRC的氧化还原平衡。此外,GDF15和Nrf2在临床CRC样本中呈正相关,GDF15和Nrf2同时过表达与接受L-OHP治疗的CRC患者预后不良有关。结论这项研究发现了一种新型的GDF15-Nrf2正反馈环路,它能驱动L-OHP耐药,并提示GDF15-Nrf2轴是治疗L-OHP耐药CRC的潜在治疗靶点。
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引用次数: 0
PIN1 promotes the metastasis of cholangiocarcinoma cells by RACK1-mediated phosphorylation of ANXA2 PIN1 通过 RACK1 介导的 ANXA2 磷酸化促进胆管癌细胞转移
IF 6.6 2区 医学 Q1 Medicine Pub Date : 2024-02-22 DOI: 10.1007/s13402-024-00924-y
Yuming Wang, Yiwei Liu, Hairong Chen, Zhenggang Xu, Wangjie Jiang, Xiao Xu, Jijun Shan, Jiang Chang, Tao Zhou, Jifei Wang, Anlan Chenyan, Shilong Fan, Zifan Tao, Ke Shao, Xiangcheng Li, Xiaofeng Chen, Guwei Ji, Xiaofeng Wu

Background

Cholangiocarcinoma (CCA), a primary hepatobiliary malignancy, is characterized by a poor prognosis and a lack of effective treatments. Therefore, the need to explore novel therapeutic approaches is urgent. While the role of Peptidylprolyl Cis/Trans Isomerase, NIMA-Interacting 1 (PIN1) has been extensively studied in various tumor types, its involvement in CCA remains poorly understood.

Methods

In this study, we employed tissue microarray (TMA), reverse transcription-polymerase chain reaction (RT-PCR), and The Cancer Genome Atlas (TCGA) database to assess the expression of PIN1. Through in vitro and in vivo functional experiments, we investigated the impact of PIN1 on the adhesion and metastasis of CCA. Additionally, we explored downstream molecular pathways using RNA-seq, western blotting, co-immunoprecipitation, immunofluorescence, and mass spectrometry techniques.

Results

Our findings revealed a negative correlation between PIN1 overexpression and prognosis in CCA tissues. Furthermore, high PIN1 expression promoted CCA cell proliferation and migration. Mechanistically, PIN1 functioned as an oncogene by regulating ANXA2 phosphorylation, thereby promoting CCA adhesion. Notably, the interaction between PIN1 and ANXA2 was facilitated by RACK1. Importantly, pharmacological inhibition of PIN1 using the FDA-approved drug all-trans retinoic acid (ATRA) effectively suppressed the metastatic potential of CCA cells in a nude mouse lung metastasis model.

Conclusion

Overall, our study emphasizes the critical role of the PIN1/RACK1/ANXA2 complex in CCA growth and functionality, highlighting the potential of targeting PIN1 as a promising therapeutic strategy for CCA.

Graphical Abstract

背景胆管癌(CCA)是一种原发性肝胆恶性肿瘤,其特点是预后不良且缺乏有效的治疗方法。因此,探索新的治疗方法迫在眉睫。本研究采用组织芯片(TMA)、反转录聚合酶链反应(RT-PCR)和癌症基因组图谱(TCGA)数据库来评估 PIN1 的表达。通过体外和体内功能实验,我们研究了 PIN1 对 CCA 粘附和转移的影响。此外,我们还利用 RNA-seq、Western 印迹、共免疫沉淀、免疫荧光和质谱技术探索了下游分子通路。此外,PIN1 的高表达促进了 CCA 细胞的增殖和迁移。从机理上讲,PIN1 通过调节 ANXA2 磷酸化,从而促进 CCA 的粘附,起到了癌基因的作用。值得注意的是,PIN1 和 ANXA2 之间的相互作用是由 RACK1 促进的。总之,我们的研究强调了 PIN1/RACK1/ANXA2 复合物在 CCA 生长和功能中的关键作用,突出了靶向 PIN1 作为 CCA 治疗策略的潜力。
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引用次数: 0
Extracellular vesicles related gene HSPH1 exerts anti-tumor effects in prostate cancer via promoting the stress response of CD8 + T cells 细胞外囊泡相关基因 HSPH1 通过促进 CD8 + T 细胞的应激反应对前列腺癌发挥抗肿瘤作用
IF 6.6 2区 医学 Q1 Medicine Pub Date : 2024-01-02 DOI: 10.1007/s13402-023-00905-7

Abstract

Background

T cell stress response state (TSTR), as a novel immune concept previous studies have proposed, has not yet been explored in prostate cancer (PC). As a type of cellular efflux, exosomes play important roles in the occurrence and development of PC.

