Cellular signalling最新文献_第4页

TRIM35 inhibits endometrial cancer progression via ubiquitination and degradation of EIF3E TRIM35通过泛素化和EIF3E的降解抑制子宫内膜癌的进展。

IF 3.7 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2025-12-20 DOI: 10.1016/j.cellsig.2025.112339

Qi Wang, Ning Ning, Yan Li

Endometrial carcinoma (EC), recognized as the predominant gynecologic malignancy, is associated with substantial mortality rates. While chemotherapy serves as a critical component in adjuvant and primary treatments, existing pharmacological interventions demonstrate limited efficacy in significantly extending overall survival. Consequently, deciphering the molecular mechanisms driving EC pathogenesis is essential for developing innovative therapies. Existing evidence implicates TRIM35 in tumor proliferation, invasion, and metastatic processes across multiple cancers. To investigate TRIM35's role in EC, we performed integrated bioinformatics analysis followed by experimental validation via RT-qPCR and western blotting, which confirmed its significant downregulation in EC tissues. Subsequently, we transfected endometrial cancer cells with lentiviral plasmids overexpressing TRIM35 to investigate its Impact on cellular proliferation, cell cycle, invasion, and migration. We found that overexpressing TRIM35 significantly inhibited proliferation, invasion, and migration. Further research revealed that TRIM35 regulates the ubiquitination of EIF3E. Additionally, TRIM35 modulates the CDK4/Cyclin D1 signaling pathway, suppressing EC cell proliferation. Intriguingly, overexpressing EIF3E reversed the inhibitory effects of TRIM35 in EC cells. In conclusion, our study demonstrates that TRIM35 regulates the ubiquitination of EIF3E and inhibits the CDK4/Cyclin D1 signaling pathway, thereby suppressing the malignant proliferation of EC. These findings suggested that TRIM35 has potential as a therapeutic target for EC.

子宫内膜癌（EC）是公认的主要妇科恶性肿瘤，其死亡率很高。虽然化疗是辅助治疗和主要治疗的关键组成部分，但现有的药物干预在显着延长总生存期方面的效果有限。因此，破译驱动EC发病机制的分子机制对于开发创新疗法至关重要。现有证据表明TRIM35参与多种癌症的肿瘤增殖、侵袭和转移过程。为了研究TRIM35在EC中的作用，我们进行了综合生物信息学分析，并通过RT-qPCR和western blotting进行了实验验证，证实了其在EC组织中的显著下调。随后，我们用过表达TRIM35的慢病毒质粒转染子宫内膜癌细胞，研究其对细胞增殖、细胞周期、侵袭和迁移的影响。我们发现过表达TRIM35显著抑制增殖、侵袭和迁移。进一步研究发现TRIM35调控EIF3E的泛素化。此外，TRIM35调节CDK4/Cyclin D1信号通路，抑制EC细胞增殖。有趣的是，过表达EIF3E逆转了TRIM35在EC细胞中的抑制作用。综上所述，我们的研究表明TRIM35调节EIF3E的泛素化，抑制CDK4/Cyclin D1信号通路，从而抑制EC的恶性增殖。这些发现表明TRIM35有潜力作为EC的治疗靶点。

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引用次数: 0

PERK-eIF2alpha-mediated translational inhibition of MCL-1 contributes to potential 2-deoxy-D-glucose and BAD mimetic combinatorial cancer therapy perk - eif2alpha介导的MCL-1的翻译抑制有助于潜在的2-脱氧-d-葡萄糖和BAD模拟联合癌症治疗。

IF 3.7 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2025-12-19 DOI: 10.1016/j.cellsig.2025.112333

Mengning Sun , Li Li , Rongrong Fu, Qinglan Yang, Wenjuan Chen, Yi Sun, Hui Gao, Hang Gao, Na Dong

