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Correction. 更正。
IF 3.6 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-12-31 Epub Date: 2023-12-26 DOI: 10.1080/15384047.2024.2299054
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引用次数: 0
Hypoxia promotes non-small cell lung cancer cell stemness, migration, and invasion via promoting glycolysis by lactylation of SOX9. 低氧可通过 SOX9 的乳化作用促进糖酵解,从而促进非小细胞肺癌细胞的干性、迁移和侵袭。
IF 3.6 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-12-31 Epub Date: 2024-01-16 DOI: 10.1080/15384047.2024.2304161
Fei Yan, Yue Teng, Xiaoyou Li, Yuejiao Zhong, Chunyi Li, Feng Yan, Xia He

Background: Lung cancer is the deadliest form of malignancy and the most common subtype is non-small cell lung cancer (NSCLC). Hypoxia is a typical feature of solid tumor microenvironment. In the current study, we clarified the effects of hypoxia on stemness and metastasis and the molecular mechanism.

Methods: The biological functions were assessed using the sphere formation assay, Transwell assay, and XF96 extracellular flux analyzer. The protein levels were detected by western blot. The lactylation modification was assessed by western blot and immunoprecipitation. The role of SOX9 in vivo was explored using a xenografted tumor model.

Results: We observed that hypoxia promoted sphere formation, migration, invasion, glucose consumption, lactate production, glycolysis, and global lactylation. Inhibition of glycolysis suppressed cell stemness, migration, invasion, and lactylation. Moreover, hypoxia increased the levels of SOX9 and lactylation of SOX9, whereas inhibition of glycolysis reversed the increase. Additionally, knockdown of SOX9 abrogated the promotion of cell stemness, migration, and invasion. In tumor-bearing mice, overexpression of SOX9 promoted tumor growth, and inhibition of glycolysis suppressed tumor growth.

Conclusion: Hypoxia induced the lactylation of SOX9 to promote stemness, migration, and invasion via promoting glycolysis. The findings suggested that targeting hypoxia may be an effective way for NSCLC treatment and reveal a new mechanism of hypoxia in NSCLC.

背景:肺癌是最致命的恶性肿瘤,最常见的亚型是非小细胞肺癌(NSCLC)。缺氧是实体瘤微环境的典型特征。本研究阐明了缺氧对干细胞和转移的影响及其分子机制:方法:使用球形成试验、Transwell 试验和 XF96 细胞外通量分析仪评估生物功能。蛋白水平通过 Western 印迹检测。乳化修饰通过 Western 印迹和免疫沉淀进行评估。利用异种移植肿瘤模型探讨了SOX9在体内的作用:结果:我们观察到缺氧促进了球体形成、迁移、侵袭、葡萄糖消耗、乳酸产生、糖酵解和全乳化。抑制糖酵解可抑制细胞干性、迁移、侵袭和乳化。此外,缺氧会增加 SOX9 和 SOX9 乳化的水平,而抑制糖酵解会逆转这种增加。此外,敲除SOX9可抑制对细胞干性、迁移和侵袭的促进作用。在肿瘤小鼠中,过表达 SOX9 会促进肿瘤生长,而抑制糖酵解则会抑制肿瘤生长:结论:缺氧诱导SOX9乳化,通过促进糖酵解促进干性、迁移和侵袭。研究结果表明,以缺氧为靶点可能是治疗 NSCLC 的有效方法,并揭示了 NSCLC 中缺氧的新机制。
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引用次数: 0
The role of liver cancer stem cells in hepatocellular carcinoma metastasis. 肝癌干细胞在肝细胞癌转移中的作用。
IF 3.6 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-12-31 Epub Date: 2024-02-23 DOI: 10.1080/15384047.2024.2321768
Qinghui Niu, Susu Ye, Liu Zhao, Yanzhi Qian, Fengchao Liu

Metastasis accounts for the vast majority of cancer deaths; however, this complex process has yet to be fully explained. To form metastases, cancer cells must undergo a series of steps, known as the "Metastatic cascade", each of which requires a specific functional transformation. Cancer stem cells (CSCs) play a vital role in tumor metastasis, but their dynamic behavior and regulatory mechanisms have not been fully elucidated. Based on the "Metastatic cascade" theory, this review summarizes the effect of liver CSCs on the metastatic biological programs that underlie the dissemination and metastatic growth of cancer cells. Liver CSCs have the capacity to initiate distant organ metastasis via EMT, and the microenvironment transformation that supports the ability of these cells to disseminate, evade immune surveillance, dormancy, and regenerate metastasis. Understanding the heterogeneity and traits of liver CSCs in these processes is critical for developing strategies to prevent and treat metastasis of advanced hepatocellular carcinoma (HCC).

