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Chimerization of human ESC-derived extraembryonic cells with the mouse blastocyst. 人类胚外干细胞与小鼠胚泡的嵌合。
IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-23 eCollection Date: 2024-01-01 DOI: 10.7150/ijbs.99519
Siyi Fu, Borong Huang, Enqin Li, Xiaoling Xu, Ren-He Xu

It has been reported that human embryonic stem cells (hESCs) treated with BMP4 and inhibitors of TGFβ signaling (A83-01) and FGF signaling (PD173074), called BAP, can efficiently differentiate to extraembryonic (ExE) cells in vitro. Due to restricted access to human embryos, it is ethically impossible to test the developmental potential of ExE cells in vivo. Here, we demonstrate that most ExE cells expressed molecular markers for both trophoblasts (TBs) and amniotic cells (ACs). Following intra-uterine transplantation, ExE cells contributed to the mouse placenta. More interestingly, ExE cells could chimerize with the mouse blastocyst as, after injection into the blastocyst, they penetrated its trophectoderm. After implantation of the injected blastocysts into surrogate mice, human cells were found at E14 in placental labyrinth, junction zones, and even near the uterine decidua, expressed placental markers, and secreted human chorionic gonadotropin. Surprisingly, ExE cells also contributed to cartilages of the chimeric embryo with some expressing the chondrogenic marker SOX9, consistent with the mesodermal potential of TBs and ACs in the placenta. Deleting MSX2, a mesodermal determinant, restricted the contribution of ExE cells to the placenta. Thus, we conclude that hESC-derived ExE cells can chimerize with the mouse blastocyst and contribute to both the placenta and cartilages of the chimera consistent with their heteogenious nature. Intra-uterus and intra-blastocyst injections are novel and sensitive methods to study the developmental potential of ExE cells.

据报道,经 BMP4 和 TGFβ 信号转导抑制剂(A83-01)及 FGF 信号转导抑制剂(PD173074)(称为 BAP)处理的人类胚胎干细胞(hESCs)可在体外有效分化为胚外细胞(ExE)。由于人类胚胎的获取受到限制,从伦理角度讲不可能在体内测试 ExE 细胞的发育潜能。在这里,我们证明了大多数 ExE 细胞表达滋养层细胞(TB)和羊膜细胞(AC)的分子标记。在宫内移植后,ExE细胞为小鼠胎盘做出了贡献。更有趣的是,ExE 细胞注入小鼠胚泡后,可以穿透其滋养层,与胚泡嵌合。将注入的胚泡植入代孕小鼠体内后,在 E14 期的胎盘迷宫、交界区甚至子宫蜕膜附近都发现了人类细胞,它们表达胎盘标记,并分泌人类绒毛膜促性腺激素。令人惊讶的是,ExE 细胞也对嵌合胚胎的软骨有贡献,其中一些表达软骨标志物 SOX9,这与胎盘中的 TB 和 AC 的中胚层潜能一致。删除中胚层决定因子 MSX2 限制了 ExE 细胞对胎盘的贡献。因此,我们得出结论:源于 hESC 的 ExE 细胞能与小鼠胚泡嵌合,并对嵌合体的胎盘和软骨做出贡献,这与其同种异体性质是一致的。宫腔内注射和囊胚内注射是研究 ExE 细胞发育潜能的新颖而灵敏的方法。
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引用次数: 0
Exploring the Mechanism of Ferroptosis Induction by Sappanone A in Cancer: Insights into the Mitochondrial Dysfunction Mediated by NRF2/xCT/GPX4 Axis. 探索萨帕酮 A 在癌症中诱导铁氧化的机制:洞察由 NRF2/xCT/GPX4 轴介导的线粒体功能障碍
IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-23 eCollection Date: 2024-01-01 DOI: 10.7150/ijbs.96748
Junyan Wang, Haowen Zhuang, Xiaocui Yang, Zhijiang Guo, Kainan Zhou, Nanyang Liu, Yang An, Ye Chen, Zhongzheng Zhang, Mengyuan Wang, Jinhong Chen, Chun Li, Xing Chang

