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METTL16 Promotes Stability of SYNPO2L mRNA and leading to Cancer Cell Lung Metastasis by Secretion of COL10A1 and attract the Cancer-Associated Fibroblasts. METTL16 通过分泌 COL10A1 和吸引癌症相关成纤维细胞促进 SYNPO2L mRNA 的稳定并导致癌细胞肺转移。
IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-01 eCollection Date: 2024-01-01 DOI: 10.7150/ijbs.95375
Jianlong Wu, Peng Ouyang, Rui Huang, Yao Cui, Zhihao Yang, Wei Xu, Rui Ma, Guoan Xiang, Wei Zeng, Wang Wu, Jian Li

The occurrence of metastasis is a major factor contributing to poor prognosis in colorectal cancer. Different stages of the disease play a crucial role in distant metastasis. Furthermore, m6A has been demonstrated to play a significant role in regulating tumor metastasis. Therefore, we conducted an analysis of transcriptome data from high-stage and low-stage colorectal cancer patients in The Cancer Genome Atlas (TCGA) to identify genes associated with m6A-related regulation. We identified SYNPO2L as a core gene regulated by m6A, and it is correlated with adverse prognosis and metastasis in patients. Additionally, we demonstrated that the m6A writer gene Mettl16 can regulate the stability of SYNPO2L through interaction with YTHDC1. Subsequently, using Weighted Gene Co-expression Network Analysis (WGCNA), we discovered that SYNPO2L can regulate COL10A1, mediating the actions of Cancer-Associated Fibroblasts. SYNPO2L promotes the secretion of COL10A1 and the infiltration of tumor-associated fibroblasts, thereby facilitating Epithelial-Mesenchymal Transition (EMT) in tumor cells and making them more prone to distant metastasis.

发生转移是导致大肠癌预后不良的一个主要因素。疾病的不同阶段对远处转移起着至关重要的作用。此外,m6A 已被证实在调控肿瘤转移中发挥重要作用。因此,我们对癌症基因组图谱(TCGA)中高分期和低分期结直肠癌患者的转录组数据进行了分析,以确定与m6A相关调控有关的基因。我们发现SYNPO2L是受m6A调控的核心基因,它与患者的不良预后和转移相关。此外,我们还证明了 m6A 写入基因 Mettl16 可通过与 YTHDC1 相互作用来调控 SYNPO2L 的稳定性。随后,我们利用加权基因共表达网络分析(WGCNA)发现,SYNPO2L 可调控 COL10A1,从而介导癌症相关成纤维细胞的作用。SYNPO2L 促进 COL10A1 的分泌和肿瘤相关成纤维细胞的浸润,从而促进肿瘤细胞的上皮-间质转化(EMT),使其更容易发生远处转移。
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引用次数: 0
N6-methyladenosine modification of LATS2 promotes hepatoblastoma progression by inhibiting ferroptosis through the YAP1/ATF4/PSAT1 axis. LATS2的N6-甲基腺苷修饰通过YAP1/ATF4/PSAT1轴抑制铁突变,从而促进肝母细胞瘤的进展。
IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-01 eCollection Date: 2024-01-01 DOI: 10.7150/ijbs.92413
Guoqing Zhu, Yi Xie, Zhixuan Bian, Ji Ma, Ni Zhen, Tianshu Chen, Jiabei Zhu, Siwei Mao, Xiaochen Tang, Li Liu, Song Gu, Miao Ding, Qiuhui Pan

Ferroptosis has attracted extensive interest from cancer researchers due to its substantial potential as a therapeutic target. The role of LATS2, a core component of the Hippo pathway cascade, in ferroptosis initiation in hepatoblastoma (HB) has not yet been investigated. Furthermore, the underlying mechanism of decreased LATS2 expression remains largely unknown. In the present study, we demonstrated decreased LATS2 expression in HB and that LATS2 overexpression inhibits HB cell proliferation by inducing ferroptosis. Increased LATS2 expression reduced glycine and cysteine concentrations via the ATF4/PSAT1 axis. Physical binding between YAP1/ATF4 and the PSAT1 promoter was confirmed through ChIP‒qPCR. Moreover, METTL3 was identified as the writer of the LATS2 mRNA m6A modification at a specific site in the 5' UTR. Subsequently, YTHDF2 recognizes the m6A modification site and recruits the CCR4-NOT complex, leading to its degradation by mRNA deadenylation. In summary, N6-methyladenosine modification of LATS2 facilitates its degradation. Reduced LATS2 expression promotes hepatoblastoma progression by inhibiting ferroptosis through the YAP1/ATF4/PSAT1 axis. Targeting LATS2 is a potential strategy for HB therapy.