转移是绝大多数癌症死亡的原因;然而,这一复杂的过程尚未得到充分解释。要形成转移,癌细胞必须经历一系列步骤,即所谓的 "转移级联",其中每个步骤都需要特定的功能转变。癌症干细胞(CSCs)在肿瘤转移中扮演着重要角色,但其动态行为和调控机制尚未完全阐明。基于 "转移级联 "理论,本综述总结了肝脏干细胞对转移生物程序的影响,这些程序是癌细胞扩散和转移生长的基础。肝脏造血干细胞有能力通过EMT启动远处器官转移,而微环境的转变则支持这些细胞的扩散、逃避免疫监视、休眠和再生转移的能力。了解肝脏间充质干细胞在这些过程中的异质性和特征对于制定预防和治疗晚期肝细胞癌(HCC)转移的策略至关重要。
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引用次数: 0
Repression of the SUMO-conjugating enzyme UBC9 is associated with lowered double minutes and reduced tumor progression. SUMO-结合酶UBC9的抑制与双分钟降低和肿瘤进展减慢有关。
IF 3.6 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-12-31 Epub Date: 2024-03-11 DOI: 10.1080/15384047.2024.2323768
Yusi Wang, Hongyan Zou, Wei Ji, Min Huang, Benhui You, Nan Sun, Yuandong Qiao, Peng Liu, Lidan Xu, Xuelong Zhang, Mengdi Cai, Ye Kuang, Songbin Fu, Wenjing Sun, Xueyuan Jia, Jie Wu

Double minutes (DMs), extrachromosomal gene fragments found within certain tumors, have been noted to carry onco- and drug resistance genes contributing to tumor pathogenesis and progression. After screening for SUMO-related molecule expression within various tumor sample and cell line databases, we found that SUMO-conjugating enzyme UBC9 has been associated with genome instability and tumor cell DM counts, which was confirmed both in vitro and in vivo. Karyotyping determined DM counts post-UBC9 knockdown or SUMOylation inhibitor 2-D08, while RT-qPCR and Western blot were used to measure DM-carried gene expression in vitro. In vivo, fluorescence in situ hybridization (FISH) identified micronucleus (MN) expulsion. Western blot and immunofluorescence staining were then used to determine DNA damage extent, and a reporter plasmid system was constructed to detect changes in homologous recombination (HR) and non-homologous end joining (NHEJ) pathways. Our research has shown that UBC9 inhibition is able to attenuate DM formation and lower DM-carried gene expression, in turn reducing tumor growth and malignant phenotype, via MN efflux of DMs and lowering NHEJ activity to increase DNA damage. These findings thus reveal a relationship between heightened UBC9 activity, increased DM counts, and tumor progression, providing a potential approach for targeted therapies, via UBC9 inhibition.

