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Anlotinib induces neuronal-like differentiation of neuroblastoma by downregulating CRMP5. 安罗替尼通过下调CRMP5诱导神经母细胞瘤的神经元样分化
IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-01 Epub Date: 2024-05-23 DOI: 10.1002/mc.23745
Junwen Hu, Wenlong Yang, Kang Wang, Hongyan Xu, Tianxiang Chen, Chao Li, Ting Xiong, Han Xu, Ming Luo, Shouhua Zhang, Jinlong Yan

The therapeutic effect of anlotinib on neuroblastoma is still not fully understood. This study aims to explore the differentiation therapeutic effects of anlotinib on neuroblastoma and its potential association with the neural development regulatory protein collapsin response mediator protein 5 (CRMP5), both in vivo and in vitro. A patient-derived xenograft (PDX) model was established to observe the therapeutic effect of anlotinib. Neuroblastoma cell lines SK-N-SH and SK-N-AS were cultured to observe the morphological impact of anlotinib. Transwell assay was used to evaluate the cell invasion, and Western blot analysis and immunohistochemistry were employed to detect the expressions of neuronal differentiation-related proteins. Results indicate that anlotinib effectively inhibited tumor growth in the PDX model, modulated the expressions of neuronal differentiation markers. In vitro, anlotinib treatment induced neurite outgrowth in neuroblastoma cells and inhibited their invasive ability, reflecting a change in neuronal marker expression patterns consistent with the PDX model. Similarly, in the SK-N-AS mouse xenograft model, anlotinib demonstrated comparable tumor-suppressing effects and promoted neuronal-like differentiation. Additionally, anlotinib significantly downregulated CRMP5 expression in neuroblastoma both in vivo and in vitro. Overexpression of CRMP5 significantly reversed the differentiation therapy effect of anlotinib, exacerbating the aggressiveness and reducing the differentiation level of neuroblastoma. These findings highlight the potential of anlotinib as an anti-neuroblastoma agent. It may suppress tumor proliferation and invasion by promoting the differentiation of tumor cells towards a neuronal-like state, and this differentiation therapy effect involves the inhibition of CRMP5 signaling.

安罗替尼对神经母细胞瘤的治疗效果尚不完全清楚。本研究旨在探讨安罗替尼对神经母细胞瘤的分化治疗作用及其与神经发育调控蛋白塌缩素反应介导蛋白5(CRMP5)在体内和体外的潜在关联。为了观察安罗替尼的治疗效果,我们建立了一个患者来源异种移植(PDX)模型。培养神经母细胞瘤细胞系SK-N-SH和SK-N-AS,观察安罗替尼的形态学影响。采用Transwell试验评估细胞侵袭,并采用Western印迹分析和免疫组化检测神经元分化相关蛋白的表达。结果表明,安罗替尼能有效抑制PDX模型中肿瘤的生长,调节神经元分化标志物的表达。在体外,安罗替尼治疗可诱导神经母细胞瘤细胞神经元外生,并抑制其侵袭能力,反映出神经元标志物表达模式的变化与PDX模型一致。同样,在SK-N-AS小鼠异种移植模型中,安罗替尼也表现出了类似的肿瘤抑制作用,并促进了神经元样分化。此外,无论在体内还是体外,安罗替尼都能显著下调神经母细胞瘤中 CRMP5 的表达。CRMP5的过度表达明显逆转了安罗替尼的分化治疗效果,加剧了神经母细胞瘤的侵袭性并降低了其分化水平。这些发现凸显了安罗替尼作为抗神经母细胞瘤药物的潜力。它可以通过促进肿瘤细胞向神经元样状态分化来抑制肿瘤的增殖和侵袭,而这种分化治疗效应涉及到对CRMP5信号传导的抑制。
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引用次数: 0
IGF2BP2 inhibits invasion and migration of clear cell renal cell carcinoma via targeting Netrin-4 in an m6A-dependent manner. IGF2BP2 以 m6A 依赖性方式通过靶向 Netrin-4 抑制透明细胞肾细胞癌的侵袭和迁移。
IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-01 Epub Date: 2024-05-23 DOI: 10.1002/mc.23746
Gui Wang, Tao Zhuang, Fei Zhen, Chu Zhang, Qichao Wang, Xu Miao, Nienie Qi, Ruiqin Yao