Non-small cell lung cancer (NSCLC), a major subtype of lung cancer, encompasses squamous cell carcinoma, adenocarcinoma, and large cell carcinoma. Compared to small cell lung cancer, NSCLC cells grow and divide more slowly, and their metastasis occurs at a later stage. Currently, chemotherapy is the primary treatment for this disease. Sappanone A (SA) is a flavonoid compound extracted from the plant Caesalpinia sappan, known for its antitumor, redox-regulating, and anti-inflammatory properties. Recent studies have investigated the interaction of SA with mitochondrial pathways in regulating cell death through the Nrf-2/GPX-4/xCT axis. This study specifically explores the mechanism by which SA affects mitochondrial morphology and structure through the regulation of mitophagy and mitochondrial biogenesis in tumor cells. The study primarily utilizes second-generation transcriptomic sequencing data and molecular docking techniques to elucidate the role of SA in regulating programmed cell death in tumor cells. The omics results indicate that SA treatment significantly targets genes involved in oxidative phosphorylation, mitophagy, mitochondrial dynamics, and oxidative stress. Further findings confirmed that the Nrf-2/GPX4/xCT pathway serves as a crucial target of SA in the treatment of NSCLC. Knockdown of Nrf-2 (si-Nrf-2) and Nrf-2 overexpression (ad-Nrf-2) were shown to modulate the therapeutic efficacy of SA to varying degrees. Additionally, modifications to the GPX4/xCT genes significantly affected the regulatory effects of SA on mitochondrial autophagy, biogenesis, and energy metabolism. These regulatory mechanisms may be mediated through the caspase pathway and ferroptosis-related signaling. Molecular biology experiments have demonstrated that SA intervention further inhibits the phosphorylation of FUNDC1 at Tyr18 and downregulates TOM20 expression. SA treatment was found to reduce the expression of PGC1α, Nrf-1, and Tfam, resulting in a decrease in mitochondrial respiration and energy metabolism. Overexpression of Nrf-2 was shown to counteract the regulatory effects of SA on mitophagy and mitochondrial biogenesis. Confocal microscopy experiments further revealed that SA treatment increases mitochondrial fragmentation, subsequently inducing mitochondrial pathway-mediated programmed cell death. However, genetic modification of the Nrf-2/GPX4/xCT pathway significantly altered the regulatory effects of SA on tumor cells. In conclusion, SA has been identified as a promising therapeutic agent for NSCLC. The mitochondrial pathway-mediated apoptosis and ferroptosis may represent key mechanisms in regulating tumor cell death. Targeting the Nrf-2/GPX-4/xCT axis offers a novel therapeutic approach for maintaining mitochondrial homeostasis within the cellular microenvironment.

非小细胞肺癌(NSCLC)是肺癌的一个主要亚型,包括鳞状细胞癌、腺癌和大细胞癌。与小细胞肺癌相比,NSCLC 细胞的生长和分裂速度更慢,转移发生的时间也更晚。目前,化疗是治疗这种疾病的主要方法。Sappanone A(SA)是从植物 Caesalpinia sappan 中提取的一种类黄酮化合物,以其抗肿瘤、氧化还原调节和抗炎特性而闻名。最近的研究调查了 SA 在通过 Nrf-2/GPX-4/xCT 轴调节细胞死亡过程中与线粒体途径的相互作用。本研究特别探讨了南澳大利亚通过调控肿瘤细胞的有丝分裂吞噬和线粒体生物生成影响线粒体形态和结构的机制。研究主要利用第二代转录组测序数据和分子对接技术来阐明SA在调控肿瘤细胞程序性细胞死亡中的作用。omics研究结果表明,SA处理能显著靶向参与氧化磷酸化、有丝分裂吞噬、线粒体动力学和氧化应激的基因。进一步的研究结果证实,Nrf-2/GPX4/xCT通路是SA治疗NSCLC的关键靶点。研究表明,敲除Nrf-2(si-Nrf-2)和Nrf-2过表达(ad-Nrf-2)在不同程度上调节了SA的疗效。此外,对 GPX4/xCT 基因的修饰会显著影响 SA 对线粒体自噬、生物生成和能量代谢的调节作用。这些调控机制可能是通过 Caspase 通路和铁蛋白沉积相关信号传导介导的。分子生物学实验证明,SA 的干预进一步抑制了 FUNDC1 在 Tyr18 处的磷酸化,并下调了 TOM20 的表达。研究发现,SA 处理会降低 PGC1α、Nrf-1 和 Tfam 的表达,导致线粒体呼吸和能量代谢下降。研究表明,过量表达 Nrf-2 可以抵消 SA 对有丝分裂吞噬和线粒体生物生成的调节作用。共聚焦显微镜实验进一步发现,SA 处理会增加线粒体碎片,进而诱导线粒体途径介导的细胞程序性死亡。然而,对Nrf-2/GPX4/xCT通路的基因修饰会显著改变SA对肿瘤细胞的调控作用。总之,SA已被确定为一种治疗NSCLC的有前途的药物。线粒体途径介导的凋亡和铁凋亡可能是调控肿瘤细胞死亡的关键机制。靶向 Nrf-2/GPX-4/xCT 轴为维持细胞微环境中的线粒体平衡提供了一种新的治疗方法。
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引用次数: 0
A new perspective on the therapeutic potential of tumor metastasis: targeting the metabolic interactions between TAMs and tumor cells. 肿瘤转移治疗潜力的新视角:靶向 TAMs 与肿瘤细胞之间的代谢相互作用。
IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-23 eCollection Date: 2024-01-01 DOI: 10.7150/ijbs.99680
Xuan Zhao, Tong Ren, Sijin Li, Xu Wang, Rui Hou, Zhangchun Guan, Dan Liu, Junnian Zheng, Ming Shi