Glycolysis inhibitor 2-Deoxy-D-glucose (2DG) has been extensively studied as a potential therapeutic agent because tumors depend more on aerobic glycolysis than normal cells for their energy supply. However, the precise mechanism underlying 2DG's toxicity remains not so clear. In this study, we confirmed that 2DG induces apoptosis primarily by disrupting glycosylation rather than glycolysis. We observed that glucose depletion or 2DG treatment leads to a significant reduction of MCL-1 protein levels. Further analysis revealed that 2DG toxicity required MCL-1 degradation. Moreover, BAD was identified as the only BH3-only protein whose single knockout can block 2DG-induced apoptosis. The downregulation of MCL-1, combined with the dephosphorylation of BAD at Serine 155, contribute to the simultaneous inactivation of the anti-apoptotic functions of both MCL-1 and BCL-xL, which is sufficient to induce 2DG toxicity. Additionally, our experiments showed that Endoplasmic Reticulum (ER) stress induced PERK-eIF2α pathway mediated translational inhibition of MCL-1 contributes to 2DG toxicity. Based on these findings, the combined use of 2DG with BAD BH3 mimetic have proven effective against various types of cancer cells. In conclusion, this study provides a theoretical basis and rationale for the combined use of 2DG and BH3 mimetics as a promising therapeutic strategy for cancers.

糖酵解抑制剂2-脱氧葡萄糖（2DG）作为一种潜在的治疗剂被广泛研究，因为肿瘤比正常细胞更依赖于有氧糖酵解来提供能量。然而，2DG毒性的确切机制尚不清楚。在这项研究中，我们证实2DG主要通过破坏糖基化而不是糖酵解来诱导细胞凋亡。我们观察到葡萄糖消耗或2DG处理导致MCL-1蛋白水平显著降低。进一步分析表明2DG毒性需要MCL-1降解。此外，通过敲除实验，BAD被鉴定为2dg诱导的凋亡所必需的唯一BH3-only蛋白。MCL-1的下调，结合BAD丝氨酸155处的去磷酸化，导致MCL-1和BCL-xL的抗凋亡功能同时失活，足以诱导2DG毒性。此外，我们的实验表明内质网（ER）应激诱导的PERK-eIF2α途径介导的MCL-1的翻译抑制有助于2DG毒性。基于这些发现，2DG与BAD BH3模拟物的联合使用已被证明对各种类型的癌细胞有效。总之，本研究为联合使用2DG和BH3模拟物作为一种有前景的癌症治疗策略提供了理论基础和理论依据。

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引用次数: 0

Oxytocin regulation of intestinal stem cell self-renewal and differentiation 催产素对肠干细胞自我更新和分化的调节。

IF 3.7 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2025-12-19 DOI: 10.1016/j.cellsig.2025.112337

Junfei Liu , Mengnan Guo , Mingze Geng , Wenqian Lv , Yixin Liang , Yibo Zhang , Xuhao Meng , Jingxin Li , Xia Wang , Xiuli Zuo

The intestinal mucosa undergoes a tightly regulated process of proliferation and differentiation, essential for maintaining gut homeostasis. We have previously demonstrated that oxytocin (OXT), a novel gastrointestinal (GI) hormone, plays a crucial role in regulating intestinal injury. However, its functional significance in intestinal epithelial cells (IECs) remains largely uncharacterized. In this study, we demonstrate that the OXT/OXTR signaling axis enhanced proliferation and differentiation of IECs in mouse small intestinal organoids. Pharmacological inhibition or genetic knockout (KO) of OXTR in IECs leads to impaired intestinal stem cell self-renewal, reduced Paneth cell abundance, and exacerbated 5-fluorouracil (5-FU)-induced mucositis. Mechanistically, OXT stimulates prostaglandin E2 (PGE2) production via upregulation of prostaglandin-endoperoxide synthases (COX-1/COX-2), and activates the PGE2 receptor EP4. Notably, the OXT-driven effects are abrogated by COX or EP4 inhibition. Furthermore, OXT signaling enhances YAP activation through a PGE2/EP4-dependent mechanism, linking the OXT/PGE2/EP4 axis to modulation of the Hippo pathway. Our findings establish that OXT orchestrates intestinal epithelial regeneration by promoting stem cell self-renewal via the PGE2/EP4/Hippo/YAP signaling cascade. These results highlight the therapeutic potential of OXT in mitigating chemotherapy-induced intestinal injury.