双分体(DMs)是在某些肿瘤内发现的染色体外基因片段,它携带的抗肿瘤和抗药性基因有助于肿瘤的发病和进展。在对各种肿瘤样本和细胞系数据库中的 SUMO 相关分子表达进行筛选后,我们发现 SUMO 结合酶 UBC9 与基因组不稳定性和肿瘤细胞 DM 数量有关,这一点在体外和体内都得到了证实。核型分析确定了UBC9敲除或SUMO化抑制剂2-D08后的DM数量,而RT-qPCR和Western印迹则用于测量体外DM携带基因的表达。在体内,荧光原位杂交(FISH)确定了微核(MN)的排出。然后用 Western 印迹和免疫荧光染色来确定 DNA 损伤程度,并构建了一个报告质粒系统来检测同源重组(HR)和非同源末端连接(NHEJ)途径的变化。我们的研究表明,抑制 UBC9 能够通过 DM 的 MN 外流和降低 NHEJ 活性来增加 DNA 损伤,从而减少 DM 的形成和降低携带 DM 的基因表达,进而减少肿瘤的生长和恶性表型。因此,这些发现揭示了 UBC9 活性增强、DM 数量增加和肿瘤进展之间的关系,为通过抑制 UBC9 进行靶向治疗提供了一种潜在的方法。
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引用次数: 0
CPT1A mediates the succinylation of SP5 which activates transcription of PDPK1 to promote the viability and glycolysis of prostate cancer cells. CPT1A 介导 SP5 的琥珀酰化,SP5 激活 PDPK1 的转录,从而促进前列腺癌细胞的活力和糖酵解。
IF 3.6 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-12-31 Epub Date: 2024-03-17 DOI: 10.1080/15384047.2024.2329372
Shufeng Liu, Xiaoguang Chen, Liqi Zhang, Bo Lu

Succinylation modification involves in the progression of human cancers. The present study aimed to investigate the role of CPT1A, which is a succinyltransferase in the progression of prostate cancer (PCa). CCK-8 was used to detect the cell viability. Seahorse was performed to evaluate the cell glycolysis. Luciferase assay was used to detect the transcriptional regulation. ChIP was performed to assess the binding between transcriptional factors with the promoters. Co-IP was used to assess the binding between proteins. We found that CPT1A was highly expressed in PCa tissues and cell lines. Silencing of CPT1A inhibited the viability and glycolysis of PCa cells. Mechanistically, CPT1A promoted the succinylation of SP5, which strengthened the binding between SP5 and the promoter of PDPK1. SP5 activated PDPK1 transcription and PDPK1 activated the AKT/mTOR signal pathway. These findings might provide novel targets for the diagnosis or therapy of prostate cancer.

琥珀酰化修饰涉及人类癌症的进展。本研究旨在探讨琥珀酰基转移酶 CPT1A 在前列腺癌(PCa)进展过程中的作用。CCK-8用于检测细胞活力。海马试验用于评估细胞糖酵解。荧光素酶测定用于检测转录调控。ChIP 用于评估转录因子与启动子之间的结合。Co-IP 用于评估蛋白质之间的结合。我们发现 CPT1A 在 PCa 组织和细胞系中高表达。沉默CPT1A可抑制PCa细胞的活力和糖酵解。从机制上讲,CPT1A 促进了 SP5 的琥珀酰化,从而加强了 SP5 与 PDPK1 启动子的结合。SP5 激活了 PDPK1 的转录,而 PDPK1 激活了 AKT/mTOR 信号通路。这些发现可能会为前列腺癌的诊断或治疗提供新的靶点。
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引用次数: 0
METTL14 decreases FTH1 mRNA stability via m6A methylation to promote sorafenib-induced ferroptosis of cervical cancer. METTL14通过m6A甲基化降低FTH1 mRNA的稳定性,从而促进索拉非尼诱导的宫颈癌铁变态反应。
IF 4.4 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-12-31 Epub Date: 2024-05-13 DOI: 10.1080/15384047.2024.2349429
Lijie Li, Jie Zeng, Sili He, Yanfei Yang, Chen Wang