Tumor-associated macrophages (TAMs) undergo metabolic reprogramming, encompassing glucose, amino acid, fatty acid metabolism, tricarboxylic acid (TCA) cycle, purine metabolism, and autophagy, within the tumor microenvironment (TME). The metabolic interdependencies between TAMs and tumor cells critically influence macrophage recruitment, differentiation, M2 polarization, and secretion of epithelial-mesenchymal transition (EMT)-related factors, thereby activating intratumoral EMT pathways and enhancing tumor cell invasion and metastasis. Tumor cell metabolic alterations, including hypoxia, metabolite secretion, aerobic metabolism, and autophagy, affect the TME's metabolic landscape, driving macrophage recruitment, differentiation, M2 polarization, and metabolic reprogramming, ultimately facilitating EMT, invasion, and metastasis. Additionally, macrophages can induce tumor cell EMT by reprogramming their aerobic glycolysis. Recent experimental and clinical studies have focused on the metabolic interactions between macrophages and tumor cells to control metastasis and inhibit tumor progression. This review highlights the regulatory role of TAM-tumor cell metabolic codependencies in EMT, offering valuable insights for TAM-targeted therapies in highly metastatic tumors. Modulating the metabolic interplay between tumors and TAMs represents a promising therapeutic strategy for treating patients with metastatic cancers.

肿瘤相关巨噬细胞(TAMs)在肿瘤微环境(TME)中进行代谢重编程,包括葡萄糖、氨基酸、脂肪酸代谢、三羧酸(TCA)循环、嘌呤代谢和自噬。TAMs和肿瘤细胞之间的代谢相互依存关系对巨噬细胞的募集、分化、M2极化以及上皮-间质转化(EMT)相关因子的分泌产生了关键影响,从而激活了瘤内EMT通路,增强了肿瘤细胞的侵袭和转移。肿瘤细胞的新陈代谢改变,包括缺氧、代谢物分泌、有氧代谢和自噬,会影响肿瘤组织间质(TME)的新陈代谢格局,推动巨噬细胞的招募、分化、M2 极化和新陈代谢重编程,最终促进 EMT、侵袭和转移。此外,巨噬细胞还能通过对其有氧糖酵解进行重编程来诱导肿瘤细胞的 EMT。最近的实验和临床研究重点关注巨噬细胞和肿瘤细胞之间的代谢相互作用,以控制转移和抑制肿瘤进展。本综述强调了巨噬细胞-肿瘤细胞代谢相互依存关系在 EMT 中的调控作用,为针对高度转移性肿瘤的巨噬细胞-肿瘤细胞靶向疗法提供了宝贵的见解。调节肿瘤和 TAM 之间的代谢相互作用是治疗转移性癌症患者的一种很有前景的治疗策略。
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引用次数: 0
KIF15 promotes human glioblastoma progression under the synergistic transactivation of REST and P300. KIF15 在 REST 和 P300 的协同转录激活作用下促进人类胶质母细胞瘤的发展。
IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-23 eCollection Date: 2024-01-01 DOI: 10.7150/ijbs.98668
Wendan Yu, Shilong Han, Sheng Hu, Liyuan Ru, Chunyu Hua, Guoqing Xue, Guohui Zhang, Kuan Lv, Hanxiao Ge, Meiyi Wang, Lina Zheng, Jie Zhou, Shuai Hou, Yun Teng, Wuguo Deng, Wei Guo