Clear cell renal cell carcinoma (ccRCC), the most common subtype of renal cell carcinoma, often leads to a poor prognosis due to metastasis. The investigation of N6-methyladenosine (m6A) methylation, a crucial RNA modification, and its role in ccRCC, particularly through the m6A reader insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2), revealed significant insights. We found that IGF2BP2 was notably downregulated in ccRCC, which correlated with tumor aggressiveness and poor prognosis. Thus, IGFBP2 has emerged as an independent prognostic factor of ccRCC. Moreover, a strong positive correlation was observed between the expression of IGF2BP2 and Netrin-4. Netrin-4 was also downregulated in ccRCC, and its lower levels were associated with increased malignancy and poor prognosis. Overexpression of IGF2BP2 and Netrin-4 suppressed the invasion and migration of ccRCC cells, while Netrin-4 knockdown reversed these effects in ccRCC cell lines. RNA immunoprecipitation (RIP)-quantitative polymerase chain reaction validated the robust enrichment of Netrin-4 mRNA in anti-IGF2BP2 antibody immunoprecipitates. MeRlP showed significantly increased Netrin4 m6A levels after lGF2BP2 overexpression. Moreover, we found that IGF2BP2 recognized and bound to the m6A site within the coding sequence of Netrin-4, enhancing its mRNA stability. Collectively, these results showed that IGF2BP2 plays a suppressive role in the invasion and migration of ccRCC cells by targeting Netrin-4 in an m6A-dependent manner. These findings underscore the potential of IGF2BP2/Netrin-4 as a promising prognostic biomarker and therapeutic target in patients with ccRCC metastasis.

透明细胞肾细胞癌(ccRCC)是肾细胞癌中最常见的亚型,往往因转移而导致预后不良。N6-甲基腺苷(m6A)甲基化是一种关键的RNA修饰,研究它在ccRCC中的作用,特别是通过m6A读取胰岛素样生长因子2 mRNA结合蛋白2(IGF2BP2)的甲基化,揭示了重要的见解。我们发现,IGF2BP2 在 ccRCC 中明显下调,这与肿瘤的侵袭性和预后不良有关。因此,IGFBP2 已成为 ccRCC 的一个独立预后因素。此外,还观察到 IGF2BP2 的表达与 Netrin-4 之间存在很强的正相关性。Netrin-4也在ccRCC中下调,其水平较低与恶性程度增加和预后不良有关。在ccRCC细胞系中,过表达IGF2BP2和Netrin-4可抑制ccRCC细胞的侵袭和迁移,而Netrin-4的敲除可逆转这些效应。RNA免疫沉淀(RIP)-定量聚合酶链反应验证了抗IGF2BP2抗体免疫沉淀物中Netrin-4 mRNA的强力富集。MeRlP显示,lGF2BP2过表达后,Netrin4 m6A水平明显增加。此外,我们还发现 IGF2BP2 能识别并结合 Netrin-4 编码序列中的 m6A 位点,从而增强其 mRNA 的稳定性。总之,这些结果表明,IGF2BP2 通过以 m6A 依赖性方式靶向 Netrin-4 在 ccRCC 细胞的侵袭和迁移中起抑制作用。这些发现强调了IGF2BP2/Netrin-4作为ccRCC转移患者预后生物标志物和治疗靶点的潜力。
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引用次数: 0
LDHA-mediated M2-type macrophage polarization via tumor-derived exosomal EPHA2 promotes renal cell carcinoma progression. LDHA通过肿瘤外泌体EPHA2介导的M2型巨噬细胞极化促进了肾细胞癌的进展。
IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-01 Epub Date: 2024-05-23 DOI: 10.1002/mc.23737
Xinxin Gan, Jiatao Hu, Qingyang Pang, Rui Yan, Yi Bao, Ying Liu, Jiaao Song, Zheng Wang, Weihao Sun, Fuzhao Huang, Chen Cai, Linhui Wang