肠黏膜的增殖和分化过程受到严格调控，对维持肠道内稳态至关重要。我们之前已经证明催产素（OXT）是一种新型胃肠道激素，在调节肠道损伤中起着至关重要的作用。然而，其在肠上皮细胞（IECs）中的功能意义在很大程度上仍未明确。在这项研究中，我们证明了OXT/OXTR信号轴促进了小鼠小肠类器官iec的增殖和分化。IECs中OXTR的药理抑制或基因敲除（KO）导致肠道干细胞自我更新受损，Paneth细胞丰度降低，并加重5-氟尿嘧啶（5-FU）诱导的粘膜炎。从机制上讲，OXT通过上调前列腺素内过氧化物合成酶（COX-1/COX-2）来刺激前列腺素E2 （PGE2）的产生，并激活PGE2受体EP4。值得注意的是，oxt驱动的效应被COX或EP4抑制所消除。此外，OXT信号通过PGE2/EP4依赖机制增强YAP激活，将OXT/PGE2/EP4轴与Hippo通路的调节联系起来。我们的研究结果表明，OXT通过PGE2/EP4/Hippo/YAP信号级联促进干细胞自我更新，从而协调肠上皮细胞的再生。这些结果突出了OXT在减轻化疗引起的肠道损伤方面的治疗潜力。

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引用次数: 0

N-α-Acetyltransferase 40 promotes oral squamous cell carcinoma progression by enhancing FEN1 transcription and suppressing CD8+ T cell antitumor immunity N-α-乙酰转移酶40通过增强FEN1转录和抑制CD8+ T细胞抗肿瘤免疫促进口腔鳞状细胞癌的进展。

IF 3.7 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2025-12-19 DOI: 10.1016/j.cellsig.2025.112335

Kun Jiao , Liou Jin , Ye Zheng , Yuan Zhang , Zhi Cui

Oral squamous cell carcinoma (OSCC) is the eighth most common malignancy worldwide and the predominant type of head and neck cancer. N-α-acetyltransferase 40 (NAA40), a histone acetyltransferase specifically modifying histones H4 and H2A, has been implicated in oncogenic processes across multiple tumor types. However, its role in OSCC remains unexplored. This study aimed to investigate the functional significance of NAA40 in OSCC and delineate its underlying molecular mechanisms. Bioinformatics analyses were performed to evaluate NAA40 expression and its prognostic value in OSCC tissues. Quantitative real-time PCR, western blot, chromatin immunoprecipitation, CD8⁺ T cell isolation, co-culture, flow cytometry, and humanized immune-reconstituted subcutaneous xenograft/syngeneic transplantation models were used to clarify its function, mechanism, and therapeutic efficacy. Results showed that NAA40 was upregulated in OSCC tissues, and this upregulation was associated with worse overall survival in patients. In vitro experiments revealed that NAA40 overexpression inhibited T cell activation and their cytotoxic capacity against OSCC cells by upregulating programmed death-ligand 1 (PD-L1) expression, whereas NAA40 knockdown yielded the opposite effect. In vivo studies further suggested that downregulation of NAA40 effectively inhibited tumor growth in immunocompetent mice. Mechanistically, NAA40 promotes histone H4 lysine acetylation enrichment at the lap endonuclease-1 (FEN1) promoter and its transcriptional activation through an indirect mechanism, which is mediated by its regulation of H4 N-terminal acetylation at the first serine residue. This cascade ultimately upregulates PD-L1 expression. Knockdown of FEN1 reversed the suppression of CD8⁺ T cell activation and antitumor immunity caused by NAA40 overexpression. This study demonstrates NAA40 promotes OSCC progression via enhancing FEN1 transcription and suppressing CD8⁺ T cell function, suggesting that NAA40 may serve as a novel prognostic marker and therapeutic target for OSCC.

口腔鳞状细胞癌（OSCC）是全球第八大最常见的恶性肿瘤，也是头颈部癌症的主要类型。N-α-乙酰转移酶40 （NAA40）是一种特异性修饰组蛋白H4和H2A的组蛋白乙酰转移酶，与多种肿瘤类型的致癌过程有关。然而，它在OSCC中的作用仍未被探索。本研究旨在探讨NAA40在OSCC中的功能意义，并揭示其潜在的分子机制。应用生物信息学分析评价NAA40在OSCC组织中的表达及其预后价值。采用实时荧光定量PCR、western blot、染色质免疫沉淀、CD8+ T细胞分离、共培养、流式细胞术、人源化免疫重构皮下异种移植/同基因移植模型等方法研究其功能、机制和治疗效果。结果显示，NAA40在OSCC组织中上调，这种上调与患者的总生存率降低有关。体外实验显示，NAA40过表达通过上调程序性死亡配体1 （programmed death-ligand 1, PD-L1）表达，抑制T细胞活化及其对OSCC细胞的细胞毒能力，而NAA40敲低则产生相反的效果。体内研究进一步表明，下调NAA40可有效抑制免疫功能小鼠的肿瘤生长。在机制上，NAA40通过间接机制促进组蛋白H4赖氨酸乙酰化在lap endonuclease-1 （FEN1）启动子上的富集和转录激活，这是通过调节第一个丝氨酸残基上H4 n端乙酰化介导的。这个级联最终上调PD-L1的表达。FEN1的敲低逆转了NAA40过表达引起的CD8+ T细胞活化和抗肿瘤免疫的抑制。本研究表明NAA40通过增强FEN1转录和抑制CD8+ T细胞功能促进OSCC进展，提示NAA40可能作为OSCC新的预后标志物和治疗靶点。

