Cellular signalling最新文献_第4页

PYGB targeted by androgen receptor contributes to tumor progression and metabolic reprogramming in esophageal squamous carcinoma 以雄激素受体为靶点的PYGB有助于食管鳞癌的肿瘤进展和代谢重编程。

IF 4.4 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2024-10-21 DOI: 10.1016/j.cellsig.2024.111481

Huikai Miao , Chunmei Xu , Wuyou Gao , Leqi Zhong , Hongmu Li , Zhesheng Wen , Qiannan Ren , Youfang Chen

Background

The incidence and mortality rates of esophageal squamous cell carcinoma (ESCC) are conspicuously augmented in men in contrast to women. The androgen receptor (AR), prevalently associated with the manifestation of male characteristics, is regarded as a pivotal determinant in tumor progression. Nevertheless, its exact role in ESCC remains insufficiently delineated.

Methods

In this study, we probed the expression levels of AR and glucose metabolism enzymes in ESCC tissues by means of immunohistochemistry. We exploited chromatin immunoprecipitation and dual luciferase reporter assays to delve into the transcriptional regulatory interrelationships between AR and these enzymes. A gamut of molecular techniques—including multi-omics sequencing, colony formation assays, cell counting kit 8 (CCK8), 5-Ethynyl-2′-deoxyuridine (EdU) incorporation assays, wound-healing assays, transwell migration assays, extracellular acidification rate (ECAR) measurements, lipid droplet fluorescence imaging, and xenograft models—were enlisted to illuminate the functions of these enzymes within ESCC cells.

Results

Our discoveries manifested that AR expression was strikingly higher in male ESCC tissues than in their female counterparts. Significantly, we discerned that glycogen phosphorylase B (PYGB), a cardinal enzyme implicated in glucose metabolism, demonstrated not only a positive correlation with AR expression but also an association with adverse prognostic outcomes for ESCC patients. Moreover, AR directly binds to the promoter region of the PYGB gene, thereby potentiating its transcriptional activity. This upregulation of PYGB was ascertained to facilitate proliferation, invasion, and metastasis among ESCC cells while intensifying glycolysis and modifying lipid metabolism pathways within these cells. In animal models employing nude mice, elevated PYGB levels were witnessed to expedite subcutaneous tumor growth as well as lung metastasis.

Conclusions

Collectively, our study establishes PYGB as a direct target of AR that assumes an indispensable role in both tumor progression and metabolic reprogramming affiliated with ESCC, thus paving novel avenues for therapeutic strategies centered on metabolic intercessions.

背景：男性食管鳞状细胞癌（ESCC）的发病率和死亡率明显高于女性。雄激素受体（AR）通常与男性特征的表现有关，被认为是肿瘤进展的关键决定因素。然而，它在 ESCC 中的确切作用仍未得到充分阐明：本研究采用免疫组化方法检测了 ESCC 组织中 AR 和葡萄糖代谢酶的表达水平。我们利用染色质免疫沉淀和双荧光素酶报告实验深入研究了AR与这些酶之间的转录调控相互关系。我们采用了多种分子技术--包括多组学测序、菌落形成检测、细胞计数试剂盒8（CCK8）、5-乙炔基-2'-脱氧尿苷（EdU）掺入检测、伤口愈合检测、透孔迁移检测、细胞外酸化率（ECAR）测量、脂滴荧光成像和异种移植模型--来阐明这些酶在ESCC细胞中的功能：我们的发现表明，男性 ESCC 组织中 AR 的表达明显高于女性。值得注意的是，我们发现糖原磷酸化酶 B (PYGB)--一种参与葡萄糖代谢的主要酶--不仅与 AR 表达呈正相关，而且还与 ESCC 患者的不良预后结果有关。此外，AR 可直接与PYGB 基因的启动子区域结合，从而增强其转录活性。研究发现，PYGB 基因的上调促进了 ESCC 细胞的增殖、侵袭和转移，同时加强了这些细胞内的糖酵解并改变了脂质代谢途径。在采用裸鼠的动物模型中，PYGB 水平的升高被证实会加速皮下肿瘤的生长和肺转移：总之，我们的研究证实PYGB是AR的一个直接靶点，在ESCC的肿瘤进展和代谢重编程过程中发挥着不可或缺的作用，从而为以代谢干预为中心的治疗策略开辟了新的途径。