由于铁突变具有作为治疗靶点的巨大潜力,因此引起了癌症研究人员的广泛兴趣。LATS2是Hippo通路级联的核心成分,它在肝母细胞瘤(HB)铁突变启动过程中的作用尚未得到研究。此外,LATS2 表达减少的潜在机制在很大程度上仍不清楚。在本研究中,我们证实了 LATS2 在肝母细胞瘤中的表达减少,并且 LATS2 的过表达通过诱导铁变态反应抑制了肝母细胞瘤细胞的增殖。LATS2 表达的增加通过 ATF4/PSAT1 轴降低了甘氨酸和半胱氨酸的浓度。通过 ChIP-qPCR 验证了 YAP1/ATF4 与 PSAT1 启动子之间的物理结合。此外,还发现 METTL3 是 LATS2 mRNA m6A 修饰在 5' UTR 特定位点上的作者。随后,YTHDF2 识别出 m6A 修饰位点,并招募 CCR4-NOT 复合物,导致 mRNA 死酰化降解。总之,LATS2的N6-甲基腺苷修饰促进了其降解。LATS2 表达的降低会通过 YAP1/ATF4/PSAT1 轴抑制铁变态反应,从而促进肝母细胞瘤的进展。靶向 LATS2 是治疗肝母细胞瘤的一种潜在策略。
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引用次数: 0
Catalpol attenuates hepatic glucose metabolism disorder and oxidative stress in triptolide-induced liver injury by regulating the SIRT1/HIF-1α pathway. 梓醇通过调节SIRT1/HIF-1α途径减轻三苯氧胺诱导的肝损伤中的肝糖代谢紊乱和氧化应激。
IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-01 eCollection Date: 2024-01-01 DOI: 10.7150/ijbs.97362
Weijue Nie, Hong Zhu, Xin Sun, Jie Zhou, Heng Xu, Zhichao Yu, Minghao Lu, Baoping Jiang, Lingling Zhou, Xueping Zhou

Triptolide (TP), known for its effectiveness in treating various rheumatoid diseases, is also associated with significant hepatotoxicity risks. This study explored Catalpol (CAT), an iridoid glycoside with antioxidative and anti-inflammatory effects, as a potential defense against TP-induced liver damage. In vivo and in vitro models of liver injury were established using TP in combination with different concentrations of CAT. Metabolomics analyses were conducted to assess energy metabolism in mouse livers. Additionally, a Seahorse XF Analyzer was employed to measure glycolysis rate, mitochondrial respiratory functionality, and real-time ATP generation rate in AML12 cells. The study also examined the expression of proteins related to glycogenolysis and gluconeogenesis. Using both in vitro SIRT1 knockout/overexpression and in vivo liver-specific SIRT1 knockout models, we confirmed SIRT1 as a mechanism of action for CAT. Our findings revealed that CAT could alleviate TP-induced liver injury by activating SIRT1, which inhibited lysine acetylation of hypoxia-inducible factor-1α (HIF-1α), thereby restoring the balance between glycolysis and oxidative phosphorylation. This action improved mitochondrial dysfunction and reduced glucose metabolism disorder and oxidative stress caused by TP. Taken together, these insights unveil a hitherto undocumented mechanism by which CAT ameliorates TP-induced liver injury, positioning it as a potential therapeutic agent for managing TP-induced hepatotoxicity.