Lactate dehydrogenase A (LDHA) is known to promote the growth and invasion of various types of tumors, affects tumor resistance, and is associated with tumor immune escape. But how LDHA reshapes the tumor microenvironment and promotes the progression of renal cell carcinoma (RCC) remains unclear. In this study, we found that LDHA was highly expressed in clear cell RCC (ccRCC), and this high expression was associated with macrophage infiltration, while macrophages were highly infiltrated in ccRCC, affecting patient prognosis via M2-type polarization. Our in vivo and in vitro experiments demonstrated that LDHA and M2-type macrophages could enhance the proliferation, invasion, and migration abilities of ccRCC cells. Mechanistically, high expression of LDHA in ccRCC cells upregulated the expression of EPHA2 in exosomes derived from renal cancer. Exosomal EPHA2 promoted M2-type polarization of macrophages by promoting activation of the PI3K/AKT/mTOR pathway in macrophages, thereby promoting the progression of ccRCC. All these findings suggest that EPHA2 may prove to be a potential therapeutic target for advanced RCC.

众所周知,乳酸脱氢酶A(LDHA)可促进各类肿瘤的生长和侵袭,影响肿瘤的抗药性,并与肿瘤免疫逃逸有关。但LDHA如何重塑肿瘤微环境并促进肾细胞癌(RCC)的进展仍不清楚。在这项研究中,我们发现LDHA在透明细胞RCC(ccRCC)中高表达,这种高表达与巨噬细胞浸润有关,而巨噬细胞在ccRCC中高度浸润,通过M2型极化影响患者的预后。我们的体内和体外实验证明,LDHA和M2型巨噬细胞能增强ccRCC细胞的增殖、侵袭和迁移能力。从机理上讲,LDHA在ccRCC细胞中的高表达会上调肾癌外泌体中EPHA2的表达。外泌体EPHA2通过促进巨噬细胞中PI3K/AKT/mTOR通路的活化来促进巨噬细胞的M2型极化,从而促进ccRCC的进展。所有这些发现表明,EPHA2可能被证明是晚期RCC的潜在治疗靶点。
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引用次数: 0
Curcuminoid PBPD induces cuproptosis and endoplasmic reticulum stress in cervical cancer via the Notch1/RBP-J/NRF2/FDX1 pathway. 姜黄素PBPD通过Notch1/RBP-J/NRF2/FDX1途径诱导宫颈癌的杯突症和内质网应激反应
IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-01 Epub Date: 2024-05-27 DOI: 10.1002/mc.23735
Min-Jie Zhang, Mengna Shi, Yang Yu, Rongying Ou, Ren-Shan Ge, Ping Duan