Cervical cancer (CC) is a prevalent malignancy among women worldwide. This study was designed to investigate the role of METTL14 in sorafenib-induced ferroptosis in CC. METTL14 expression and m6A methylation were determined in CC tissues, followed by analyzes correlating these factors with clinical features. Subsequently, METTL14 was knocked down in CC cell lines, and the effects on cell proliferation, mitochondrial morphology and ferroptosis were assessed using CCK-8, microscopy, and markers associated with ferroptosis, respectively. The regulatory relationship between METTL14 and FTH1 was verified using qRT-PCR and luciferase reporter assays. The functional significance of this interaction was further investigated both in vitro and in vivo by co-transfecting cells with overexpression vectors or shRNAs targeting METTL14 and FTH1 after sorafenib treatment. METTL14 expression and m6A methylation were significantly reduced in CC tissues, and lower METTL14 expression levels were associated with a poorer CC patients' prognosis. Notably, METTL14 expression increased during sorafenib-induced ferroptosis, and METTL14 knockdown attenuated the ferroptotic response induced by sorafenib in CC cells. FTH1 was identified as a direct target of METTL14, with METTL14 overexpression leading to increased m6A methylation of FTH1 mRNA, resulting in reduced stability and expression of FTH1 in CC. Furthermore, FTH1 overexpression or treatment with LY294002 partially counteracted the promotion of sorafenib-induced ferroptosis by METTL14. In vivo xenograft experiments demonstrated that inhibiting METTL14 reduced the anticancer effects of sorafenib, whereas suppression of FTH1 significantly enhanced sorafenib-induced ferroptosis and increased its anticancer efficacy. METTL14 reduces FTH1 mRNA stability through m6A methylation, thereby enhancing sorafenib-induced ferroptosis, which contributes to suppressing CC progression via the PI3K/Akt signaling pathway.

宫颈癌(CC)是全球妇女中普遍存在的恶性肿瘤。本研究旨在探讨METTL14在索拉非尼诱导的宫颈癌铁中毒中的作用。研究测定了CC组织中METTL14的表达和m6A甲基化,并分析了这些因素与临床特征的相关性。随后,在CC细胞系中敲除METTL14,并使用CCK-8、显微镜和与铁变态相关的标记物分别评估其对细胞增殖、线粒体形态和铁变态的影响。通过 qRT-PCR 和荧光素酶报告实验验证了 METTL14 和 FTH1 之间的调控关系。索拉非尼治疗后,通过过表达载体或靶向 METTL14 和 FTH1 的 shRNAs 共同转染细胞,进一步研究了这种相互作用在体外和体内的功能意义。在CC组织中,METTL14的表达和m6A甲基化明显降低,而较低的METTL14表达水平与CC患者较差的预后有关。值得注意的是,在索拉非尼诱导的铁变态反应过程中,METTL14的表达会增加,而METTL14的敲除会减弱索拉非尼在CC细胞中诱导的铁变态反应。FTH1被确定为METTL14的直接靶标,METTL14过表达会导致FTH1 mRNA的m6A甲基化增加,从而降低FTH1在CC中的稳定性和表达。此外,FTH1过表达或用LY294002治疗可部分抵消METTL14对索拉非尼诱导的铁变态反应的促进作用。体内异种移植实验表明,抑制METTL14会降低索拉非尼的抗癌效果,而抑制FTH1则会显著增强索拉非尼诱导的铁细胞沉降,提高其抗癌疗效。METTL14通过m6A甲基化降低了FTH1 mRNA的稳定性,从而增强了索拉非尼诱导的铁变态反应,这有助于通过PI3K/Akt信号通路抑制CC的进展。
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引用次数: 0
The antipsychotic drug pimozide promotes apoptosis through the RAF/ERK pathway and enhances autophagy in breast cancer cells. 抗精神病药物匹莫齐特通过RAF/ERK途径促进乳腺癌细胞凋亡,并增强自噬作用。
IF 3.6 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-12-31 Epub Date: 2024-02-14 DOI: 10.1080/15384047.2024.2302413
Ge Jiang, Xingzhi Zhou, Ye Hu, Xiaoyu Tan, Dan Wang, Lina Yang, Qinggao Zhang, Shuangping Liu