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引用次数: 0

Lipopolysaccharide-regulated RNF31/NRF2 axis in colonic epithelial cells mediates homeostasis of the intestinal barrier in ulcerative colitis 结肠上皮细胞中受脂多糖调控的 RNF31/NRF2 轴介导了溃疡性结肠炎肠屏障的平衡。

IF 4.4 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2024-10-20 DOI: 10.1016/j.cellsig.2024.111480

Chao-Tao Tang , Zi-de Liu , Peng Wang , Chun-Yan Zeng , You-Xiang Chen

Background

Although previous studies have shown that the Ring Finger Protein 31 (RNF31) gene confers susceptibility to inflammatory disease and colorectal cancer, the exact function of this protein in ulcerative colitis (UC) has not been determined.

Methods

A mouse dextran sulfate sodium (DSS)-induced experimental colitis model was used to study RNF31 and NRF2 in colitis. RNF31 silencing or overexpression in vitro was applied to address the role of RNF31 in colonic mucosal barrier damage. Immunohistochemistry and silico analysis was performed to investigate the expression of RNF31 via taking advantage of UC tissue samples and Gene Expression Omnibus (GEO) data, respectively. The cycloheximide (CHX)-chase experiment and Co-Immunoprecipitation (Co-IP) assays were conducted to explore the association of RNF31 protein with NRF2 and P62.

Results

RNF31 is highly expressed in UC patients, in inflamed murine colon induced DSS and Lipopolysaccharide (LPS)-treated epithelial cells, while the express of NRF2 was Tabdecreased. RNF31-knockdown mice in the DSS-induced colitis model had a less severe phenotype, which was associated with a more integrated barrier of colon epithelial cells. While depletion of NRF2 in colitis model exacerbated intestinal inflammation. Mechanistically, RNF31 promoted the degradation of NRF2 by regulating its ubiquitination. Upon stimulation by RNF31, NRF2 is K63 ubiquitinated, which is associated with the C871 residue of RNF31. Moreover, downregulated NRF2 mediates inflammation by promoting the secretion of IL1β and IL18, leading to damage of the intestinal barrier. Upon LPS stimulation, the interaction of the PUB domain of RNF31 with the UBA domain of P62 increased, resulting in decreased degradation of the RNF31 protein via autophagy.

Conclusion

Overall, depletion of RNF31 effectively relieves DSS-induced colitis in mice by inhibiting NRF2 degradation, suggesting that RNF31 may be a potential therapy for human ulcerative colitis.

背景：尽管先前的研究表明环指蛋白 31（RNF31）基因易导致炎症性疾病和结直肠癌，但该蛋白在溃疡性结肠炎（UC）中的确切功能尚未确定：方法：采用小鼠葡聚糖硫酸钠（DSS）诱导的实验性结肠炎模型研究 RNF31 和 NRF2 在结肠炎中的作用。方法：利用小鼠葡聚糖硫酸钠（DSS）诱导的实验性结肠炎模型研究 RNF31 和 NRF2 在结肠炎中的作用，并在体外应用 RNF31 沉默或过表达来探讨 RNF31 在结肠粘膜屏障损伤中的作用。研究人员利用 UC 组织样本和基因表达总库（Gene Expression Omnibus，GEO）数据，分别对 RNF31 的表达进行了免疫组化和硅学分析。研究人员还进行了环己亚胺（CHX）-酶实验和共免疫沉淀（Co-IP）实验，以探讨RNF31蛋白与NRF2和P62的关联：结果：RNF31在UC患者、DSS诱导的炎症小鼠结肠和脂多糖（LPS）处理的上皮细胞中高表达，而NRF2的表达量则下降。在 DSS 诱导的结肠炎模型中，剔除 RNF31 的小鼠表型较轻，这与结肠上皮细胞的屏障更加完整有关。而在结肠炎模型中消耗 NRF2 会加剧肠道炎症。从机理上讲，RNF31通过调节NRF2的泛素化来促进其降解。在 RNF31 的刺激下，NRF2 被 K63 泛素化，这与 RNF31 的 C871 残基有关。此外，下调的 NRF2 通过促进 IL1β 和 IL18 的分泌来介导炎症，导致肠道屏障受损。在 LPS 刺激下，RNF31 的 PUB 结构域与 P62 的 UBA 结构域的相互作用增加，导致 RNF31 蛋白通过自噬降解的减少：总之，通过抑制NRF2降解，消耗RNF31可有效缓解DSS诱导的小鼠结肠炎，这表明RNF31可能是人类溃疡性结肠炎的一种潜在疗法。