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引用次数: 0

Icariin attenuates premature ovarian insufficiency via a phytoestrogenic mechanism mediated by the ERβ/SIRT3 pathway 淫羊藿苷通过ERβ/SIRT3途径介导的植物雌激素机制减轻卵巢早衰。

IF 3.7 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2025-12-18 DOI: 10.1016/j.cellsig.2025.112334

Jiaojiao Yang , Ning Wang , Siyao Tong , Piwen Zhao

Premature ovarian insufficiency (POI) affects up to 1 % of the female population worldwide. Icariin (ICA) has shown promising potential for the alleviation of POI. However, the molecular mechanisms underlying the protective effects of ICA warrant further exploration. In this study, we aimed to elucidate the mechanisms by which ICA improves ovarian function via antioxidant effects mediated by the ERβ/SIRT3 pathway. Cisplatin-induced murine models of POI were used to systematically investigate the cytoprotective efficacy of ICA by comprehensive ovarian histopathological analysis, follicular quantification, estrous cycle monitoring, serum hormonal profiling, and the evaluation of biomarkers of ovarian oxidative stress and apoptosis. Then, an integrated methodological approach encompassing molecular docking, dual-luciferase reporter gene assay, and chromatin immunoprecipitation, was implemented to analyze the mechanism of the ERβ/SIRT3 pathway in conferring antioxidant protection in vitro against ICA. In cisplatin-induced murine models of POI, the administration of ICA significantly elevated follicle counts, restored normal estrous cyclicity, and normalized serum hormone levels (p < 0.01). Furthermore, ICA activated the ERβ/SIRT3 pathway, thus ameliorating cisplatin-induced ovarian oxidative damage. In vitro, ICA conferred protection against H₂O₂-induced injury in KGN cells. Mechanistically, ICA enhanced the binding of ERβ to the promoter of the SIRT3 gene, thereby promoting the activation of SIRT3. Critically, the protective effects of ICA were abolished following the pharmacological inhibition of ERβ or SIRT3. ICA ameliorated cisplatin-induced ovarian oxidative damage by activating the ERβ/SIRT3 pathway, providing scientific evidence for its potential as a therapeutic agent for POI. This finding facilitates further optimization of drug design and could enhance the quality-of-life for patients with POI.

卵巢功能不全（POI）影响高达1% 全球女性人口。淫羊藿苷（ICA）在缓解POI方面显示出良好的潜力。然而，ICA保护作用的分子机制有待进一步探索。在这项研究中，我们旨在阐明ICA通过ERβ/SIRT3途径介导的抗氧化作用改善卵巢功能的机制。采用顺铂诱导的POI小鼠模型，通过综合卵巢组织病理学分析、卵泡定量、发情周期监测、血清激素谱分析、卵巢氧化应激和凋亡生物标志物评估，系统研究ICA的细胞保护作用。然后，采用包括分子对接、双荧光素酶报告基因测定和染色质免疫沉淀在内的综合方法，分析了ERβ/SIRT3途径在体外赋予ICA抗氧化保护的机制。在顺铂诱导的POI小鼠模型中，ICA可显著提高卵泡计数，恢复正常的发情周期，并使血清激素水平正常化（p 2.2诱导的KGN细胞损伤）。在机制上，ICA增强了ERβ与SIRT3基因启动子的结合，从而促进了SIRT3的激活。关键的是，ICA的保护作用在ERβ或SIRT3的药理学抑制后被取消。ICA通过激活ERβ/SIRT3通路改善顺铂诱导的卵巢氧化损伤，为其作为POI治疗药物的潜力提供了科学证据。这一发现有助于进一步优化药物设计，并可提高POI患者的生活质量。

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引用次数: 0

ANXA1 regulates microglia polarization and autophagy via PI3K/Akt/mTOR pathway to reduce inflammatory injury after cerebral ischemia-reperfusion ANXA1通过PI3K/Akt/mTOR通路调控小胶质细胞极化和自噬，减轻脑缺血再灌注后的炎症损伤

IF 3.7 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2025-12-18 DOI: 10.1016/j.cellsig.2025.112336

Hua Wang , Xiaohui Li , Ziyu Liu , Ruirui Lu , Xiaopeng Li , Xiaoguang Zhang

Background

Annexin A1 (ANXA1) can be activated by ischemia/reperfusion (I/R) events or inflammatory processes, but its specific regulatory mechanisms need further investigation.