Method

Here, we conducted a combined analysis on extracellular vesicle related genes (EVRGs) in PC using data from single-cell RNA (scRNA), spatial transcriptome (ST), and bulk RNA sequencing.

Result

Preliminary findings have revealed that heat shock protein family H (Hsp110) member 1 (HSPH1) possesses two identities, one being EVRGs and the other being a member of the heat shock protein family involved in TSTR, which may promote the differentiation of conventional T cells towards Th1 or Th2 cells through the pathway of IL2-MYC-IL2RA, thereby promoting the increase of CD8 + T cells in the tumor area, especially in the invasive zone, and inhibiting the invasion of PCs. We also notice the negative response of HSPH1 + CD8 + T cell related genes in immune checkpoint blockade (ICB). Western blot (WB) and droplet digital Polymerase Chain Reaction (ddPCR) demonstrated that the mRNA and protein levels of HSPH1 in EVs of PCs were significantly higher than those in adjacent tissues.

Conclusion

Results above indicate the potential of HSPH1 as a critical therapeutic target in PC.

摘要 背景 T细胞应激反应状态(TSTR)是以往研究提出的一种新的免疫概念,但尚未在前列腺癌(PC)中得到探讨。外泌体作为一种细胞外流体,在前列腺癌的发生和发展中发挥着重要作用。 方法 我们利用单细胞 RNA(scRNA)、空间转录组(ST)和大容量 RNA 测序数据,对 PC 中的细胞外囊泡相关基因(EVRGs)进行了综合分析。 结果 初步研究结果表明,热休克蛋白家族 H(Hsp110)成员 1(HSPH1)具有两种身份,一种是 EVRGs,另一种是参与 TSTR 的热休克蛋白家族成员,可能通过 IL2-MYC-IL2RA 途径促进传统 T 细胞向 Th1 或 Th2 细胞分化,从而促进肿瘤区域尤其是侵袭区 CD8 + T 细胞的增加,抑制 PCs 的侵袭。我们还注意到 HSPH1 + CD8 + T 细胞相关基因在免疫检查点阻断(ICB)中的负反应。Western blot(WB)和液滴数字聚合酶链反应(ddPCR)表明,PCs EVs 中 HSPH1 的 mRNA 和蛋白水平明显高于邻近组织。 结论 上述结果表明,HSPH1 有可能成为 PC 的关键治疗靶点。
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引用次数: 0
Sirtuin 5-mediated deacetylation of TAZ at K54 promotes melanoma development Sirtuin 5 介导的 K54 处 TAZ 去乙酰化促进了黑色素瘤的发展
IF 6.6 2区 医学 Q1 Medicine Pub Date : 2023-12-19 DOI: 10.1007/s13402-023-00910-w
Garam Kim, Poshan Yugal Bhattarai, Sung-Chul Lim, Kwang Youl Lee, Hong Seok Choi

Purpose

Nuclear accumulation of YAP/TAZ promotes tumorigenesis in several cancers, including melanoma. Although the mechanisms underlying the nuclear retention of YAP are known, those underlying the retention of TAZ remain unclear. Our study investigates a novel acetylation/deacetylation switch in TAZ, governing its subcellular localization in melanoma tumorigenesis.

Methods

Immunoprecipitation/Western blot assessed TAZ protein interactions and acetylation. SIRT5 activity was quantified with enzyme-linked immunosorbent assay. Immunofluorescence indicated TAZ nuclear localization. TEAD transcriptional activity was measured through luciferase reporter assays. ChIP detected TAZ binding to the CTGF promoter. Transwell and wound healing assays quantified melanoma cell invasiveness and migration. Metastasis was evaluated using a mouse model via tail vein injections. Clinical relevance was explored via immunohistochemical staining of patient tumors.