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引用次数: 0

Sirt1-mediated deacetylation of PGC-1α alleviated hepatic steatosis in type 2 diabetes mellitus via improving mitochondrial fatty acid oxidation Sirt1 介导的 PGC-1α 去乙酰化可通过改善线粒体脂肪酸氧化减轻 2 型糖尿病患者的肝脂肪变性。

IF 4.4 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2024-10-18 DOI: 10.1016/j.cellsig.2024.111478

Jiale Pang , Longxiang Yin , Wenjie Jiang , Haiyan Wang , Qian Cheng , Zhenzhou Jiang , Yanjuan Cao , Xia Zhu , Baojing Li , Sitong Qian , Xiaoxing Yin , Tao Wang , Qian Lu , Tingting Yang

Being activated by deacetylation, peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) has become an important regulator of metabolic-related diseases. The activation of Sirtuin 1 (Sirt1) by resveratrol was likely to deacetylate PGC-1α. However, the role of deacetylated PGC-1α in the alleviation of activated Sirt1 on type 2 diabetes mellitus (T2DM)-related fatty liver disease (FLD) remained unexplored. The aim of this study was to investigate the potential impact of Sirt1-mediated deacetylation of PGC-1α on T2DM-associated FLD and its underlying mechanisms. Our findings revealed that, along with the decreased Sirt1, the levels of acetylated PGC-1α were up-regulated in hepatocytes co-stimulated with high glucose (HG) and free fatty acids (FFA). Down-regulated Sirt1 inactivated PGC-1α by inhibiting its deacetylation, while activating Sirt1 improved hepatic injury by reducing lipid droplet accumulation through the deacetylation of PGC-1α. However, the beneficial effects of Sirt1 activation on hepatic steatosis were inhibited by PGC-1α antagonist in vitro. Mechanistically, activating Sirt1 enhanced mitochondrial function by promoting PGC-1α activity, thereby facilitating hepatic fatty acid oxidation (FAO). In conclusion, Sirt1-mediated deacetylation of PGC-1α mitigated hepatic lipotoxicity by enhancing mitochondrial FAO, which contributed to the restoration of mitochondrial function in T2DM. The activation of Sirt1-mediated PGC-1α deacetylation might represent a promising therapeutic approach for T2DM-associated FLD.