The antipsychotic drug pimozide has been demonstrated to inhibit cancer. However, the precise anti-cancer mechanism of pimozide remains unclear. The purpose of this study was to investigate the effects of pimozide on human MCF-7 and MDA-MB-231 breast cancer cell lines, and the potential involvement in the RAF/ERK signaling. The effects of pimozide on cells were examined by 4,5-dimethylthiazol-2-yl-3,5-diphenylformazan, wound healing, colony formation, transwell assays, and caspase activity assay. Flow cytometry and acridine orange and ethidium bromide staining were performed to assess changes in cells. Transmission electron microscopy and monodansylcadaverine staining were used to observe autophagosomes. The cyclic adenosine monophosphate was evaluated using the FRET system. Immunohistochemistry, immunofluorescence, RNA interference, and western blot investigated the expression of proteins. Mechanistically, we focus on the RAF1/ERK signaling. We detected pimozide was docked to RAF1 by Schrodinger software. Pimozide down-regulated the phosphorylation of RAF1, ERK 1/2, Bcl-2, and Bcl-xl, up-regulated Bax, and cleaved caspase-9 to induce apoptosis. Pimozide might promote autophagy by up-regulating cAMP. The enhancement of autophagy increased the conversion of LC3-I to LC3-II and down-regulated p62 expression. But mTOR signaling was not involved in promoting autophagy. The knockdown of RAF1 expression induced autophagy and apoptosis in breast cancer cells, consistent with the results of pimozide or sorafenib alone. Blocked autophagy by chloroquine resulted in the impairment of pimozide-induced apoptosis. These data showed that pimozide inhibits breast cancer by regulating the RAF/ERK signaling pathway and might activate cAMP-induced autophagy to promote apoptosis and it may be a potential drug for breast cancer treatment.

抗精神病药物匹莫齐特已被证实具有抑制癌症的作用。然而,匹莫齐特的确切抗癌机制仍不清楚。本研究旨在探讨匹莫齐特对人类 MCF-7 和 MDA-MB-231 乳腺癌细胞系的影响,以及可能参与 RAF/ERK 信号转导的情况。匹莫齐特对细胞的影响通过4,5-二甲基噻唑-2-基-3,5-二苯基甲臢、伤口愈合、菌落形成、透孔试验和caspase活性测定进行了检验。流式细胞仪、吖啶橙和溴化乙锭染色法用于评估细胞的变化。透射电子显微镜和单丹参素染色用于观察自噬体。使用 FRET 系统对环磷酸腺苷进行评估。免疫组化、免疫荧光、RNA 干扰和 Western 印迹检查了蛋白质的表达。在机制上,我们关注 RAF1/ERK 信号传导。我们用 Schrodinger 软件检测到匹莫齐特与 RAF1 对接。匹莫齐特可下调RAF1、ERK 1/2、Bcl-2和Bcl-xl的磷酸化,上调Bax和裂解的caspase-9,从而诱导细胞凋亡。匹莫齐特可能通过上调cAMP促进自噬。自噬的增强增加了 LC3-I 向 LC3-II 的转化,并下调了 p62 的表达。但mTOR信号转导并未参与促进自噬。敲除 RAF1 可诱导乳腺癌细胞自噬和凋亡,这与单独使用匹莫齐特或索拉非尼的结果一致。氯喹阻断自噬会导致匹莫齐德诱导的细胞凋亡受损。这些数据表明,匹莫齐特通过调节RAF/ERK信号通路抑制乳腺癌,并可能激活cAMP诱导的自噬促进细胞凋亡,可能是治疗乳腺癌的潜在药物。
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引用次数: 0
SATB1 mediated tumor colonization and β-catenin nuclear localization are associated with colorectal cancer progression. SATB1 介导的肿瘤定植和 β-catenin 核定位与结直肠癌的进展有关。
IF 3.6 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-12-31 Epub Date: 2024-02-22 DOI: 10.1080/15384047.2024.2320307
Luan Sun, Feng Wang, Xufei Wang, Feiying Zhang, Sujuan Ma, Jinghuan Lv

Colorectal cancer (CRC) is a malignancy with high incidence and poor prognosis. It is urgent to identify valuable biomarkers for early diagnosis and potent therapeutic targets. It has been reported that SATB1 is associated with the malignant progression in CRC. To explore the role of SATB1 in CRC progression and the underlying mechanism, we evaluated the expression of SATB1 in the paired CRC tissues with immunohistochemistry. The results showed that the expression of SATB1 in lymph node metastasis was higher than that in primary lesion, and that in distant organ metastasis was higher than that in primary lesion. The retrospective analysis showed that patients with high expression of SATB1 had a significantly worse prognosis than those with negative and moderate expression. In vitro experiments that employing SATB1 over-expressing and depleted CRC cell lines confirmed that SATB1 contributes to cell proliferation and colonization, while inhibiting cell motility. Furthermore, the tissue immunofluorescence assay, Co-IP and Western blot were conducted to reveal that SATB1 induced translocation of β-catenin and formed a protein complex with it in the nuclei. In conclusion, SATB1 mediated tumor colonization and β-catenin nuclear localization are associated with the malignant progression and poor prognosis of CRC.