Glioblastoma (GBM) is highly invasive and lethal. The failure to cure GBM highlights the necessity of developing more effective targeted therapeutic strategies. KIF15 is a motor protein to be involved in cell mitosis promotion, cell structure assembly and cell signal transduction. The precise biological function and the potential upstream regulatory mechanisms of KIF15 in GBM remain elusive. Here, we demonstrated that KIF15 was abnormally up-regulated in GBM and predicted poor prognosis of GBM patients. KIF15 promotes GBM cell proliferation, metastasis and cell cycle progression. REST could bind to KIF15 promoter and transactivate KIF15. Furthermore, REST interacts with P300 and depends on its histone acetyltransferase (HAT) activity to co-regulate KIF15 expression. Both REST and P300 were highly expressed in GBM and predicted poor prognosis of GBM patients alone or in combination with KIF15. The tumorigenic function of KIF15 in GBM was regulated by REST in vitro and in vivo and the combinational treatment of cell cycle inhibitor Palbociclib with P300 HAT inhibitor inhibited GBM xenografts survival more significantly. Our findings indicate that KIF15 promotes GBM progression under the synergistic transactivation of REST and P300. P300/REST/KIF15 signaling axis is expected to be served as a cascade of candidate therapeutic targets in anti-GBM.

胶质母细胞瘤(GBM)具有高度侵袭性和致命性。GBM无法治愈,这凸显了开发更有效的靶向治疗策略的必要性。KIF15 是一种参与细胞有丝分裂促进、细胞结构组装和细胞信号传导的运动蛋白。KIF15在GBM中的确切生物学功能和潜在上游调控机制仍未确定。在这里,我们证实了 KIF15 在 GBM 中的异常上调,并预测了 GBM 患者的不良预后。KIF15促进GBM细胞增殖、转移和细胞周期进展。REST可与KIF15启动子结合并转激活KIF15。此外,REST与P300相互作用,并依赖其组蛋白乙酰转移酶(HAT)活性共同调控KIF15的表达。REST 和 P300 在 GBM 中均高表达,单独或与 KIF15 共同作用可预测 GBM 患者的不良预后。KIF15在GBM中的致瘤功能在体外和体内均受到REST的调控,细胞周期抑制剂Palbociclib与P300 HAT抑制剂联合治疗能更显著地抑制GBM异种移植物的存活。我们的研究结果表明,KIF15在REST和P300的协同转录激活下促进了GBM的进展。P300/REST/KIF15信号轴有望成为抗GBM的级联候选治疗靶点。
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引用次数: 0
PRDX1 inhibits ferroptosis by binding to Cullin-3 as a molecular chaperone in colorectal cancer. PRDX1 作为结直肠癌中的分子伴侣,通过与 Cullin-3 结合抑制铁突变。
IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-23 eCollection Date: 2024-01-01 DOI: 10.7150/ijbs.99804
Yujia Song, Xiaohui Wang, Yuqi Sun, Nianhua Yu, Yajie Tian, Jinli Han, Xianjun Qu, Xinfeng Yu

Peroxiredoxin 1 (PRDX1) is a potent antioxidant protein that displays a unique molecular chaperone activity. However, the role of overexpression of PRDX1 in colorectal cancer (CRC) was elusive. Herein, we found that the number of AOM/DSS-induced colitis-associated CRC in PRDX1 knockout mice was significantly lower than that in wild-type mice, concomitant with the downregulation of NRF2 and GPX4. Mechanistically, RNA sequencing results indicated that knockdown of PRDX1 resulted in a significant reduction of NRF2, which further triggered ROS-induced mitochondrial dysfunction and lipid peroxidation-induced ferroptosis in CRC cells. Notably, PRDX1 inhibited NRF2 degradation and promoted NRF2 nuclear translocation, thereby triggering the transcription of GPX4. Immunoprecipitation-mass spectrometry (IP-MS) and Co-immunoprecipitation (Co-IP) assays revealed that PRDX1 could act as a molecular chaperone by binding to CUL3 to inhibit NRF2 ubiquitination. Importantly, the binding of PRDX1 to CUL3 was enhanced by conoidin A but abolished by the PRDX1 Cys83Ser mutant. The inhibitory effects of PRDX1 knockdown on CRC could be attenuated by NRF2 activation or ferrostatin-1 administration in vivo. Collectively, these results provide a novel insight into the molecular chaperone activity of PRDX1 in promoting CRC progression through suppression of CUL3-mediated NRF2 degradation, suggesting PRDX1 Cys83 is a potential drug target in inhibiting CRC.