过氧化物酶体增殖激活受体-γ辅激活子-1α（PGC-1α）通过去乙酰化被激活，已成为代谢相关疾病的重要调节因子。白藜芦醇对 Sirtuin 1（Sirt1）的激活作用可能是使 PGC-1α 去乙酰化。然而，去乙酰化的 PGC-1α 在缓解活化的 Sirt1 对与 2 型糖尿病（T2DM）相关的脂肪肝（FLD）的影响方面所起的作用仍有待探索。本研究旨在探讨 Sirt1 介导的 PGC-1α 去乙酰化对 T2DM 相关脂肪肝的潜在影响及其内在机制。我们的研究结果表明，在高糖（HG）和游离脂肪酸（FFA）共同刺激的肝细胞中，随着 Sirt1 的减少，乙酰化 PGC-1α 的水平也上调。下调的 Sirt1 通过抑制 PGC-1α 的去乙酰化使其失活，而激活的 Sirt1 则通过 PGC-1α 的去乙酰化减少脂滴积累，从而改善肝损伤。然而，体外 PGC-1α 拮抗剂抑制了激活 Sirt1 对肝脏脂肪变性的有益作用。从机制上讲，激活 Sirt1 可通过促进 PGC-1α 的活性来增强线粒体功能，从而促进肝脏脂肪酸氧化（FAO）。总之，Sirt1介导的PGC-1α去乙酰化可通过增强线粒体脂肪酸氧化作用减轻肝脏脂肪毒性，从而有助于恢复T2DM的线粒体功能。激活 Sirt1 介导的 PGC-1α 去乙酰化可能是治疗 T2DM 相关 FLD 的一种有前景的方法。

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引用次数: 0

GALNT14-mediated O-glycosylation drives lung adenocarcinoma progression by reducing endogenous reactive oxygen species generation GALNT14 介导的 O 型糖基化通过减少内源性活性氧的生成来推动肺腺癌的发展。

IF 4.4 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2024-10-18 DOI: 10.1016/j.cellsig.2024.111477

Bingbing Tang , Kelong Wang , Qiulei Ren , Junshuo Zhou , Yuewen Xu , Liaoyuan Liu , Bin Yin , Yaling Zhang , Qian Huang , Ruiqi Lv , Zhiguo Luo , Hongyan Zhao , Li Shen

Aberrant glycosylation, resulting from dysregulated expression of glycosyltransferases, is a prevalent feature of cancer cells. N-acetylgalactosaminyltransferase-14 (GALNT14) serves as a pivotal enzyme responsible for initiating O-GalNAcylation. It remains unclear whether and how GALNT14 affects lung adenocarcinoma (LUAD). Here, GALNT14 expression in LUAD was analyzed by searching public databases and verified by examining clinical samples. Bioinformatics, LC-MS/MS, RNA-seq, and RIP-seq analyses were used to uncover the mechanism underlying GALNT14. We observed that GALNT14 was frequently overexpressed in LUAD tissues. High GALNT14 expression was positively associated with advanced TNM stage, larger tumor size, and unfavorable prognosis. Functionally, GALNT14 facilitated LUAD cell proliferation, migration, and invasion in vitro and accelerated tumor growth in vivo. Mechanistically, GALNT14 reduced the accumulation of endogenous reactive oxygen species (ROS) to exert its oncogenic function via O-glycosylating hnRNPUL1 to upregulate AKR1C2 expression. Meanwhile, GALNT14 expression was directly modulated by miR-125a.These findings indicated that GALNT14-mediated O-GalNAcylation could drive LUAD progression via eliminating ROS and might be a valuable therapeutic target.

由于糖基转移酶表达失调而导致的异常糖基化是癌细胞的一个普遍特征。N-乙酰半乳糖氨基转移酶-14（GALNT14）是启动O-GalNA酰化的关键酶。目前仍不清楚 GALNT14 是否以及如何影响肺腺癌（LUAD）。在此，我们通过检索公共数据库分析了 GALNT14 在 LUAD 中的表达情况，并通过检查临床样本进行了验证。生物信息学、LC-MS/MS、RNA-seq和RIP-seq分析被用来揭示GALNT14的作用机制。我们观察到，GALNT14在LUAD组织中经常过表达。GALNT14的高表达与TNM分期晚期、肿瘤体积增大和预后不良呈正相关。在功能上，GALNT14 在体外促进 LUAD 细胞增殖、迁移和侵袭，在体内加速肿瘤生长。从机理上讲，GALNT14通过O-糖基化hnRNPUL1上调AKR1C2的表达，减少内源性活性氧（ROS）的积累，从而发挥其致癌功能。这些研究结果表明，GALNT14介导的O-GalNAcylation可通过消除ROS驱动LUAD进展，可能是一个有价值的治疗靶点。