Methods

ANXA1 in BV-2 cells was knocked down or overexpressed, and OGD/R induced injury, while 740YP and LY294002 were used for intervention. Microglia polarization phenotype and marker levels were assessed through flow cytometry, RT-qPCR and western blot. Autophagic flux and lysosomal function were evaluated by mCherry-GFP-LC3B, acridine orange (AO) staining and LysoTracker staining. ANXA1 and PI3K/Akt/mTOR proteins were detected by western blot. The tMCAO/R mouse model was established. Longa score, behavioral test and pathological staining to assess the extent of nerve injury, and microglia polarization and autophagy indicators were detected.

Results

ANXA1 expression was decreased in OGD/R-treated microglia. ANXA1 overexpression facilitated the transformation of microglia phenotype from M1-like phenotype to M2-like phenotype, increased CD206 and IL-10 expression, reduced the GFP/mCherry ratio and LysoTracker positive cells, and increased the red fluorescence of AO staining. ANXA1 overexpression also significantly reduced PI3K, Akt and mTOR phosphorylation. Moreover, ANXA1 overexpression markedly decreased Longa score, brain water content and infarct size, improved motor and neurological impairment in tMCAO/R mice, elevated Nissl bodies and Iba-1⁺CD206⁺ positive area, and reduced necrotic neuron numbers, inflammatory factor content and autophagy protein levels. In addition, 740YP significantly inhibited the improvement of ANXA1 overexpression, and LY294002 significantly enhanced the improvement of ANXA1 overexpression.

Conclusion

Overexpression of ANXA1 regulated microglia polarization and autophagic flux via regulating PI3K/Akt/mTOR pathway, and improved cerebral I/R inflammatory injury.

dannexin A1 （ANXA1）可被缺血/再灌注（I/R）事件或炎症过程激活，但其具体调控机制有待进一步研究。方法利用740YP和LY294002对BV-2细胞进行干预，敲低或过表达sanxa1，诱导OGD/R损伤。通过流式细胞术、RT-qPCR和western blot检测小胶质细胞极化表型和标志物水平。采用mCherry-GFP-LC3B、吖啶橙（AO）染色和LysoTracker染色评价自噬通量和溶酶体功能。western blot检测ANXA1和PI3K/Akt/mTOR蛋白。建立tMCAO/R小鼠模型。采用Longa评分、行为测试和病理染色评估神经损伤程度，检测小胶质细胞极化和自噬指标。结果OGD/ r处理的小胶质细胞中sanxa1表达降低。过表达ANXA1促进小胶质细胞表型由m1样表型向m2样表型转化，增加CD206和IL-10表达，降低GFP/mCherry比例和LysoTracker阳性细胞，增加AO染色的红色荧光。过表达ANXA1也显著降低了PI3K、Akt和mTOR的磷酸化。此外，过表达ANXA1可显著降低tMCAO/R小鼠的Longa评分、脑含水量和梗死面积，改善运动和神经功能障碍，提高Nissl小体和Iba-1+CD206+阳性面积，降低坏死神经元数量、炎症因子含量和自噬蛋白水平。740YP显著抑制ANXA1过表达的改善，LY294002显著增强ANXA1过表达的改善。结论过表达ANXA1通过调节PI3K/Akt/mTOR通路调节小胶质细胞极化和自噬通量，改善脑I/R炎症损伤。

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引用次数: 0

The snoRNA SNORA21 promotes gastric tumorigenesis by attenuating P53 activity through CHK1 phosphorylation inhibition and PERP-dependent feedback loops snoRNA SNORA21通过抑制CHK1磷酸化和perp依赖的反馈回路降低P53活性，从而促进胃肿瘤的发生

IF 3.7 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2025-12-17 DOI: 10.1016/j.cellsig.2025.112326