Curcumin has been shown to have antitumor properties, but its low potency and bioavailability has limited its clinical application. We designed a novel curcuminoid, [1-propyl-3,5-bis(2-bromobenzylidene)-4-piperidinone] (PBPD), which has higher antitumor strength and improves bioavailability. Cell counting kit-8 was used to detect cell activity. Transwell assay was used to detect cell invasion and migration ability. Western blot and quantitative polymerase chain reaction were used to detect protein levels and their messenger RNA expression. Immunofluorescence was used to detect the protein location. PBPD significantly inhibited the proliferation of cervical cancer cells, with an IC50 value of 4.16 μM for Hela cells and 3.78 μM for SiHa cells, leading to the induction of cuproptosis. Transcriptome sequencing analysis revealed that PBPD significantly inhibited the Notch1/Recombination Signal Binding Protein for Immunoglobulin kappa J Region (RBP-J) and nuclear factor erythroid 2-related factor 2 (NRF2) signaling pathways while upregulating ferredoxin 1 (FDX1) expression. Knockdown of Notch1 or RBP-J significantly inhibited NRF2 expression and upregulated FDX1 expression, leading to the inhibition of nicotinamide adenine dinucleotide phosphate activity and the induction of oxidative stress, which in turn activated endoplasmic reticulum stress and induced cell death. The overexpression of Notch1 or RBP-J resulted in the enrichment of RBP-J within the NRF2 promoter region, thereby stimulating NRF2 transcription. NRF2 knockdown resulted in increase in FDX1 expression, leading to cuproptosis. In addition, PBPD inhibited the acidification of tumor niche and reduced cell metabolism to inhibit cervical cancer cell invasion and migration. In conclusion, PBPD significantly inhibits the proliferation, invasion, and migration of cervical cancer cells and may be a novel potential drug candidate for treatment of cervical cancer.

姜黄素已被证明具有抗肿瘤特性,但其低效力和低生物利用度限制了其临床应用。我们设计了一种新型姜黄素[1-丙基-3,5-双(2-溴亚苄基)-4-哌啶酮](PBPD),它具有更强的抗肿瘤能力并提高了生物利用度。细胞计数试剂盒-8 用于检测细胞活性。Transwell 试验用于检测细胞的侵袭和迁移能力。采用 Western 印迹和定量聚合酶链反应检测蛋白质水平及其信使 RNA 表达。免疫荧光用于检测蛋白质的位置。PBPD能明显抑制宫颈癌细胞的增殖,对Hela细胞的IC50值为4.16 μM,对SiHa细胞的IC50值为3.78 μM,从而诱导杯状突变。转录组测序分析表明,PBPD 能显著抑制 Notch1/Recombination Signal Binding Protein for Immunoglobulin kappa J Region (RBP-J) 和核因子红细胞 2 相关因子 2 (NRF2) 信号通路,同时上调铁毒素 1 (FDX1) 的表达。敲除Notch1或RBP-J可显著抑制NRF2的表达,上调FDX1的表达,从而抑制烟酰胺腺嘌呤二核苷酸磷酸酯的活性,诱导氧化应激,进而激活内质网应激,诱导细胞死亡。Notch1或RBP-J的过表达导致RBP-J在NRF2启动子区域富集,从而刺激NRF2的转录。敲除 NRF2 会导致 FDX1 表达增加,从而导致杯突。此外,PBPD 还能抑制肿瘤龛的酸化,降低细胞代谢,从而抑制宫颈癌细胞的侵袭和迁移。总之,PBPD 能显著抑制宫颈癌细胞的增殖、侵袭和迁移,可能是治疗宫颈癌的一种新型潜在候选药物。
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引用次数: 0
KNTC1 knockdown inhibits the proliferation and migration of osteosarcoma cells by MCM2. 敲除 KNTC1 可通过 MCM2 抑制骨肉瘤细胞的增殖和迁移。
IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-01 Epub Date: 2024-05-31 DOI: 10.1002/mc.23748
Lei Zhong, Yuanwei Dong, Shuqin Liu

Osteosarcoma (OS) is a common primary malignant bone tumor, and it is necessary to further investigate the molecular mechanism of OS progression. The expression of kinetochore associated protein 1 (KNTC1) and minichromosome maintenance 2 (MCM2) was detected by immunohistochemistry, quantitative PCR (qPCR) and Western blot. Gene knockdown or overexpression cell models were constructed and the proliferation, apoptosis, cell cycle and migration were detected in vitro, besides, xenograft models were established to explore the effects of KNTC1 downregulation in vivo. Public databased and bioinformatics analysis were performed to screen the downstream molecules and determine the expression of MCM2 in cancers. KNTC1 was overexpressed in OS tissues and positively correlated with overall survival of OS patients. KNTC1 knockdown inhibited the proliferation and migration, and arrested G2 phase, and induced apoptosis. Besides, KNTC1 downregulation restricted the xenograft tumor formation. MCM2, one of the coexpressed genes, was highly expressed in sarcoma and downregulated after KNTC1 knockdown. MCM2 overexpression heightened the proliferation and migration ability of OS cells, which was reversed the inhibiting effects of KNTC1 knockdown. KNTC1 was overexpressed in OS and promoted the progression of OS by upregulating MCM2.