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引用次数: 0

Foxd3/SLC5A6 axis regulates apoptosis in LUAD cells by controlling mitochondrial biotin uptake Foxd3/SLC5A6轴通过控制线粒体生物素摄取调节LUAD细胞的凋亡。

IF 4.4 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2024-10-18 DOI: 10.1016/j.cellsig.2024.111473

Chong Zheng , Wenxuan Hu , Danni Wu , Ruiheng Chen , Chun Xu , Risheng Huang

Lung cancer remains one of the leading causes of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) accounting for over 85 % of cases. Lung adenocarcinoma (LUAD) is the most common subtype of NSCLC, and while targeted therapies and immune checkpoint inhibitors have improved outcomes, many patients exhibit resistance, necessitating the development of novel treatments. This study explores the role of the SLC5A6 gene, which encodes a sodium-dependent multivitamin transporter critical for mitochondrial function, in LUAD progression. We found that SLC5A6 is significantly upregulated in LUAD tissues and is associated with poor prognosis. Overexpression of SLC5A6 enhanced cell proliferation and migration, while knockout of SLC5A6 impaired these processes and induced apoptosis by disrupting mitochondrial function. Additionally, we identified Foxd3 as a key transcription factor regulating SLC5A6 expression. In vivo experiments demonstrated that SLC5A6 knockout effectively inhibited tumor growth. These findings suggest that SLC5A6 is a potential therapeutic target for LUAD, offering a new avenue for treatment strategies.

肺癌仍然是全球癌症相关死亡的主要原因之一，其中非小细胞肺癌（NSCLC）占 85% 以上。肺腺癌（LUAD）是 NSCLC 最常见的亚型，虽然靶向疗法和免疫检查点抑制剂改善了治疗效果，但许多患者表现出耐药性，因此有必要开发新型疗法。本研究探讨了编码对线粒体功能至关重要的钠依赖性多维生素转运体的 SLC5A6 基因在 LUAD 进展中的作用。我们发现，SLC5A6 在 LUAD 组织中明显上调，并与不良预后相关。过表达 SLC5A6 会增强细胞增殖和迁移，而敲除 SLC5A6 则会损害这些过程，并通过破坏线粒体功能诱导细胞凋亡。此外，我们还发现 Foxd3 是调控 SLC5A6 表达的关键转录因子。体内实验表明，敲除 SLC5A6 能有效抑制肿瘤生长。这些发现表明，SLC5A6是LUAD的潜在治疗靶点，为治疗策略提供了一条新途径。

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引用次数: 0

NSUN5 promotes tumorigenic phenotypes through the WNT signaling pathway and immunosuppression of CD8+ T cells in gastric cancer NSUN5 通过 WNT 信号通路和 CD8+ T 细胞的免疫抑制促进胃癌的致瘤表型。

IF 4.4 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2024-10-18 DOI: 10.1016/j.cellsig.2024.111475

Shuhao Liu , Yong Liu , Yijun Zhou , Gaoshui Xia , Haibo Liu , Yu Zeng , Zhihui Pei , Jing Cao , Guifang Jing , Hailin Zou , Chuanwen Liao

NSUN5, a key member of the M5C methylation family, plays a significant role in fundamental biological processes like cell proliferation and differentiation. However, its specific function and mechanisms in gastric cancer remain insufficiently understood. Initially, we examined NSUN5's differential expression in gastric cancer versus normal tissues, along with survival trends, associated signaling pathways, and immune infiltration using the TCGA database. Subsequently, we conducted immunohistochemistry experiments to assess NSUN5 expression in gastric cancer tissues. Gain-and loss-of-function experiments were carried out to investigate NSUN5's impact on the proliferation, stemness, and migratory capabilities of gastric cancer cells, as well as the expression of vital proteins in pertinent signaling pathways. Our findings demonstrate that NSUN5 is not only overexpressed in gastric cancer tissues, but also positively associated with tumor stage and inversely linked with patient prognosis. NSUN5 promotes the in vitro proliferation, stemness, and migration of gastric cancer cells, and the in vivo growth of these cells, chiefly through the activation of the WNT/β-catenin signaling pathway. Additionally, NSUN5 appears to diminish the infiltration of CD8+ T cells in gastric cancer, contributing to immune evasion. In conclusion, NSUN5 functions as a proto-oncogene in the progression of gastric cancer and may serve as a potential therapeutic target.