过氧化物歧化酶 1(Peroxiredoxin 1,PRDX1)是一种强效抗氧化蛋白,具有独特的分子伴侣活性。然而,PRDX1的过表达在结直肠癌(CRC)中的作用却难以捉摸。在本文中,我们发现 PRDX1 基因敲除小鼠中 AOM/DSS 诱导的结肠炎相关 CRC 的数量明显低于野生型小鼠,同时 NRF2 和 GPX4 下调。从机理上讲,RNA测序结果表明,PRDX1基因敲除会导致NRF2的显著降低,从而进一步引发ROS诱导的线粒体功能障碍和脂质过氧化诱导的铁变态反应。值得注意的是,PRDX1 可抑制 NRF2 降解并促进 NRF2 核转位,从而引发 GPX4 的转录。免疫沉淀-质谱(IP-MS)和共免疫沉淀(Co-IP)检测发现,PRDX1可作为分子伴侣与CUL3结合,从而抑制NRF2泛素化。重要的是,PRDX1与CUL3的结合在类球蛋白A的作用下会增强,但在PRDX1 Cys83Ser突变体的作用下会消失。在体内激活NRF2或服用铁前列素-1可减轻PRDX1敲除对CRC的抑制作用。总之,这些结果提供了一个新的视角,揭示了PRDX1通过抑制CUL3介导的NRF2降解促进CRC进展的分子伴侣活性,表明PRDX1 Cys83是抑制CRC的潜在药物靶点。
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引用次数: 0
HNF4A-AS1 inhibits the progression of hepatocellular carcinoma by promoting the ubiquitin-modulated degradation of PCBP2 and suppressing the stability of ARG2 mRNA. HNF4A-AS1通过促进泛素调控的PCBP2降解和抑制ARG2 mRNA的稳定性来抑制肝细胞癌的进展。
IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-23 eCollection Date: 2024-01-01 DOI: 10.7150/ijbs.95276
Wenbo Jia, Liang Yu, Bin Xu, Yanzhi Feng, Jinyi Wang, Deming Zhu, Chao Xu, Litao Liang, Yongping Zhou, Lianbao Kong, Wenzhou Ding

Hepatocellular carcinoma (HCC) is a highly aggressive malignant tumor with a poor prognosis. Extensive research has revealed the significant role of long noncoding RNAs (lncRNAs) in the regulation of tumor development. In this study, high-throughput sequencing analysis was used to assess the expression levels of lncRNAs in three pairs of HCC tissues and their corresponding noncancerous tissues. Through quantitative real-time polymerase chain reaction (qRT-PCR) analysis and clinicopathological analysis, it was discovered that HNF4A-AS1 was downregulated in HCC tissues. Furthermore, its expression levels were found to be positively correlated with the prognosis of HCC patients. Subsequent in vitro and in vivo functional studies demonstrated that HNF4A-AS1 inhibits the proliferation, invasion, and stemness of HCC cells. Mechanistically, it was observed that HNF4A-AS1 physically interacts with the KH3 domain of PCBP2 through a specific segment (491-672 nt). This interaction facilitates the recruitment of PCBP2 by AIP4, leading to the ubiquitination and subsequent degradation of PCBP2. Furthermore, HNF4A-AS1 was found to regulate the stability of AGR2 mRNA by modulating PCBP2, thereby influencing the malignant phenotype of HCC. Overall, our study demonstrated a positive association between the decrease in HNF4A-AS1 expression and the prognosis of patients with HCC in a clinical setting. HNF4A-AS1 can suppress the stability of ARG2 mRNA by promoting the ubiquitin-modulated degradation of PCBP2, which suppresses HCC progression. HNF4A-AS1 may serve as a potential therapeutic target for HCC.