骨肉瘤(Osteosarcoma,OS)是一种常见的原发性恶性骨肿瘤,有必要进一步研究OS进展的分子机制。本研究通过免疫组化、定量 PCR(qPCR)和 Western 印迹检测了动点相关蛋白 1(KNTC1)和迷你染色体维护 2(MCM2)的表达。此外,还建立了异种移植模型,以探讨 KNTC1 下调在体内的影响。通过公共数据库和生物信息学分析筛选下游分子,确定MCM2在癌症中的表达。KNTC1在OS组织中过表达,并与OS患者的总生存率呈正相关。敲除 KNTC1 可抑制细胞的增殖、迁移、G2 期停滞并诱导细胞凋亡。此外,KNTC1 的下调还限制了异种移植肿瘤的形成。MCM2是共表达基因之一,在肉瘤中高表达,在KNTC1敲除后下调。MCM2 的过表达增强了 OS 细胞的增殖和迁移能力,从而逆转了 KNTC1 的抑制作用。KNTC1在OS中过表达,并通过上调MCM2促进OS的进展。
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引用次数: 0
Multifaceted roles of PD-1 in tumorigenesis: From immune checkpoint to tumor cell-intrinsic function. PD-1 在肿瘤发生中的多重作用:从免疫检查点到肿瘤细胞内在功能
IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-01 Epub Date: 2024-05-15 DOI: 10.1002/mc.23740
Huiqing Chen, Jiayu Wei, Zhen Zhu, Yongzhong Hou

Programmed cell death 1 (PD-1), a key immune checkpoint receptor, has been extensively studied for its role in regulating immune responses in cancer. However, recent research has unveiled a complex and dual role for PD-1 in tumorigenesis. While PD-1 is traditionally associated with immune cells, this article explores its expression in various cancer cells and its impact on cancer progression. PD-1's functions extend beyond immune regulation, as it has been found to both promote and suppress tumor growth, depending on the cancer type. These findings have significant implications for the future of cancer treatment and our understanding of the immune response in the context of cancer. This article calls for further research into the multifaceted roles of PD-1 to optimize its therapeutic potential and improve patient outcomes in the fight against cancer.

程序性细胞死亡 1(PD-1)是一种关键的免疫检查点受体,它在调节癌症免疫反应方面的作用已被广泛研究。然而,最近的研究揭示了 PD-1 在肿瘤发生中的复杂和双重作用。虽然 PD-1 传统上与免疫细胞有关,但本文探讨了它在各种癌细胞中的表达及其对癌症进展的影响。PD-1 的功能超出了免疫调节的范畴,因为它既能促进肿瘤生长,也能抑制肿瘤生长,这取决于癌症的类型。这些发现对未来的癌症治疗以及我们对癌症免疫反应的理解具有重要意义。本文呼吁进一步研究 PD-1 的多方面作用,以优化其治疗潜力,改善患者的抗癌疗效。
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引用次数: 0
RETRACTION: "LncAPC Drives Wnt/Β-Catenin Activation and Liver TIC Self-Renewal Through EZH2 Mediated APC Transcriptional Inhibition". 返回:《LncAPC 通过 EZH2 介导的 APC 转录抑制驱动 Wnt/Β-Catenin 激活和肝脏 TIC 自我更新》。
IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-01 Epub Date: 2024-06-19 DOI: 10.1002/mc.23780