Fanqi Wu , Wangyue Wu , Xueni Ma , Huimei Xu , Dekui Zhang

Small nucleolar RNAs (snoRNAs) have emerged as critical regulators in cancer progression, yet their mechanistic roles in gastric cancer (GC) remain poorly understood. Here, we identify SNORA21 as an oncogenic snoRNA that drives GC pathogenesis through P53 pathway inactivation. We demonstrated significant SNORA21 upregulation in GC tissues and cell lines compared to normal controls. Functional studies revealed that SNORA21 knockdown inhibited tumor growth, while its overexpression promoted malignant phenotypes, establishing its crucial role in determining GC cell fate. Transcriptomic profiling and mechanistic investigations uncovered that SNORA21 represses P53 tumor suppressor activity through a novel CHK1-dependent mechanism. Specifically, SNORA21 attenuated DNA damage responses by inhibiting CHK1 phosphorylation, thereby preventing P53 activation. Remarkably, SNORA21 depletion triggered PERP induction – a P53 effector – which formed a positive feedback loop by suppressing MDM2-mediated P53 degradation. This dual regulatory mechanism (CHK1 inhibition and PERP-MDM2 feedback) explains how SNORA21 sustains P53 inactivation in GC cells. In vivo xenograft models confirmed that SNORA21 silencing suppressed tumor growth while enhancing P53 signaling activity. Our work not only elucidates SNORA21 as a master regulator of the P53 pathway in GC but also reveals its therapeutic potential. The discovery of the SNORA21-CHK1-PERP-MDM2 axis provides a conceptual framework for targeting snoRNA-mediated P53 regulation in GC treatment. These findings position SNORA21 as both a prognostic biomarker and a candidate for RNA-based therapeutics in P53-wildtype gastric cancers.

小核核rna （snoRNAs）已成为癌症进展的关键调节因子，但其在胃癌（GC）中的机制作用仍知之甚少。本研究中，我们发现SNORA21是一种致癌的snoRNA，通过P53通路失活驱动GC发病。我们发现，与正常对照相比，在GC组织和细胞系中，SNORA21表达明显上调。功能研究显示，SNORA21敲低抑制肿瘤生长，而其过表达促进恶性表型，确立了其在决定GC细胞命运中的关键作用。转录组学分析和机制研究发现，SNORA21通过一种新的依赖chk1的机制抑制P53肿瘤抑制活性。具体来说，SNORA21通过抑制CHK1磷酸化来减弱DNA损伤反应，从而阻止P53激活。值得注意的是，SNORA21缺失触发了P53效应物PERP诱导，通过抑制mdm2介导的P53降解形成了一个正反馈回路。这种双重调节机制（CHK1抑制和PERP-MDM2反馈）解释了SNORA21如何在GC细胞中维持P53失活。体内异种移植模型证实，SNORA21沉默抑制肿瘤生长，同时增强P53信号活性。我们的工作不仅阐明了SNORA21作为胃癌中P53通路的主要调节因子，而且揭示了其治疗潜力。SNORA21-CHK1-PERP-MDM2轴的发现为在GC治疗中靶向snorna介导的P53调控提供了一个概念框架。这些发现将SNORA21定位为p53野生型胃癌的预后生物标志物和基于rna的治疗候选物。

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引用次数: 0

The LPA2 receptor PDZ domain affects canonical Wnt signaling in colon cancer cells LPA2受体PDZ结构域影响结肠癌细胞的典型Wnt信号

IF 3.7 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2025-12-17 DOI: 10.1016/j.cellsig.2025.112318

M. Cristina Castañeda-Patlán , Juan Carlos Martínez- Morales , Marco Antonio Morquecho-León , Paola Briseño-Díaz , K. Helivier Solís , M. Teresa Romero-Ávila , J. Adolfo García-Sáinz , Martha Robles-Flores