Results

CBP facilitated TAZ acetylation at K54 in response to epidermal growth factor stimulation, while SIRT5 mediated deacetylation. Acetylation correlated with phosphorylation, regulating TAZ’s binding with LATS2 or TEAD. TAZ K54 acetylation enhanced its S89 phosphorylation, promoting cytosolic retention via LATS2 interaction. SIRT5-mediated deacetylation enhanced TAZ-TEAD interaction and nuclear retention. Chromatin IP showed SIRT5-deacetylated TAZ recruited to CTGF promoter, boosting transcriptional activity. In a mouse model, SIRT5 overexpression induced melanoma metastasis to lung tissue following the injection of B16F10 melanocytes via the tail vein, and this effect was prevented by verteporfin treatment.

Conclusions

Our study revealed a novel mechanism of TAZ nuclear retention regulated by SIRT5-mediated K54 deacetylation and demonstrated the significance of TAZ deacetylation in CTGF expression. This study highlights the potential implications of the SIRT5/TAZ axis for treating metastatic melanoma.

目的YAP/TAZ的核聚集会促进包括黑色素瘤在内的多种癌症的肿瘤发生。尽管YAP在核内滞留的机制已为人所知,但TAZ在核内滞留的机制仍不清楚。我们的研究调查了TAZ的一种新型乙酰化/去乙酰化开关,该开关控制着TAZ在黑色素瘤肿瘤发生过程中的亚细胞定位。用酶联免疫吸附试验对SIRT5的活性进行定量。免疫荧光显示了 TAZ 的核定位。通过荧光素酶报告实验测定了 TEAD 的转录活性。ChIP 检测了 TAZ 与 CTGF 启动子的结合。透孔试验和伤口愈合试验量化了黑色素瘤细胞的侵袭性和迁移性。通过尾静脉注射的小鼠模型对转移进行了评估。在表皮生长因子刺激下,CBP 促进 TAZ 在 K54 处乙酰化,而 SIRT5 则介导去乙酰化。乙酰化与磷酸化相关,可调节 TAZ 与 LATS2 或 TEAD 的结合。TAZ K54的乙酰化增强了其S89的磷酸化,通过LATS2的相互作用促进了其在细胞质中的保留。SIRT5 介导的去乙酰化增强了 TAZ 与 TEAD 的相互作用和核保留。染色质 IP 显示,SIRT5-去乙酰化的 TAZ 被招募到 CTGF 启动子,增强了转录活性。在小鼠模型中,经尾静脉注射 B16F10 黑色素细胞后,SIRT5 过表达诱导黑色素瘤转移至肺组织,而 verteporfin 处理可阻止这种效应。这项研究强调了SIRT5/TAZ轴对治疗转移性黑色素瘤的潜在意义。
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引用次数: 0
ATF3-induced activation of NF-κB pathway results in acquired PARP inhibitor resistance in pancreatic adenocarcinoma ATF3 诱导的 NF-κB 通路激活导致胰腺腺癌对 PARP 抑制剂产生获得性耐药性
IF 6.6 2区 医学 Q1 Medicine Pub Date : 2023-12-15 DOI: 10.1007/s13402-023-00907-5
Yang Liu, Yizhi Cao, Pengyi Liu, Shuyu Zhai, Yihao Liu, Xiaomei Tang, Jiayu Lin, Minmin Shi, Debin Qi, Xiaxing Deng, Youwei Zhu, Weishen Wang, Baiyong Shen

Purpose

Olaparib, an inhibitor of poly-(adenosine diphosphate-ribose) polymerase (PARP), has been shown to have anticancer benefits in patients with pancreatic cancer who have a germline mutation in BRCA1/2. However, resistance acquired on long-term exposure to olaparib significantly impedes clinical efficacy.

Methods

In this study, the chromatin accessibility and differentially expressed transcripts of parental and olaparib-resistant pancreatic cancer cell lines were assessed using the Assay for Transposase Accessible Chromatin with sequencing (ATAC-seq) and mRNA-seq. Detection of downstream genes regulated by transcription factors using ChIP (Chromatin immunoprecipitation assay).

Results

According to pathway enrichment analysis, differentially expressed genes in olaparib-resistant cells were remarkably enriched in the NF-κB signaling pathway. With ATAC-seq, we identified chromatin regions with higher accessibility in olaparib-resistant cells and predicted a series of important transcription factors. Among them, activating transcription factor 3 (ATF3) was significantly highly expressed. Functional experiments verified that inhibition of ATF3 suppressed the NF-κB pathway significantly and restored olaparib sensitivity in olaparib-resistant cells.