雷公藤内酯(Triptolide,TP)因其在治疗各种类风湿疾病方面的功效而闻名,但它也有很大的肝毒性风险。本研究探讨了具有抗氧化和抗炎作用的鸢尾甙--梓醇(CAT),将其作为防止 TP 引起的肝损伤的潜在疗法。通过将 TP 与不同浓度的 CAT 结合使用,建立了肝损伤的体内和体外模型。代谢组学分析评估了小鼠肝脏的能量代谢。此外,还采用海马 XF 分析仪测量 AML12 细胞的糖酵解率、线粒体呼吸功能和实时 ATP 生成率。研究还检测了与糖原分解和葡萄糖生成有关的蛋白质的表达。利用体外 SIRT1 基因敲除/外显和体内肝脏特异性 SIRT1 基因敲除模型,我们证实了 SIRT1 是 CAT 的作用机制。我们的研究结果表明,CAT 可通过激活 SIRT1 缓解 TP 诱导的肝损伤,SIRT1 可抑制缺氧诱导因子-1α(HIF-1α)的赖氨酸乙酰化,从而恢复糖酵解和氧化磷酸化之间的平衡。这一作用改善了线粒体功能障碍,减少了 TP 引起的葡萄糖代谢紊乱和氧化应激。综上所述,这些见解揭示了一种迄今为止尚未记录的机制,即 CAT 可改善 TP 引起的肝损伤,从而使其成为控制 TP 引起的肝毒性的一种潜在治疗药物。
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引用次数: 0
Exosomes: Emerging Insights into the Progression of Pancreatic Cancer. 外泌体:胰腺癌进展的新见解。
IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-01 eCollection Date: 2024-01-01 DOI: 10.7150/ijbs.97076
Xulin Zhou, Yongmin Yan, Ye Shen, Min Xu, Wenrong Xu

Pancreatic cancer is a very aggressive and fatal malignancy with few therapeutic choices and a poor prognosis. Understanding the molecular pathways that drive its growth is critical for developing effective therapeutic strategies. Exosomes, small extracellular vesicles secreted by numerous cell types, have recently emerged as essential intercellular communication mediators, with implications for tumor growth and metastasis. In this article, we present a review of current knowledge about exosomes and their role in pancreatic cancer progression We discuss the biogenesis and characteristics of exosomes, as well as their cargo and functional significance in tumor growth, immune evasion, angiogenesis, invasion, and metastasis. We further emphasize the potential of exosomes as diagnostic biomarkers and therapeutic targets for pancreatic cancer. Finally, we discuss the challenges and future perspectives in using exosomes to improve patient outcomes in pancreatic cancer.

胰腺癌是一种侵袭性极强的致命恶性肿瘤,治疗方法少,预后差。了解驱动其生长的分子途径对于制定有效的治疗策略至关重要。外泌体是由多种类型细胞分泌的小型细胞外囊泡,近来已成为细胞间重要的通讯介质,对肿瘤的生长和转移具有影响。我们讨论了外泌体的生物发生和特征,以及它们在肿瘤生长、免疫逃避、血管生成、侵袭和转移中的载体和功能意义。我们进一步强调了外泌体作为胰腺癌诊断生物标记物和治疗靶点的潜力。最后,我们讨论了利用外泌体改善胰腺癌患者预后的挑战和未来前景。
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引用次数: 0
FGF7 and FGF10 Promote Fate Transition of Human Epidermal Cell-derived Organoids to an Eccrine Gland Phenotype. FGF7和FGF10促进人表皮细胞衍生的器官组织向生殖腺表型的命运转变
IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-01 eCollection Date: 2024-01-01 DOI: 10.7150/ijbs.97422
Junhong Zhao, Lei Zhang, Yonghong Zhang, Manxiu Cao, Cangyu Wang, Anqi Hu, Leilei Cao, Qizhi Luo, Zhen You, Xueping Ma, Liang Gong, Cuiping Zhang, Haihong Li

Rationale: Reconstruction of hair follicles (HFs) and eccrine sweat glands (ESGs) is essential for functional skin regeneration. In skin reconstruction research, we found that foreskin-derived epidermal cells reconstructed HF organoids unidirectionally, but not ESG organoids. Methods: To investigate key genes and pathways influencing the fate of ESG and HF, a transcriptome profiling of ESG placode-containing skin and HF placode-containing skin was employed, and key DEGs were identified and validated by RT-qPCR and immunofluorescence staining in mice and rats. Subsequently, adult human epidermal cell-derived organoids were reconstructed to probe functional roles and mechanisms of FGF7 and FGF10 by series of approaches integrating RT-qPCR, immunofluorescence-staining, WB, apoptosis assay, and pathway interference assay. Results: All members of FGF7 subfamily were among the key DEGs screened, the differential expression of FGF7 and FGF10 and their receptors FGFR1/FGFR2 was verified between ESG placode-containing skin and HF placode-containing skin. In vivo and in vitro Matrigel plug models showed that both FGF7 and FGF10 promoted fate transition of human epidermal cell-derived organoids to ESG phenotype organoids, FGF7 and FGF10 had a synergistic effect, and mainly function through the FGFR1/2-MEK1/2-ERK1/2 pathway. Conclusions: Adult epidermal cells can be manipulated to reconstruct personalized HF and ESG to meet different needs.