结直肠癌(CRC)是一种发病率高、预后差的恶性肿瘤。当务之急是找到有价值的生物标志物,用于早期诊断和有效的治疗靶点。据报道,SATB1 与 CRC 的恶性进展有关。为了探讨 SATB1 在 CRC 恶性进展中的作用及其内在机制,我们用免疫组化方法评估了 SATB1 在配对 CRC 组织中的表达。结果显示,SATB1在淋巴结转移中的表达高于原发病灶,在远处器官转移中的表达高于原发病灶。回顾性分析表明,SATB1高表达患者的预后明显差于阴性和中度表达患者。采用 SATB1 高表达和低表达的 CRC 细胞系进行的体外实验证实,SATB1 有助于细胞增殖和定植,同时抑制细胞运动。此外,通过组织免疫荧光检测、Co-IP 和 Western 印迹发现,SATB1 能诱导β-catenin 转位,并与其在细胞核中形成蛋白复合物。总之,SATB1介导的肿瘤定植和β-catenin核定位与CRC的恶性进展和不良预后有关。
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引用次数: 0
RND1 inhibits epithelial-mesenchymal transition and temozolomide resistance of glioblastoma via AKT/GSK3-β pathway. RND1通过AKT/GSK3-β途径抑制胶质母细胞瘤的上皮-间质转化和替莫唑胺耐药性
IF 3.6 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-12-31 Epub Date: 2024-03-05 DOI: 10.1080/15384047.2024.2321770
Qian Sun, Junjie Xu, Fan'en Yuan, Yan Liu, Qianxue Chen, Lirui Guo, Huimin Dong, Baohui Liu

GBM is one of the most malignant tumor in central nervous system. The resistance to temozolomide (TMZ) is inevitable in GBM and the characterization of TMZ resistance seriously hinders clinical treatment. It is worthwhile exploring the underlying mechanism of aggressive invasion and TMZ resistance in GBM treatment. Bioinformatic analysis was used to analyze the association between RND1 and a series of EMT-related genes. Colony formation assay and cell viability assay were used to assess the growth of U87 and U251 cells. The cell invasion status was evaluated based on transwell and wound-healing assays. Western blot was used to detect the protein expression in GBM cells. Treatment targeted RND1 combined with TMZ therapy was conducted in nude mice to evaluate the potential application of RND1 as a clinical target for GBM. The overexpression of RND1 suppressed the progression and migration of U87 and U251 cells. RND1 knockdown facilitated the growth and invasion of GBM cells. RND1 regulated the EMT of GBM cells via inhibiting the phosphorylation of AKT and GSK3-β. The promoted effects of RND1 on TMZ sensitivity was identified both in vitro and in vivo. This research demonstrated that the overexpression of RND1 suppressed the migration and EMT status by downregulating AKT/GSK3-β pathway in GBM. RND1 enhanced the TMZ sensitivity of GBM cells both in vitro and in vivo. Our findings may contribute to the targeted therapy for GBM and the understanding of mechanisms of TMZ resistance in GBM.