Conclusion

Experiments in vitro and in vivo indicate ATF3 enhances olaparib resistance through the NF-κB signaling pathway, suggesting that ATF3 could be employed as an olaparib sensitivity and prognostic indicator in patients with pancreatic cancer.

目的奥拉帕利是一种聚腺苷二磷酸核糖聚合酶(PARP)抑制剂,已被证明对BRCA1/2基因突变的胰腺癌患者有抗癌作用。方法在这项研究中,使用转座酶可及染色质测序法(ATAC-seq)和mRNA-seq评估了亲代胰腺癌细胞系和奥拉帕尼耐药胰腺癌细胞系的染色质可及性和差异表达转录本。结果根据通路富集分析,奥拉帕尼耐药细胞中的差异表达基因明显富集在 NF-κB 信号通路中。通过ATAC-seq,我们发现了奥拉帕尼耐药细胞中具有较高可及性的染色质区域,并预测了一系列重要的转录因子。其中,激活转录因子3(ATF3)明显高表达。结论体外和体内实验表明,ATF3可通过NF-κB信号通路增强奥拉帕尼耐药性,这表明ATF3可作为胰腺癌患者奥拉帕尼敏感性和预后指标。
{"title":"ATF3-induced activation of NF-κB pathway results in acquired PARP inhibitor resistance in pancreatic adenocarcinoma","authors":"Yang Liu, Yizhi Cao, Pengyi Liu, Shuyu Zhai, Yihao Liu, Xiaomei Tang, Jiayu Lin, Minmin Shi, Debin Qi, Xiaxing Deng, Youwei Zhu, Weishen Wang, Baiyong Shen","doi":"10.1007/s13402-023-00907-5","DOIUrl":"https://doi.org/10.1007/s13402-023-00907-5","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Purpose</h3><p>Olaparib, an inhibitor of poly-(adenosine diphosphate-ribose) polymerase (PARP), has been shown to have anticancer benefits in patients with pancreatic cancer who have a germline mutation in BRCA1/2. However, resistance acquired on long-term exposure to olaparib significantly impedes clinical efficacy.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>In this study, the chromatin accessibility and differentially expressed transcripts of parental and olaparib-resistant pancreatic cancer cell lines were assessed using the Assay for Transposase Accessible Chromatin with sequencing (ATAC-seq) and mRNA-seq. Detection of downstream genes regulated by transcription factors using ChIP (Chromatin immunoprecipitation assay).</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>According to pathway enrichment analysis, differentially expressed genes in olaparib-resistant cells were remarkably enriched in the NF-κB signaling pathway. With ATAC-seq, we identified chromatin regions with higher accessibility in olaparib-resistant cells and predicted a series of important transcription factors. Among them, activating transcription factor 3 (ATF3) was significantly highly expressed. Functional experiments verified that inhibition of ATF3 suppressed the NF-κB pathway significantly and restored olaparib sensitivity in olaparib-resistant cells.</p><h3 data-test=\"abstract-sub-heading\">Conclusion</h3><p>Experiments in vitro and in vivo indicate ATF3 enhances olaparib resistance through the NF-κB signaling pathway, suggesting that ATF3 could be employed as an olaparib sensitivity and prognostic indicator in patients with pancreatic cancer.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":"197 1","pages":""},"PeriodicalIF":6.6,"publicationDate":"2023-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138682630","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
DNA repair in tumor radioresistance: insights from fruit flies genetics 肿瘤放射抗性中的 DNA 修复:果蝇遗传学的启示
IF 6.6 2区 医学 Q1 Medicine Pub Date : 2023-12-14 DOI: 10.1007/s13402-023-00906-6
Antonella Porrazzo, Matteo Cassandri, Andrea D’Alessandro, Patrizia Morciano, Rossella Rota, Francesco Marampon, Giovanni Cenci

Background

Radiation therapy (RT) is a key anti-cancer treatment that involves using ionizing radiation to kill tumor cells. However, this therapy can lead to short- and long-term adverse effects due to radiation exposure of surrounding normal tissue. The type of DNA damage inflicted by radiation therapy determines its effectiveness. High levels of genotoxic damage can lead to cell cycle arrest, senescence, and cell death, but many tumors can cope with this damage by activating protective mechanisms. Intrinsic and acquired radioresistance are major causes of tumor recurrence, and understanding these mechanisms is crucial for cancer therapy. The mechanisms behind radioresistance involve processes like hypoxia response, cell proliferation, DNA repair, apoptosis inhibition, and autophagy.