肝细胞癌(HCC)是一种侵袭性极强的恶性肿瘤,预后极差。大量研究表明,长非编码 RNA(lncRNA)在调控肿瘤发生发展中发挥着重要作用。本研究利用高通量测序分析评估了三对HCC组织及其相应的非癌组织中lncRNAs的表达水平。通过定量实时聚合酶链反应(qRT-PCR)分析和临床病理分析,发现HNF4A-AS1在HCC组织中表达下调。此外,研究还发现HNF4A-AS1的表达水平与HCC患者的预后呈正相关。随后的体外和体内功能研究表明,HNF4A-AS1 可抑制 HCC 细胞的增殖、侵袭和干性。从机理上观察到,HNF4A-AS1 通过一个特定的片段(491-672 nt)与 PCBP2 的 KH3 结构域发生物理相互作用。这种相互作用促进了 PCBP2 被 AIP4 招募,导致 PCBP2 泛素化并随后降解。此外,研究还发现 HNF4A-AS1 可通过调节 PCBP2 来调节 AGR2 mRNA 的稳定性,从而影响 HCC 的恶性表型。总之,我们的研究表明,在临床环境中,HNF4A-AS1表达的减少与HCC患者的预后呈正相关。HNF4A-AS1可通过促进泛素调控的PCBP2降解来抑制ARG2 mRNA的稳定性,从而抑制HCC的进展。HNF4A-AS1可作为HCC的潜在治疗靶点。
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引用次数: 0
HSPD1 Supports Osteosarcoma Progression through Stabilizing ATP5A1 and thus Activation of AKT/mTOR Signaling. HSPD1 通过稳定 ATP5A1 进而激活 AKT/mTOR 信号,支持骨肉瘤的发展。
IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-23 eCollection Date: 2024-01-01 DOI: 10.7150/ijbs.100015
Yiming Zhang, Ruilin Pan, Kun Li, Lek Hang Cheang, Jing Zhao, Zhangfeng Zhong, Shaoping Li, Jinghao Wang, Xiaofang Zhang, Yanmei Cheng, Xiaofei Zheng, Rongrong He, Huajun Wang

Malignant transformation is concomitant with excessive activation of stress response pathways. Heat shock proteins (HSPs) are stress-inducible proteins that play a role in folding and processing proteins, contributing to the non-oncogene addiction of stressed tumor cells. However, the detailed role of the HSP family in osteosarcoma has not been investigated. Bulk and single-cell transcriptomic data from the GEO and TARGET databases were used to identify HSPs associated with prognosis in osteosarcoma patients. The expression level of HSPD1 was markedly increased in osteosarcoma, correlating with a negative prognosis. Through in vitro and in vivo experiments, we systematically identified HSPD1 as an important contributor to the regulation of proliferation, metastasis, and apoptosis in osteosarcoma by promoting the epithelial-mesenchymal transition (EMT) and activating AKT/mTOR signaling. Subsequently, ATP5A1 was determined as a potential target of HSPD1 using immunoprecipitation followed by mass spectrometry. Mechanistically, HSPD1 may interact with ATP5A1 to reduce the K48-linked ubiquitination and degradation of ATP5A1, which ultimately activates the AKT/mTOR pathway to ensure osteosarcoma progression and EMT process. These findings expand the potential mechanisms by which HSPD1 exerts biological effects and provide strong evidence for its inclusion as a potential therapeutic target in osteosarcoma.

恶性转化伴随着应激反应途径的过度激活。热休克蛋白(HSPs)是应激诱导蛋白,在折叠和处理蛋白质方面发挥作用,有助于应激肿瘤细胞的非基因成瘾。然而,HSP 家族在骨肉瘤中的详细作用尚未得到研究。研究人员利用 GEO 和 TARGET 数据库中的大量和单细胞转录组数据,确定了与骨肉瘤患者预后相关的 HSPs。HSPD1在骨肉瘤中的表达水平明显升高,与不良预后相关。通过体外和体内实验,我们系统地发现 HSPD1 通过促进上皮-间质转化(EMT)和激活 AKT/mTOR 信号转导,是调控骨肉瘤增殖、转移和凋亡的重要因素。随后,利用免疫沉淀法和质谱法确定 ATP5A1 为 HSPD1 的潜在靶标。从机理上讲,HSPD1可能与ATP5A1相互作用,减少K48连接的泛素化和ATP5A1的降解,最终激活AKT/mTOR通路,确保骨肉瘤的进展和EMT过程。这些发现拓展了 HSPD1 发挥生物学效应的潜在机制,为将其列为骨肉瘤的潜在治疗靶点提供了有力证据。
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引用次数: 0
USP44 inactivation accelerates the progression of thyroid cancer by inducing ubiquitylation and degradation of p21. USP44 失活会诱导 p21 泛素化和降解,从而加速甲状腺癌的进展。
IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-23 eCollection Date: 2024-01-01 DOI: 10.7150/ijbs.99817
Yan Liu, Mengmeng Yuan, Xinxin Xu, Huini Yang, Yao Yao, Peng Hou, Wei Yu, Meiju Ji