理由:毛囊(HF)和泌汗腺(ESG)的重建对皮肤功能再生至关重要。在皮肤重建研究中,我们发现源自包皮的表皮细胞能单向重建 HF 器质性组织,但不能重建 ESG 器质性组织。研究方法为了研究影响ESG和HF命运的关键基因和通路,我们对小鼠和大鼠含ESG胎盘的皮肤和含HF胎盘的皮肤进行了转录组分析,并通过RT-qPCR和免疫荧光染色鉴定和验证了关键的DEGs。随后,通过RT-qPCR、免疫荧光染色、WB、细胞凋亡检测和通路干扰检测等一系列方法,重建了成人表皮细胞来源的器官组织,以探究FGF7和FGF10的功能作用和机制。结果显示FGF7和FGF10及其受体FGFR1/FGFR2在含ESG胎盘的皮肤和含HF胎盘的皮肤中的表达差异得到了验证。体内和体外Matrigel塞模型显示,FGF7和FGF10都能促进人表皮细胞衍生的器官组织向ESG表型器官组织的命运转变,FGF7和FGF10具有协同作用,并主要通过FGFR1/2-MEK1/2-ERK1/2途径发挥作用。结论成年表皮细胞可通过操作重建个性化的HF和ESG,以满足不同需求。
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引用次数: 0
NRF2-HIF2α Signaling Attenuates Endothelial Cell Senescence and Maintains Intercellular Junctions in Diabetes. NRF2-HIF2α信号传导可减轻糖尿病内皮细胞衰老并维持细胞间连接
IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-22 eCollection Date: 2024-01-01 DOI: 10.7150/ijbs.96719
Jian Shen, Yifan Lai, Yaner Lu, Yabin Liu, Jinlong Zhang, Yan Wu, Yunan Pan, Haibo Chen, Qiyue Gao, Qucheng Wei, Yuwen Chen, Jian Ye, Yinuo Lin, Bingchen Liu, Jun Jiang, Jinliang Nan

In the context of diabetes, endothelial cells frequently exhibit compromised intercellular junctions and accelerated cellular senescence simultaneously. The precise mechanisms underlying these issues and the identification of effective treatments remain largely undefined. Our findings reveal that human umbilical vein endothelial cells (HUVECs) can counteract senescence and uphold the integrity of intercellular junctions under mildly to moderately elevated glucose levels (10 mM and 15 mM) via two primary mechanisms: i) The acetylation of NRF2 at lysine residues K56, K68, and K52 prevents its ubiquitination, enhancing the transcription of antioxidant genes GST, SOD1, and GPX1. This activity diminishes cytoplasmic oxidative stress, thereby mitigating endothelial cell senescence. ii) The interaction between the Neh2 domain of NRF2 and the PAS-B domain of HIF-2α within the nucleus curtails the attachment of HIF-2α to the NOX4/p22phox promoter. This action lessens oxidative stress near the cell membrane, maintaining intercellular junctions by safeguarding the disulfide bonds in occludin and E-cadherin from disruption. However, these protective strategies prove insufficient under severe hyperglycemic conditions (25 mM). Further investigation has identified Oltipraz, an activator of NRF2, as also promoting the degradation of HIF-2α. Through its simultaneous modulation of NRF2 and HIF-2α, Oltipraz significantly reduces cellular senescence and prevents the deterioration of intercellular junctions in HUVECs subjected to high glucose concentrations (25 mM). Our research positions Oltipraz as a promising therapeutic candidate for mitigating diabetes-induced vascular endothelial damage, potentially offering benefits against diabetes-related atherosclerosis and valvular calcification.