Conclusion

Here we briefly review the role of genetic and epigenetic factors involved in the modulation of DNA repair and DNA damage response that promote radioresistance. In addition, leveraging our recent results on the effects of low dose rate (LDR) of ionizing radiation on Drosophila melanogaster we discuss how this model organism can be instrumental in the identification of conserved factors involved in the tumor resistance to RT.

背景放射治疗(RT)是一种关键的抗癌治疗方法,它涉及到使用电离辐射杀死肿瘤细胞。然而,由于周围正常组织的辐射暴露,这种疗法可能导致短期和长期的不良反应。放射治疗造成的DNA损伤类型决定了它的效果。高水平的基因毒性损伤可导致细胞周期阻滞、衰老和细胞死亡,但许多肿瘤可以通过激活保护机制来应对这种损伤。固有和获得性放射耐药是肿瘤复发的主要原因,了解这些机制对癌症治疗至关重要。辐射抗性背后的机制包括缺氧反应、细胞增殖、DNA修复、细胞凋亡抑制和自噬等过程。本文简要综述了遗传和表观遗传因素在DNA修复和DNA损伤反应调控中促进辐射抵抗的作用。此外,利用我们最近关于低剂量率(LDR)电离辐射对黑腹果蝇的影响的研究结果,我们讨论了这种模式生物如何有助于识别参与肿瘤对放射治疗耐药的保守因子。
{"title":"DNA repair in tumor radioresistance: insights from fruit flies genetics","authors":"Antonella Porrazzo, Matteo Cassandri, Andrea D’Alessandro, Patrizia Morciano, Rossella Rota, Francesco Marampon, Giovanni Cenci","doi":"10.1007/s13402-023-00906-6","DOIUrl":"https://doi.org/10.1007/s13402-023-00906-6","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background</h3><p>Radiation therapy (RT) is a key anti-cancer treatment that involves using ionizing radiation to kill tumor cells. However, this therapy can lead to short- and long-term adverse effects due to radiation exposure of surrounding normal tissue. The type of DNA damage inflicted by radiation therapy determines its effectiveness. High levels of genotoxic damage can lead to cell cycle arrest, senescence, and cell death, but many tumors can cope with this damage by activating protective mechanisms. Intrinsic and acquired radioresistance are major causes of tumor recurrence, and understanding these mechanisms is crucial for cancer therapy. The mechanisms behind radioresistance involve processes like hypoxia response, cell proliferation, DNA repair, apoptosis inhibition, and autophagy.</p><h3 data-test=\"abstract-sub-heading\">Conclusion</h3><p>Here we briefly review the role of genetic and epigenetic factors involved in the modulation of DNA repair and DNA damage response that promote radioresistance. In addition, leveraging our recent results on the effects of low dose rate (LDR) of ionizing radiation on <i>Drosophila melanogaster</i> we discuss how this model organism can be instrumental in the identification of conserved factors involved in the tumor resistance to RT.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":"82 1","pages":""},"PeriodicalIF":6.6,"publicationDate":"2023-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138629657","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
CSGALNACT2 restricts ovarian cancer migration and invasion by modulating MAPK/ERK pathway through DUSP1 CSGALNACT2 通过 DUSP1 调节 MAPK/ERK 通路,从而限制卵巢癌的迁移和侵袭
IF 6.6 2区 医学 Q1 Medicine Pub Date : 2023-12-12 DOI: 10.1007/s13402-023-00903-9
Mingjun Ma, Chao Wang, Meixuan Wu, Sijia Gu, Jiani Yang, Yue Zhang, Shanshan Cheng, Shilin Xu, Minghai Zhang, Yongsong Wu, Yaqian Zhao, Xiu Tian, Dominic Chih-Cheng Voon, Chiaki Takahashi, Jindan Sheng, Yu Wang

Purpose

Ovarian cancer is one of the leading causes of cancer-related death among women. CSGALNACT2 is a vital Golgi transferase and is related to a variety of human diseases. However, its expression pattern and function in ovarian cancer remain uncertain.