Ubiquitin-specific peptidase 44 (USP44) belongs to the ubiquitin-specific protease family and is pivotal in the development and progression of tumors across various human cancers. However, its biological function and the underlying mechanisms in thyroid cancer remain poorly understood. In this study, we observed that USP44 was frequently downregulated by promoter hypermethylation in thyroid cancers and found that its decreased expression was closely associated with poor patient survival. Subsequent in vitro and in vivo functional studies revealed that USP44 substantially suppressed the proliferation of thyroid cancer cells by impeding the G1/S transition in cell cycle. Mechanistically, USP44 directly interacted with p21 and eliminated its K-48-linked polyubiquitination chain, thereby stabilizing p21 proteins in a cell cycle-independent manner. In addition, the rescue of p21 partially alleviated cell cycle advancement and cell proliferation induced by the depletion of USP44. Our findings, taken together, indicate that USP44 is frequently repressed in thyroid cancer due to promoter hypermethylation and functions as a tumor suppressor by stabilizing p21 via deubiquitination.

泛素特异性肽酶 44(USP44)属于泛素特异性蛋白酶家族,在各种人类癌症的发生和发展过程中起着关键作用。然而,人们对其在甲状腺癌中的生物学功能和潜在机制仍知之甚少。在这项研究中,我们观察到 USP44 在甲状腺癌中经常因启动子高甲基化而下调,并发现其表达的降低与患者生存率低密切相关。随后的体外和体内功能研究发现,USP44通过阻碍细胞周期的G1/S转换,大大抑制了甲状腺癌细胞的增殖。从机理上讲,USP44 直接与 p21 相互作用,消除了其 K-48 链接的多泛素化链,从而以不依赖细胞周期的方式稳定了 p21 蛋白。此外,p21 的拯救部分缓解了 USP44 的耗竭所诱导的细胞周期提前和细胞增殖。综上所述,我们的研究结果表明,USP44在甲状腺癌中经常因启动子超甲基化而被抑制,并通过去泛素化稳定p21而发挥肿瘤抑制因子的功能。
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引用次数: 0
Integrated analysis of tumor and adjacent non-tumor proteomic data reveals SERPINH1 as a recurrence biomarker and drug target in hepatocellular carcinoma. 对肿瘤和邻近非肿瘤蛋白质组数据的综合分析表明,SERPINH1 是肝细胞癌的复发生物标志物和药物靶点。
IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-23 eCollection Date: 2024-01-01 DOI: 10.7150/ijbs.99734
Yushan Hou, Yiming Zhang, Kun Zheng, Han Wang, Yingying Zhou, Yuanjun Zhai, Fuchu He, Chunyan Tian, Aihua Sun

The high rate of postoperative recurrence contributes to the poor outcome in hepatocellular carcinoma (HCC), and effective strategies for managing recurrence are currently lacking. Based on seven pairs of tumors and non-tumor adjacent tissues (NATs) proteomic datasets across five cancer types, this study systematically investigates the stratified and therapeutic value of tumors and NATs for tumor recurrence. NATs exhibited stable and irreplaceable independent prognostic capabilities for recurrence, complementing clinical indicators and tumor characteristics. In comparison to tumor tissues, NATs exhibit higher enrichment levels of recurrence-related proteins in pathways such as immunity, extracellular matrix, and angiogenesis. Taking HCC as an example, we identified SERPINH1 as a recurrent biomarker with drug-targeting potential that applied to both tumors and NATs and then validated them through independent immunohistochemistry cohorts and animal experiments. Patients with high SERPINH1 expression in both tumors and NATs have the highest 5-year recurrence rates, even among clinically low recurrence risk groups. Targeting SERPINH1 can effectively delay tumor occurrence and progression. This study highlights the significant importance of NATs in recurrence prediction and postoperative management, proposing a recurrence management strategy that focuses on both tumors and NATs. SERPINH1 emerges as a valuable biomarker and drug target for addressing postoperative recurrence in HCC.