Retraction: X. Fu, J. Lin, F. Qin, Z. Yang, Y. Ding, Y. Zhang, L. Han, X. Zhu and Q. Zhang, "LncAPC Drives Wnt/Β-Catenin Activation and Liver TIC Self-Renewal Through EZH2 Mediated APC Transcriptional Inhibition," Molecular Carcinogenesis 57, no. 3 (2018): 408-418, https://doi.org/10.1002/mc.22764. The above article, published online on 16 November 2017 in Wiley Online Library (wileyonlinelibrary.com), and its correction, https://doi.org/10.1002/mc.23443, have been retracted by Wiley Periodicals, LLC. The retractions have been agreed following an investigation into concerns raised by a third party, which revealed inappropriate duplications of images with overlapping field of view between this and another article that was previously published in a different scientific context. Thus, the conclusions of this manuscript are substantially compromised. The authors and their institute were informed of the decision to retract but remained unresponsive.

撤回:X. Fu, J. Lin, F. Qin, Z. Yang, Y. Ding, Y. Zhang, L. Han, X. Zhu and Q. Zhang, "LncAPC Drives Wnt/Β-Catenin Activation and Liver TIC Self-Renewal Through EZH2 Mediated APC Transcriptional Inhibition," Molecular Carcinogenesis 57, no.3 (2018):408-418, https://doi.org/10.1002/mc.22764.2017年11月16日在线发表于Wiley Online Library(wileyonlinelibrary.com)的上述文章及其更正,https://doi.org/10.1002/mc.23443,已被Wiley Periodicals, LLC撤回。在对第三方提出的疑虑进行调查后,我们同意撤回上述稿件,因为调查显示,这篇文章与之前在不同科学背景下发表的另一篇文章之间存在视野重叠的不当重复图像。因此,本稿件的结论大打折扣。我们已将撤稿决定告知作者及其所在研究所,但他们仍未做出回应。
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引用次数: 0
The serine protease CORIN promotes progression of gastric cancer by mediating the ERK1/2 MAPK pathway. 丝氨酸蛋白酶 CORIN 通过介导 ERK1/2 MAPK 通路促进胃癌的进展。
IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-01 Epub Date: 2024-05-15 DOI: 10.1002/mc.23739
Runqi Hong, Xiaotian Zhang, Yi Zhang, Lanxin Bei, Ju Yang, Jie Xia, Zhiqing Hu, Zhipeng Cao, Rui Chen, Liang Chen, Gengming Niu, Chongwei Ke

The serine protease CORIN catalyzes pro-atrial natriuretic peptide (pro-ANP) into an active ANP and maintains homeostasis of the internal environment. However, it is unclear whether CORIN participates in the regulation of tumor progression. We analyzed the expression profile of CORIN in gastric cancer tissues (GCs) and adjacent nontumoral tissues (NTs). We investigated the prognostic value of CORIN in GC patients. We characterized the in vitro and in vivo activity of CORIN in cultured GC cells with gain-of-function and loss-of-function experiments. The underlying mechanism was explored by using bioinformatics, a signaling antibody array, and confirmative western blot analyses, as well as rescue experiments with highly selective small-molecule inhibitors targeting the ERK1/2 MAPK signaling pathway. CORIN was upregulated in GCs than in NTs. Overexpression of CORIN was correlated with unfavorable prognoses in patients with GC. Ectopic expression of CORIN was promoted, whereas silencing of CORIN suppressed proliferation, colony formation, migration and invasion of GC cells, and tumor growth in vivo. Overexpression of CORIN-induced epithelial-mesenchymal transition (EMT) and activation of the ERK1/2 MAPK signaling pathway, while silencing of CORIN yielded opposite results. The in vitro tumor-promoting potency of CORIN could be antagonized by selective inhibitors targeting the ERK1/2 MAPK pathway. In conclusion, CORIN is a potential prognostic marker and therapeutic target for GC patients, which may promote tumor progression by mediating the ERK1/2 MAPK signaling pathway and EMT in GC cells.