Colorectal cancer is the third leading cause of cancer-related deaths worldwide. Aberrant canonical Wnt signaling is a hallmark of this cancer type. It has been reported that LPA is a bioactive lipid that plays different roles in colon cancer by activating its G-protein-coupled receptors, promoting cell proliferation, migration, survival, and angiogenesis. Although it has been reported that LPA activates canonical Wnt signaling, the mechanisms underlying their interaction remain unclear; this study aims to investigate them. As previously reported, LPA receptor expression changes under malignant conditions: while LPA₁ is expressed at high levels and LPA₂ is low in non-malignant 112CoN cells, the opposite occurs in malignant cells, with colon cancer cells showing low LPA₁ levels and high LPA₂ levels. We also observed that both LPA and Wnt-3a induce strong ERK activation in all colon cell lines; these effects are not additive. Additionally, LPA and Wnt-3a stimulate β-catenin transcriptional activity and its phosphorylation at residues S552 and S675, again in a non-additive manner. We further found that LPA₂ and the Wnt effectors Dvl2 and Dvl3 co-precipitate in colon cancer cells, and that the PDZ-interacting motif in the carboxyl terminus of the LPA₂ receptor is critical for their direct interaction. Moreover, expressing a mutated LPA₂₋PDZminus receptor inhibited cell migration while increasing proliferation. Remarkably, the LPA₂₋PDZminus receptor negatively affected its ability to activate canonical Wnt signaling and unexpectedly, it also impaired the Wnt-3a ligand-induced activation of canonical Wnt signaling in colon cancer cells.

结直肠癌是全球癌症相关死亡的第三大原因。异常的典型Wnt信号是这种癌症类型的标志。据报道，LPA是一种生物活性脂质，通过激活其g蛋白偶联受体，促进细胞增殖、迁移、存活和血管生成，在结肠癌中发挥不同的作用。尽管有报道称LPA激活典型Wnt信号，但它们相互作用的机制尚不清楚；本研究旨在调查他们。如前所述，恶性情况下LPA受体表达发生变化：非恶性112CoN细胞中LPA1高表达，LPA2低表达，而恶性细胞中LPA1低表达，结肠癌细胞中LPA2高表达。我们还观察到LPA和Wnt-3a在所有结肠细胞系中都能诱导强烈的ERK激活；这些影响不是相加的。此外，LPA和Wnt-3a同样以非加性的方式刺激β-catenin转录活性及其残基S552和S675的磷酸化。我们进一步发现LPA2和Wnt效应物Dvl2和Dvl3在结肠癌细胞中共同沉淀，并且LPA2受体羧基端的pdz相互作用基序对于它们的直接相互作用至关重要。此外，表达突变的LPA2 - PDZminus受体抑制细胞迁移，同时增加细胞增殖。值得注意的是，LPA2 - PDZminus受体负向影响其激活典型Wnt信号的能力，并且出乎意料的是，它还损害了结肠癌细胞中Wnt-3a配体诱导的典型Wnt信号的激活。

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引用次数: 0

Targeting CDK12 rescues C/EBPβ-mediated platinum and PARP inhibitor resistance in ovarian cancer 靶向CDK12可缓解C/ ebp β介导的卵巢癌铂和PARP抑制剂耐药

IF 3.7 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2025-12-16 DOI: 10.1016/j.cellsig.2025.112328

Jiahong Tan , Wei Dong , Daoqi Wang , Aiqing Tu , Zuheng Wang , Xiaodie Wu , Fen Zhang , Yun Zhu , Li Ren , Ying Ai , Yun Feng , Jie Zhang

Despite multimodality treatment efforts, resistance to platinum and PARP inhibitors represents a primary impediment to improve prognosis of ovarian cancer. Here, we found that ovarian cancer tissues had higher C/EBPβ expression compared with normal tissues and high C/EBPβ expression predicted unfavorable survival outcomes. Elevated C/EBPβ expression enhanced cisplatin resistance and olaparib resistance. C/EBPβ could affect DDR signals of ovarian cancer. CDK12, serving as a C/EBPβ-regulated DDR-related gene, was directly targeted by and bound with C/EBPβ. C/EBPβ could promote CDK12 expression and confer drug tolerance via CDK12. Manipulation of CDK12 could reverse the effects of C/EBPβ. Using CDK12 inhibitor THZ531 could rescue C/EBPβ-mediated cisplatin resistance and olaparib resistance. Our findings indicated that C/EBPβ is a potent DDR regulator of ovarian cancer, which directly targets CDK12 and upregulates its expression. High C/EBPβ expression mediates platinum resistance and PARP inhibitor resistance via CDK12. Targeting C/EBPβ via CDK12 inhibition could rescue drug responsiveness of ovarian cancer, thereby counteracting platinum and PARP inhibitor resistance. C/EBPβ could thus be exploited as a candidate prognostic biomarker in ovarian cancer.