在糖尿病的情况下,内皮细胞经常同时表现出细胞间连接受损和细胞衰老加速。这些问题的确切机制和有效治疗方法在很大程度上仍未确定。我们的研究结果表明,人脐静脉内皮细胞(HUVECs)能在轻度至中度升高的葡萄糖水平(10 毫摩尔和 15 毫摩尔)下通过两种主要机制抵御衰老并维护细胞间连接的完整性:i) NRF2 在赖氨酸残基 K56、K68 和 K52 上的乙酰化能阻止其泛素化,从而增强抗氧化基因 GST、SOD1 和 GPX1 的转录。ii) NRF2 的 Neh2 结构域与细胞核内 HIF-2α 的 PAS-B 结构域之间的相互作用抑制了 HIF-2α 与 NOX4/p22phox 启动子的连接。这一作用减轻了细胞膜附近的氧化应激,并通过保护闭锁素和 E-cadherin 中的二硫键不被破坏来维持细胞间的连接。然而,在严重的高血糖条件下(25 毫摩尔),这些保护策略被证明是不够的。进一步的研究发现,NRF2 的激活剂 Oltipraz 也能促进 HIF-2α 的降解。通过同时调节 NRF2 和 HIF-2α,Oltipraz 在高浓度葡萄糖(25 mM)条件下可显著减少细胞衰老,并防止 HUVEC 细胞间连接的恶化。我们的研究将Oltipraz定位为减轻糖尿病诱导的血管内皮损伤的一种有希望的候选疗法,它可能对糖尿病相关的动脉粥样硬化和瓣膜钙化有益。
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引用次数: 0
Nephron-Specific Lin28A Overexpression Triggers Severe Inflammatory Response and Kidney Damage. 肾小球特异性 Lin28A 过表达引发严重炎症反应和肾损伤
IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-22 eCollection Date: 2024-01-01 DOI: 10.7150/ijbs.97434
Anna Futorian, Leah Armon, Hiba Waldman Ben-Asher, Irit Shoval, Inbal Hazut, Ariel Munitz, Achia Urbach

The RNA-binding proteins LIN28A and LIN28B contribute to a variety of developmental biological processes. Dysregulation of Lin28A and Lin28B expression is associated with numerous types of tumors. This study demonstrates that Lin28A overexpression in the mouse nephrons leads to severe inflammation and kidney damage rather than to tumorigenesis. Notably, Lin28A overexpression causes inflammation only when expressed in nephrons, but not in the stromal cells of the kidneys, highlighting its cell context-dependent nature. The nephron-specific Lin28A-induced inflammatory response differs from previously described Lin28B-mediated inflammatory feedback loops as it is IL-6 independent. Instead, it is associated with the rapid upregulation of cytokines like Cxcl1 and Ccl2. These findings suggest that the pathophysiological effects of Lin28A overexpression extend beyond cell transformation. Our transgenic mouse model offers a valuable tool for advancing our understanding of the pathophysiology of acute kidney injury, where inflammation is a key factor.

RNA 结合蛋白 LIN28A 和 LIN28B 有助于多种发育生物过程。Lin28A和Lin28B的表达失调与多种肿瘤有关。本研究表明,Lin28A 在小鼠肾小球中的过表达会导致严重的炎症和肾损伤,而不是肿瘤发生。值得注意的是,Lin28A的过表达仅在肾小球中表达时才会导致炎症,而在肾脏的基质细胞中表达时不会,这突出了它的细胞环境依赖性。肾小球特异性 Lin28A 诱导的炎症反应不同于之前描述的 Lin28B 介导的炎症反馈回路,因为它独立于 IL-6。相反,它与 Cxcl1 和 Ccl2 等细胞因子的快速上调有关。这些发现表明,Lin28A 过表达的病理生理效应超出了细胞转化的范围。我们的转基因小鼠模型为我们进一步了解急性肾损伤的病理生理学提供了一个宝贵的工具,而炎症是急性肾损伤的一个关键因素。
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引用次数: 0
tRF-27 competitively Binds to G3BPs and Activates MTORC1 to Enhance HER2 Positive Breast Cancer Trastuzumab Tolerance. tRF-27 与 G3BPs 竞争性结合并激活 MTORC1,从而增强 HER2 阳性乳腺癌对曲妥珠单抗的耐受性。
IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-15 eCollection Date: 2024-01-01 DOI: 10.7150/ijbs.87415
Yaozhou He, Yincheng Liu, Jue Gong, Fan Yang, Chunxiao Sun, Xueqi Yan, Ningjun Duan, Yijia Hua, Tianyu Zeng, Ziyi Fu, Yan Liang, Wei Li, Xiang Huang, Jinhai Tang, Yongmei Yin