Methods

The Cancer Genome Atlas and GEPIA databases were used to assess the expression of CSGALNACT2 in ovarian cancer patients. RNA-seq, qRT-PCR, and IHC were used to verify the expression of CSGALNACT2 in ovarian cancer tissues. Then, in vivo and in vitro experiments were conducted to evaluate the role of CSGALNACT2 in the progression of ovarian cancer. RNA-seq and GSEA were used to reveal the potential biological function and oncogenic pathways of CSGALNACT2.

Results

We demonstrated that the mRNA expression and protein level of CSGALNACT2 were significantly downregulated in ovarian cancer and ovarian cancer metastatic tissues. CSGALNACT2 can significantly inhibit the migration, invasion, and clonogenic growth of ovarian cancer in vitro and is progressively lost during ovarian cancer progression in vivo. CSGALNACT2 suppresses ovarian cancer migration and invasion via DUSP1 modulation of the MAPK/ERK pathway through RNA-seq, KEGG analysis, and Western blotting. Moreover, CSGALNACT2 expression was correlated with immune cell infiltration and had prognostic value in different immune cell-enriched or decreased ovarian cancer. In addition, patients with CSGALNACT2 downregulation are less likely to benefit from immunotherapy.

Conclusion

As an ovarian cancer suppressor gene, CSGALNACT2 inhibits the development of ovarian cancer, and it might be used as a prognostic biomarker in patients with ovarian cancer.

目的卵巢癌是女性癌症相关死亡的主要原因之一。CSGALNACT2 是一种重要的高尔基体转移酶,与多种人类疾病相关。方法 利用癌症基因组图谱和 GEPIA 数据库评估 CSGALNACT2 在卵巢癌患者中的表达。采用 RNA-seq、qRT-PCR 和 IHC 验证 CSGALNACT2 在卵巢癌组织中的表达。然后,通过体内和体外实验评估 CSGALNACT2 在卵巢癌进展中的作用。结果表明,在卵巢癌和卵巢癌转移组织中,CSGALNACT2的mRNA表达和蛋白水平均显著下调。CSGALNACT2在体外能明显抑制卵巢癌的迁移、侵袭和克隆性生长,在体内卵巢癌进展过程中会逐渐消失。通过RNA-seq、KEGG分析和Western印迹,CSGALNACT2通过DUSP1调节MAPK/ERK通路抑制卵巢癌的迁移和侵袭。此外,CSGALNACT2的表达与免疫细胞浸润相关,在不同免疫细胞富集或减少的卵巢癌中具有预后价值。结论 作为一种卵巢癌抑制基因,CSGALNACT2能抑制卵巢癌的发展,可作为卵巢癌患者的预后生物标志物。
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引用次数: 0
Publisher Correction to: RETRACTED ARTICLE: Human bone marrow-derived mesenchymal stem cell-secreted exosomes overexpressing microRNA-34a ameliorate glioblastoma development via down-regulating MYCN. 过表达microRNA-34a的人骨髓间充质干细胞分泌外泌体通过下调MYCN改善胶质母细胞瘤的发展。
IF 6.6 2区 医学 Q1 Medicine Pub Date : 2023-12-01 DOI: 10.1007/s13402-023-00900-y
Bin Wang, Zhong-Hua Wu, Ping-Yang Lou, Chang Chai, Shuang-Yin Han, Jian-Fang Ning, Ming Li
{"title":"Publisher Correction to: RETRACTED ARTICLE: Human bone marrow-derived mesenchymal stem cell-secreted exosomes overexpressing microRNA-34a ameliorate glioblastoma development via down-regulating MYCN.","authors":"Bin Wang, Zhong-Hua Wu, Ping-Yang Lou, Chang Chai, Shuang-Yin Han, Jian-Fang Ning, Ming Li","doi":"10.1007/s13402-023-00900-y","DOIUrl":"10.1007/s13402-023-00900-y","url":null,"abstract":"","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":" ","pages":"1873"},"PeriodicalIF":6.6,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138476852","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Role of ELMO1 in inflammation and cancer—clinical implications ELMO1在炎症和癌症中的作用-临床意义
IF 6.6 2区 医学 Q1 Medicine Pub Date : 2022-06-06 DOI: 10.1007/s13402-022-00680-x
Stefania Tocci, Stella-Rita C. Ibeawuchi, Soumita Das, I. Sayed
{"title":"Role of ELMO1 in inflammation and cancer—clinical implications","authors":"Stefania Tocci, Stella-Rita C. Ibeawuchi, Soumita Das, I. Sayed","doi":"10.1007/s13402-022-00680-x","DOIUrl":"https://doi.org/10.1007/s13402-022-00680-x","url":null,"abstract":"","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":"45 1","pages":"505 - 525"},"PeriodicalIF":6.6,"publicationDate":"2022-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47085860","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 5
GAS41 mediates proliferation and GEM chemoresistance via H2A.Z.2 and Notch1 in pancreatic cancer. GAS41通过haa - z介导GEM的增殖和化学耐药。2和Notch1在胰腺癌中的表达
IF 6.6 2区 医学 Q1 Medicine Pub Date : 2022-06-01 Epub Date: 2022-05-03 DOI: 10.1007/s13402-022-00675-8
Shilong Han, Chuanwu Cao, Rui Liu, YiFeng Yuan, Long Pan, Minjie Xu, Chao Hu, Xiaojun Zhang, Maoquan Li, Xiaoping Zhang