尽管采取了多种治疗方法，但对铂和PARP抑制剂的耐药性是改善卵巢癌预后的主要障碍。在这里，我们发现卵巢癌组织与正常组织相比有更高的C/EBPβ表达，高C/EBPβ表达预示着不利的生存结果。升高的C/EBPβ表达增强顺铂耐药和奥拉帕尼耐药。C/EBPβ可影响卵巢癌DDR信号。CDK12作为C/EBPβ调控的ddr相关基因，被C/EBPβ直接靶向并结合。C/EBPβ可促进CDK12表达，并通过CDK12赋予药物耐受性。操纵CDK12可以逆转C/EBPβ的作用。使用CDK12抑制剂THZ531可以缓解C/ ebp β介导的顺铂耐药和奥拉帕尼耐药。我们的研究结果表明，C/EBPβ是卵巢癌的一种有效的DDR调节剂，它直接靶向CDK12并上调其表达。高C/EBPβ表达通过CDK12介导铂耐药和PARP抑制剂耐药。通过抑制CDK12靶向C/EBPβ可以挽救卵巢癌的药物反应性，从而抵消铂和PARP抑制剂的耐药性。因此，C/EBPβ可以作为卵巢癌的候选预后生物标志物。

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引用次数: 0

JOSD2 alleviates hypertensive renal disease through deubiquitinating AKT in renal tubular epithelial cells JOSD2通过在肾小管上皮细胞中去泛素化AKT减轻高血压肾病。

IF 3.7 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2025-12-16 DOI: 10.1016/j.cellsig.2025.112330

Shijie Fan , Ying Zhao , Luyao Li , Qingqing Zhao , Ziming Fang , Diyun Xu , Jingjing Shao , Yunjie Zhao , Guang Liang , Xuelin He , Hong Zhu , Yi Wang

Hypertensive renal disease (HRD) is a significant driver of end-stage renal disease. Discovering novel therapeutic targets for HRD is essential for its prevention and treatment. Deubiquitinating enzymes (DUBs) have shown increasing significance in renal diseases. Here, we investigated the role and mechanism of the DUB, Josephin domain-containing protein 2 (JOSD2), in HRD. HRD was induced in wild-type or Josd2 knockout mice via a 4-week chronic infusion of angiotensin II (Ang II). We found that deficiency of JOSD2 aggravated renal injury, epithelial-mesenchymal transition (EMT), and fibrosis in HRD mice. Single-cell RNA-seq analysis indicated that JOSD2 is mainly expressed in tubular epithelial cells (TECs) of proximal tubules. Notably, the specific overexpression of JOSD2 in renal TECs alleviated the detrimental effects in Ang II-induced HRD mice. Mechanistically, through mass spectrometry combined with co-immunoprecipitation analysis, we considered protein kinase B (AKT) as a potential substrate of JOSD2. JOSD2 deubiquitinated the K63-linked ubiquitin chain of AKT via its active site H125 and then enhanced p62-mediated autophagic degradation of AKT. This process reduced the AKT level in TECs, thereby ultimately reducing renal EMT and fibrosis. Our study elucidates the role of the JOSD2-AKT axis in HRD and suggests that JOSD2 may serve as a promising therapeutic target for HRD.

高血压肾病（HRD）是终末期肾脏疾病的重要驱动因素。发现新的HRD治疗靶点对其预防和治疗至关重要。去泛素化酶（DUBs）在肾脏疾病中的作用越来越重要。在这里，我们研究了Josephin结构域蛋白2 （JOSD2）在HRD中的作用和机制。在野生型或Josd2基因敲除小鼠中，通过4周的血管紧张素II （Ang II）慢性输注诱导HRD。我们发现，缺乏JOSD2会加重HRD小鼠的肾损伤、上皮-间质转化（EMT）和纤维化。单细胞RNA-seq分析表明，JOSD2主要表达于近端小管上皮细胞（TECs）中。值得注意的是，JOSD2在肾tec中的特异性过表达减轻了Ang ii诱导的HRD小鼠的有害影响。从机制上讲，通过质谱结合共免疫沉淀分析，我们认为蛋白激酶B （AKT）是JOSD2的潜在底物。JOSD2通过其活性位点H125使AKT的k63连接的泛素链去泛素化，进而增强p62介导的AKT自噬降解。这一过程降低了TECs中的AKT水平，从而最终减少肾脏EMT和纤维化。我们的研究阐明了JOSD2- akt轴在HRD中的作用，并提示JOSD2可能作为HRD的一个有希望的治疗靶点。

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引用次数: 0