About 20% of breast cancer patients are positive for HER2. The efficacy of current treatments is limited by primary and secondary resistance to trastuzumab. tRNA-derived fragments (tRFs) have shown crucial regulatory roles in various cancers. This study aimed to evaluate the role of tRF-27 in regulating the resistance of HER2-positive breast cancer against trastuzumab. tRF-27 was highly expressed in trastuzumab-resistant cells, and its expression level could predict the resistance to trastuzumab. High expression of tRF-27 promoted the growth and proliferation of trastuzumab-exposed cells. RNA-pulldown assay and mass spectrometry were performed to identify Ras GTPase-activating protein-binding proteins 1 and 2 (G3BPs) (two proteins targeted by tRF-27); RNA-immunoprecipitation (RIP) to confirm their bindings; co-immunoprecipitation (co-IP) and RNA-pulldown assay to determine the binding domains between G3BPs and tRF-27.tRF-27 bound to the nuclear transport factor 2 like domain(NTF2 domain) of G3BPs through a specific sequence. tRF-27 relied on G3BPs and NTF2 domain to increase trastuzumab tolerance. tRF-27 competed with lysosomal associated membrane protein 1(LAMP1) for NTF2 domain, thereby inhibiting lysosomal localization of G3BPs and tuberous sclerosis complex (TSC). Overexpression of tRF-27 inhibited phosphorylation of TSCs and promoted the activation of mechanistic target of rapamycin complex 1(MTORC1) to enhance cell proliferation and entice the resistance of HER2-positive breast cancer against trastuzumab.

大约 20% 的乳腺癌患者 HER2 呈阳性。tRNA衍生片段(tRFs)在多种癌症中显示出重要的调控作用。本研究旨在评估tRF-27在调节HER2阳性乳腺癌对曲妥珠单抗耐药性中的作用。tRF-27的高表达促进了曲妥珠单抗暴露细胞的生长和增殖。通过RNA-pulldown检测和质谱分析鉴定了Ras GTPase激活蛋白结合蛋白1和2(G3BPs)(tRF-27靶向的两种蛋白);通过RNA-免疫沉淀(RIP)确认了它们的结合;通过共免疫沉淀(co-IP)和RNA-pulldown检测确定了G3BPs和tRF-27之间的结合域。tRF-27与溶酶体相关膜蛋白1(LAMP1)竞争NTF2结构域,从而抑制了G3BPs和结节性硬化症复合体(TSC)的溶酶体定位。tRF-27的过表达抑制了TSCs的磷酸化,并促进了雷帕霉素机制靶点复合物1(MTORC1)的活化,从而增强了细胞增殖,诱使HER2阳性乳腺癌对曲妥珠单抗产生耐药性。
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引用次数: 0
The Interaction of Calcium-Sensing Receptor with KIF11 Enhances Cisplatin Resistance in Lung Adenocarcinoma via BRCA1/cyclin B1 pathway. 钙传感受体与 KIF11 的相互作用通过 BRCA1/cyclin B1 途径增强了肺腺癌对顺铂的耐药性
IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-15 eCollection Date: 2024-01-01 DOI: 10.7150/ijbs.92046
Fuhao Wang, Xing Fu, Ming Chang, Tianzi Wei, Risheng Lin, Haibo Tong, Xiao Zhang, Runzhu Yuan, Zhiqing Zhou, Xin Huang, Wei Zhang, Wenmei Su, Yi Lu, Zhen Liang, Jian Zhang

Cisplatin (DDP) is commonly used in the treatment of non-small cell lung cancer (NSCLC), including lung adenocarcinoma (LUAD), and the primary cause for its clinical inefficacy is chemoresistance. Here, we aimed to investigate a novel mechanism of chemoresistance in LUAD cells, focusing on the calcium-sensing receptor (CaSR). In this study, high CaSR expression was detected in DDP-resistant LUAD cells, and elevated CaSR expression is strongly correlated with poor prognosis in LUAD patients receiving chemotherapy. LUAD cells with high CaSR expression exhibited decreased sensitivity to cisplatin, and the growth of DDP-resistant LUAD cells was inhibited by cisplatin treatment in combination with CaSR suppression, accompanied by changes in BRCA1 and cyclin B1 protein expression both in vitro and in vivo. Additionally, an interaction between CaSR and KIF11 was identified. Importantly, suppressing KIF11 resulted in decreased protein levels of BRCA1 and cyclin B1, enhancing the sensitivity of DDP-resistant LUAD cells to cisplatin with no obvious decrease in CaSR. Here, our findings established the critical role of CaSR in promoting cisplatin resistance in LUAD cells by modulating cyclin B1 and BRCA1 and identified KIF11 as a mediator, highlighting the potential therapeutic value of targeting CaSR to overcome chemoresistance in LUAD.