GBM是中枢神经系统中恶性程度最高的肿瘤之一。GBM 对替莫唑胺(TMZ)的耐药性是不可避免的,TMZ 耐药性的特征严重阻碍了临床治疗。探讨GBM治疗中侵袭性侵袭和TMZ耐药的内在机制值得关注。生物信息学分析用于分析 RND1 与一系列 EMT 相关基因之间的关联。集落形成试验和细胞活力试验用于评估 U87 和 U251 细胞的生长情况。细胞侵袭状态的评估基于透孔试验和伤口愈合试验。用 Western 印迹法检测 GBM 细胞的蛋白表达。为了评估 RND1 作为 GBM 临床靶点的潜在应用价值,研究人员在裸鼠中进行了 RND1 靶点联合 TMZ 治疗。RND1的过表达抑制了U87和U251细胞的进展和迁移。RND1敲除促进了GBM细胞的生长和侵袭。RND1通过抑制AKT和GSK3-β的磷酸化调控GBM细胞的EMT。RND1对TMZ敏感性的促进作用在体外和体内均得到了证实。该研究表明,过表达 RND1 可通过下调 AKT/GSK3-β 通路抑制 GBM 的迁移和 EMT 状态。RND1在体外和体内都增强了GBM细胞对TMZ的敏感性。我们的发现可能有助于GBM的靶向治疗和对GBM TMZ耐药机制的理解。
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引用次数: 0
A mathematical model for predicting the spatiotemporal response of breast cancer cells treated with doxorubicin. 预测接受多柔比星治疗的乳腺癌细胞时空反应的数学模型。
IF 3.6 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-12-31 Epub Date: 2024-02-27 DOI: 10.1080/15384047.2024.2321769
Hugo J M Miniere, Ernesto A B F Lima, Guillermo Lorenzo, David A Hormuth, Sophia Ty, Amy Brock, Thomas E Yankeelov

Tumor heterogeneity contributes significantly to chemoresistance, a leading cause of treatment failure. To better personalize therapies, it is essential to develop tools capable of identifying and predicting intra- and inter-tumor heterogeneities. Biology-inspired mathematical models are capable of attacking this problem, but tumor heterogeneity is often overlooked in in-vivo modeling studies, while phenotypic considerations capturing spatial dynamics are not typically included in in-vitro modeling studies. We present a data assimilation-prediction pipeline with a two-phenotype model that includes a spatiotemporal component to characterize and predict the evolution of in-vitro breast cancer cells and their heterogeneous response to chemotherapy. Our model assumes that the cells can be divided into two subpopulations: surviving cells unaffected by the treatment, and irreversibly damaged cells undergoing treatment-induced death. MCF7 breast cancer cells were previously cultivated in wells for up to 1000 hours, treated with various concentrations of doxorubicin and imaged with time-resolved microscopy to record spatiotemporally-resolved cell count data. Images were used to generate cell density maps. Treatment response predictions were initialized by a training set and updated by weekly measurements. Our mathematical model successfully calibrated the spatiotemporal cell growth dynamics, achieving median [range] concordance correlation coefficients of > .99 [.88, >.99] and .73 [.58, .85] across the whole well and individual pixels, respectively. Our proposed data assimilation-prediction approach achieved values of .97 [.44, >.99] and .69 [.35, .79] for the whole well and individual pixels, respectively. Thus, our model can capture and predict the spatiotemporal dynamics of MCF7 cells treated with doxorubicin in an in-vitro setting.

肿瘤异质性在很大程度上导致了化疗抗药性,而化疗抗药性是治疗失败的主要原因。为了更好地实现个性化治疗,必须开发出能够识别和预测肿瘤内和肿瘤间异质性的工具。受生物学启发的数学模型能够解决这一问题,但体内建模研究往往忽略了肿瘤异质性,而体外建模研究通常不包括捕捉空间动态的表型因素。我们介绍了一种数据同化-预测管道,该管道采用包含时空成分的双表型模型,用于描述和预测体外乳腺癌细胞的演变及其对化疗的异质性反应。我们的模型假定细胞可分为两个亚群:未受治疗影响的存活细胞和因治疗而死亡的不可逆损伤细胞。MCF7 乳腺癌细胞先前在培养孔中培养长达 1000 小时,用不同浓度的多柔比星处理,并用时间分辨显微镜成像,记录时空分辨细胞计数数据。图像用于生成细胞密度图。治疗反应预测由训练集初始化,并通过每周的测量进行更新。我们的数学模型成功校准了时空细胞生长动态,在整井和单个像素上的中位数[范围]一致性相关系数分别大于.99[.88, >.99]和.73[.58, .85]。我们提出的数据同化-预测方法在全井和单个像素上的相关系数分别达到了 .97 [.44, >.99] 和 .69 [.35, .79]。因此,我们的模型可以捕捉和预测体外环境中接受多柔比星治疗的 MCF7 细胞的时空动态。
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Cancer Biology & Therapy
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