Purpose: GAS41 is a YEATS domain protein that binds to acetylated histone H3 to promote the chromatin deposition of H2A.Z in non-small cell lung cancer. The role of GAS41 in pancreatic cancer is still unknown. Here, we aimed to reveal this role.

Methods: GAS41 expression in pancreatic cancer tissues and cell lines was examined using qRT-PCR, Western blotting and immunohistochemistry. MTT, colony formation, spheroid formation and in vivo tumorigenesis assays were performed to assess the proliferation, tumorigenesis, stemness and gemcitabine (GEM) resistance of pancreatic cancer cells. Mechanistically, co-immunoprecipitation (co-IP) and chromatin immunoprecipitation (ChIP) assays were used to evaluate the roles of GAS41, H2A.Z.2 and Notch1 in pancreatic cancer.

Results: We found that GAS41 is overexpressed in human pancreatic cancer tissues and cell lines, and that its expression increases following the acquisition of GEM resistance. We also found that GAS41 up-regulates Notch, as well as pancreatic cancer cell stemness and GEM resistance in vitro and in vivo. We show that GAS41 binds to H2A.Z.2 and activates Notch and its downstream mediators, thereby regulating stemness and drug resistance. Depletion of GAS41 or H2A.Z.2 was found to down-regulate Notch and to sensitize pancreatic cancer cells to GEM.

Conclusion: Our data indicate that GAS41 mediates proliferation and GEM resistance in pancreatic cancer cells via H2A.Z.2 and Notch1.

目的:GAS41是一种YEATS结构域蛋白,在非小细胞肺癌中与乙酰化组蛋白H3结合,促进H2A.Z的染色质沉积。GAS41 在胰腺癌中的作用尚不清楚。在此,我们旨在揭示这一作用:方法:使用 qRT-PCR、Western 印迹和免疫组化技术检测 GAS41 在胰腺癌组织和细胞系中的表达。方法:利用 qRTCR、Western 印迹和免疫组化技术检测了 GAS41 在胰腺癌组织和细胞系中的表达,并进行了 MTT、菌落形成、球形体形成和体内肿瘤发生试验,以评估胰腺癌细胞的增殖、肿瘤发生、干性和吉西他滨(GEM)耐药性。从机理上讲,我们采用了共免疫沉淀(co-immunoprecipitation,co-IP)和染色质免疫沉淀(chromatin immunoprecipitation,ChIP)实验来评估GAS41、H2A.Z.2和Notch1在胰腺癌中的作用:结果:我们发现 GAS41 在人类胰腺癌组织和细胞系中过表达,并且在获得 GEM 抗性后其表达增加。我们还发现 GAS41 在体外和体内上调 Notch 以及胰腺癌细胞的干性和 GEM 抗性。我们发现,GAS41与H2A.Z.2结合并激活Notch及其下游介质,从而调节干性和耐药性。研究发现,删除 GAS41 或 H2A.Z.2 可下调 Notch,并使胰腺癌细胞对 GEM 敏感:我们的数据表明,GAS41通过H2A.Z.2和Notch1介导了胰腺癌细胞的增殖和对GEM的耐药性。
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引用次数: 5
期刊
Cellular Oncology
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