顺铂(DDP)是治疗包括肺腺癌(LUAD)在内的非小细胞肺癌(NSCLC)的常用药物,其临床疗效不佳的主要原因是化疗耐药性。在此,我们以钙感受体(CaSR)为重点,旨在研究LUAD细胞化疗耐药的新机制。在这项研究中,DDP耐药的LUAD细胞中检测到了CaSR的高表达,而CaSR的高表达与接受化疗的LUAD患者的不良预后密切相关。CaSR高表达的LUAD细胞对顺铂的敏感性降低,顺铂治疗联合CaSR抑制可抑制DDP耐药LUAD细胞的生长,同时体外和体内BRCA1和细胞周期蛋白B1的表达也会发生变化。此外,还发现了 CaSR 与 KIF11 之间的相互作用。重要的是,抑制 KIF11 会导致 BRCA1 和细胞周期蛋白 B1 蛋白水平的降低,从而增强对 DDP 抗性的 LUAD 细胞对顺铂的敏感性,而 CaSR 并没有明显降低。在此,我们的研究结果确定了CaSR通过调节细胞周期蛋白B1和BRCA1在促进LUAD细胞对顺铂耐药中的关键作用,并确定了KIF11是一个介导因子,突出了靶向CaSR克服LUAD化疗耐药的潜在治疗价值。
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引用次数: 0
Inhibition of PCSK9 enhances the anti-hepatocellular carcinoma effects of TCR-T cells and anti-PD-1 immunotherapy. 抑制 PCSK9 可增强 TCR-T 细胞和抗 PD-1 免疫疗法的抗肝细胞癌效果。
IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-15 eCollection Date: 2024-01-01 DOI: 10.7150/ijbs.93668
Weikang Xu, Minli Hu, Xinyu Lu, Yueqiong Lao, Na Ma, Yiyue Wang, Jing Li, Xingyuan Chen, Shiming Liu, Jing Liu, Wei Zhu, Hui Yang

T cells play important roles in antitumor immunity. However, given that the hepatocellular carcinoma (HCC) tumor microenvironment confers resistance to T cell-based immunotherapies, novel strategies to boost T cell-mediated antitumor efficacy are urgently needed for the treatment of HCC. Here, we show that high proprotein convertase subtilisin/kexin type9 (PCSK9) expression was negatively associated with HCC patient's overall survival and markers of CD8+ T cells. Pharmacological inhibition of PCSK9 enhanced tumor-specific killing and downregulated PD-1 expression of AFP-specific TCR-T. Inhibition of PCSK9 significantly enhances the anti-HCC efficacy of TCR-T cells and anti-PD-1 immunotherapy in vivo. Moreover, PCSK9 inhibitor suppressed HCC growth dependent on CD8+ T cells. Mechanically, pharmacological inhibition of PCSK9 promoted low-density lipoprotein receptor (LDLR)-mediated activation of mTORC1 signaling in CD8+ T cells. LDLR deficiency was shown to impair cellular mTORC1 signaling and the anti-HCC function of CD8 T cells. On the basis of our findings in this study, we propose a potential metabolic intervention strategy that could be used to enhance the antitumor effects of immunotherapy for HCC.

T 细胞在抗肿瘤免疫中发挥着重要作用。然而,鉴于肝细胞癌(HCC)肿瘤微环境会对基于 T 细胞的免疫疗法产生抗药性,因此治疗 HCC 急需提高 T 细胞介导的抗肿瘤疗效的新策略。在这里,我们发现高丙脯氨酸转化酶亚基酶/kexin9型(PCSK9)表达与HCC患者的总生存期和CD8+ T细胞标记物呈负相关。药理抑制PCSK9可增强肿瘤特异性杀伤力,并下调AFP特异性TCR-T的PD-1表达。抑制PCSK9能显著提高TCR-T细胞和体内抗PD-1免疫疗法的抗HCC疗效。此外,PCSK9抑制剂还能抑制依赖于CD8+ T细胞的HCC生长。从机制上讲,药理抑制PCSK9可促进CD8+ T细胞中低密度脂蛋白受体(LDLR)介导的mTORC1信号激活。研究表明,缺乏 LDLR 会损害细胞的 mTORC1 信号传导和 CD8 T 细胞的抗HCC 功能。根据本研究的发现,我们提出了一种潜在的代谢干预策略,可用于增强 HCC 免疫疗法的抗肿瘤效果。
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