丝氨酸蛋白酶 CORIN 可将原心房钠尿肽(pro-ANP)催化成活性 ANP,并维持内环境的平衡。然而,CORIN 是否参与肿瘤进展的调控尚不清楚。我们分析了CORIN在胃癌组织(GCs)和邻近非肿瘤组织(NTs)中的表达谱。我们研究了 CORIN 在胃癌患者中的预后价值。我们通过功能增益和功能缺失实验鉴定了CORIN在培养的胃癌细胞中的体外和体内活性。我们利用生物信息学、信号传导抗体阵列、Western印迹确证分析以及针对ERK1/2 MAPK信号传导通路的高选择性小分子抑制剂进行了挽救实验,从而探索了其潜在机制。CORIN在GCs中比在NTs中上调。CORIN的过表达与GC患者的不良预后相关。异位表达CORIN可促进GC细胞的增殖、集落形成、迁移和侵袭以及体内肿瘤的生长,而沉默CORIN则可抑制GC细胞的增殖、集落形成、迁移和侵袭。过量表达CORIN会诱导上皮-间质转化(EMT)并激活ERK1/2 MAPK信号通路,而沉默CORIN则会产生相反的结果。针对ERK1/2 MAPK通路的选择性抑制剂可拮抗CORIN的体外肿瘤促进效力。总之,CORIN是GC患者的潜在预后标志物和治疗靶点,它可能通过介导ERK1/2 MAPK信号通路和GC细胞的EMT促进肿瘤进展。
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引用次数: 0
HER3 V104 mutations regulate cell signaling, growth, and drug sensitivity in cancer. HER3 V104 突变调节癌症的细胞信号、生长和药物敏感性。
IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-01 Epub Date: 2024-05-15 DOI: 10.1002/mc.23743
Rosalin Mishra, Mary Kate Kilroy, Wasim Feroz, Hima Patel, Joan T Garrett

HER3 is mutated in ~2%-10% of cancers depending on the cancer type. We found the HER3-V104L mutation to be activating from patient-derived mutations introduced via lentiviral transduction in HER3KO HER2 + HCC1569 breast cancer cells in which endogenous HER3 was eliminated by CRISPR/Cas9. Cells expressing HER3-V104L showed higher p-HER3 and p-ERK1/2 expression versus cells expressing wild-type HER3 or HER3-V104M. Patients whose tumor expressed the HER3 V104L variant had a reduced probability of overall survival compared to patients lacking a HER3 mutation whereas we did not find a statistically significant difference in overall survival of various cancer patients with the HER3 V104M mutation. Our data showed that HER2 inhibitors suppressed cell growth of HCC1569HER3KO cells stably expressing the HER3-V104L mutation. Cancer cell lines (SNU407, UC15 and DV90) with endogenous HER3-V104M mutation showed reduced cell proliferation and p-HER2/p-ERK1/2 expression with HER2 inhibitor treatment. Knock down of HER3 abrogated cell proliferation in the above cell lines which were overall more sensitive to the ERK inhibitor SCH779284 versus PI3K inhibitors. HER3-V104L mutation stabilized HER3 protein expression in COS7 and SNUC5 cells. COS7 cells transiently transfected with the HER3-V104L mutation in the presence of HER binding partners showed higher expression of p-HER3, p-ERK1/2 versus HER3-WT in a NRG-independent manner without any change in AKT signaling. Overall, this study shows the clinical relevance of the HER3 V104L and the V104M mutations and its response to HER2, PI3K and ERK inhibitors.