肝细胞癌(HCC)术后复发率高,导致预后不佳,目前尚缺乏有效的复发管理策略。本研究基于五种癌症类型的七对肿瘤和非肿瘤邻近组织(NATs)蛋白质组数据集,系统研究了肿瘤和NATs对肿瘤复发的分层和治疗价值。NATs对复发具有稳定且不可替代的独立预后能力,是对临床指标和肿瘤特征的补充。与肿瘤组织相比,NATs在免疫、细胞外基质和血管生成等通路中显示出更高的复发相关蛋白富集水平。以 HCC 为例,我们发现 SERPINH1 是一种具有药物靶向潜力的复发生物标记物,同时适用于肿瘤和 NATs,并通过独立的免疫组化队列和动物实验进行了验证。SERPINH1在肿瘤和NAT中均有高表达的患者5年复发率最高,即使在临床上复发风险较低的群体中也是如此。以 SERPINH1 为靶点可有效延缓肿瘤的发生和发展。本研究强调了NATs在复发预测和术后管理中的重要作用,提出了一种同时关注肿瘤和NATs的复发管理策略。SERPINH1 成为解决 HCC 术后复发问题的重要生物标记物和药物靶点。
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引用次数: 0
Serum amyloid A contributes to radiation-induced lung injury by activating macrophages through FPR2/Rac1/NF-κB pathway 血清淀粉样蛋白 A 通过 FPR2/Rac1/NF-κB 通路激活巨噬细胞,导致辐射诱导的肺损伤
IF 9.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-16 DOI: 10.7150/ijbs.100823
Xinglong Liu, Yimeng Song, Songling Hu, Yang Bai, Jianghong Zhang, Guomei Tai, Chunlin Shao, Yan Pan
Patients who receive thoracic radiotherapy may suffer from radiation-induced lung injury, but the treatment options are limited as the underlying mechanisms are unclear. Using a mouse model of right thorax irradiation with fractionated doses of X-rays for three consecutive days (8 Gy/per day), this study found that the thoracic irradiation (Th-IR) induced tissue injury with aberrant infiltration of macrophages, and it significantly increased the secretion of TNF-α, IL-1β, IL-6, TGF-β1 and serum amyloid A (SAA) in mice. Interestingly, SAA could activate macrophages and then induce epithelial-mesenchymal transition (EMT) of lung epithelial cells and fibrosis progression in lung tissue. Mechanistically, SAA enhanced the transient binding of FPR2 to Rac1 protein and further activated NF-κB signaling pathway in macrophages. Inhibition of FPR2 significantly reduced pulmonary fibrosis induced by SAA administration in mice. In addition, cimetidine could reduce the level of SAA release after irradiation and attenuate the lung injury induced by SAA or Th-IR. In conclusion, our results demonstrated that SAA activated macrophages via FPR2/Rac1/NF-κB pathway and might contribute to the Th-IR induced lung injury, which may provide a new strategy to attenuate radiation-induced adverse effects during radiotherapy.
接受胸部放疗的患者可能会受到辐射诱导的肺损伤,但由于其潜在机制尚不清楚,因此治疗方案有限。本研究利用小鼠模型,连续三天(每天 8 Gy)使用分次剂量的 X 射线照射右胸,发现胸腔照射(Th-IR)会诱发组织损伤,巨噬细胞异常浸润,并显著增加小鼠体内 TNF-α、IL-1β、IL-6、TGF-β1 和血清淀粉样蛋白 A(SAA)的分泌。有趣的是,SAA能激活巨噬细胞,进而诱导肺上皮细胞的上皮-间质转化(EMT)和肺组织的纤维化进展。从机理上讲,SAA 可增强 FPR2 与 Rac1 蛋白的瞬时结合,并进一步激活巨噬细胞中的 NF-κB 信号通路。抑制 FPR2 能显著减轻小鼠因服用 SAA 而诱发的肺纤维化。此外,西咪替丁能降低照射后 SAA 的释放水平,减轻 SAA 或 Th-IR 诱导的肺损伤。总之,我们的研究结果表明,SAA通过FPR2/Rac1/NF-κB途径激活巨噬细胞,并可能导致Th-IR诱导的肺损伤,这可能为减轻放疗期间辐射诱导的不良反应提供了一种新策略。
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