根据癌症类型的不同,约有 2%-10% 的癌症发生 HER3 突变。我们发现,在通过 CRISPR/Cas9 消除内源性 HER3 的 HER3KO HER2 + HCC1569 乳腺癌细胞中,通过慢病毒转导引入的患者来源突变可激活 HER3-V104L 突变。与表达野生型 HER3 或 HER3-V104M 的细胞相比,表达 HER3-V104L 的细胞显示出更高的 p-HER3 和 p-ERK1/2 表达。与没有HER3突变的患者相比,肿瘤表达HER3 V104L变体的患者的总生存概率较低,而我们没有发现HER3 V104M突变的各种癌症患者的总生存率有显著的统计学差异。我们的数据显示,HER2抑制剂抑制了稳定表达HER3-V104L突变的HCC1569HER3KO细胞的生长。内源性HER3-V104M突变的癌细胞株(SNU407、UC15和DV90)在接受HER2抑制剂治疗后,细胞增殖和p-HER2/p-ERK1/2表达均有所下降。敲除 HER3 可抑制上述细胞株的细胞增殖,总体而言,这些细胞株对 ERK 抑制剂 SCH779284 比对 PI3K 抑制剂更敏感。HER3-V104L 突变稳定了 COS7 和 SNUC5 细胞中 HER3 蛋白的表达。在 HER 结合伴侣存在的情况下,瞬时转染了 HER3-V104L 突变基因的 COS7 细胞与 HER3-WT 细胞相比,p-HER3、p-ERK1/2 的表达量更高,且不依赖于 NRG,AKT 信号转导没有发生任何变化。总之,这项研究表明了HER3 V104L和V104M突变的临床意义及其对HER2、PI3K和ERK抑制剂的反应。
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引用次数: 0
Atypical BCR-ABL1 transcript in mixed phenotype acute leukemia with bone marrow necrosis. 混合表型急性白血病伴骨髓坏死的非典型 BCR-ABL1 转录本。
IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-01 Epub Date: 2024-06-11 DOI: 10.1002/mc.23742
Jiarui Liu, Yujie Jiang, Dai Yuan, Zhifen Zhang, Xin Liu, Wenbo Zhao, Hongzhi Xu

Mixed phenotype acute leukemia (MPAL) is a type of acute leukemia in which encompasses mixed features of myeloid, T-lymphoid, and/or B-lymphoid differentiation. Philadelphia chromosome-positive (Ph+) MPAL is a rare subgroup with a poor prognosis and accounts for <1% of adult acute leukemia. Until now, there is still no consensus on how to best treat Ph+ MPAL. Here, we report a 62-year-old male with Ph+ (atypical e13a2 BCR-ABL1 fusion protein) MPAL. This patient presented with recurrent and intense bone pain due to bone marrow necrosis (BMN). Besides, he did not achieve a complete remission for the first two chemotherapies, until he received flumatinib combined with hyper-CVAD (B) (a dose-intensive regimen include methotrexate and cytarabine). To our knowledge, this is the first report to describe the coexistence of BMN and atypical e13a2 BCR-ABL1 transcripts in patients with MPAL. This finding will bring new understandings in the diagnosis and treatment of Ph+ MPAL.

混合表型急性白血病(MPAL)是一种急性白血病,其中包含髓系、T淋巴细胞和/或B淋巴细胞分化的混合特征。费城染色体阳性(Ph+)MPAL 是一种罕见的亚群,预后较差,占成人急性白血病的 1%。迄今为止,关于如何最佳治疗 Ph+ MPAL 仍未达成共识。在此,我们报告了一名患有 Ph+(非典型 e13a2 BCR-ABL1 融合蛋白)MPAL 的 62 岁男性患者。该患者因骨髓坏死(BMN)而反复出现剧烈骨痛。此外,他在接受氟马替尼联合超CVAD(B)(一种包括甲氨蝶呤和阿糖胞苷的剂量强化方案)治疗之前,前两次化疗均未取得完全缓解。据我们所知,这是第一份描述MPAL患者同时存在BMN和非典型e13a2 BCR-ABL1转录本的报告。这一发现将为Ph+ MPAL的诊断和治疗带来新的认识。
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Molecular Carcinogenesis
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