NSUN5是M5C甲基化家族的重要成员，在细胞增殖和分化等基本生物过程中发挥着重要作用。然而，人们对其在胃癌中的具体功能和作用机制仍不甚了解。最初，我们利用 TCGA 数据库研究了 NSUN5 在胃癌与正常组织中的差异表达，以及生存趋势、相关信号通路和免疫浸润。随后，我们进行了免疫组化实验来评估NSUN5在胃癌组织中的表达。我们还进行了功能增益和功能缺失实验，以研究 NSUN5 对胃癌细胞的增殖、干性和迁移能力的影响，以及相关信号通路中重要蛋白的表达。我们的研究结果表明，NSUN5 不仅在胃癌组织中过表达，而且与肿瘤分期呈正相关，与患者预后呈反相关。NSUN5 主要通过激活 WNT/β-catenin 信号通路，促进胃癌细胞的体外增殖、干性和迁移，并促进这些细胞的体内生长。此外，NSUN5 似乎还能减少胃癌中 CD8+ T 细胞的浸润，有助于免疫逃避。总之，NSUN5 在胃癌的进展过程中起着原癌基因的作用，可作为潜在的治疗靶点。

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引用次数: 0

Notch signaling in digestive system cancers: Roles and therapeutic prospects 消化系统癌症中的 Notch 信号：作用和治疗前景

IF 4.4 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2024-10-18 DOI: 10.1016/j.cellsig.2024.111476

Yingru Liu , Xinyu Gu , Mengjuan Xuan , Na Lou , Leiya Fu , Juan Li , Chen Xue

Digestive system cancers rank among the most prevalent malignant tumors, maintaining persistently high incidence and mortality rates. Notch signaling activity, often aberrant in esophageal, gastric, hepatic, pancreatic, and colorectal cancers, plays a pivotal role in the initiation, progression, and therapy resistance of these malignancies. As a highly conserved pathway, Notch signaling is integral to cell differentiation, survival, proliferation, stem cell renewal, development, and morphogenesis. Its dysregulation has been increasingly linked to various diseases, particularly digestive system cancers. In these malignancies, altered Notch signaling influences multiple biological processes, including cell proliferation, invasion, cell cycle progression, immune evasion, drug resistance, and stemness maintenance. Understanding the mechanisms of Notch signaling in digestive system cancers is essential for the development of novel targeted therapies. Numerous Notch pathway-targeting drugs are currently in preclinical studies, demonstrating promising efficacy both as monotherapies and in combination with conventional anti-cancer treatments. This review summarizes recent high-quality findings on the involvement of Notch signaling in digestive system cancers, focusing on the expression changes and pathological mechanisms of its dysregulated components. Special emphasis is placed on the potential of translating Notch-targeted approaches into therapeutic strategies, which hold promise for overcoming the limitations of existing treatments and improving the poor prognosis associated with these cancers.

消化系统癌症是发病率最高的恶性肿瘤之一，其发病率和死亡率一直居高不下。在食管癌、胃癌、肝癌、胰腺癌和结直肠癌中，Notch 信号活动常常出现异常，在这些恶性肿瘤的发生、发展和耐药性方面起着关键作用。作为一种高度保守的通路，Notch 信号转导是细胞分化、存活、增殖、干细胞更新、发育和形态发生不可或缺的组成部分。它的失调与各种疾病，尤其是消化系统癌症的关系日益密切。在这些恶性肿瘤中，Notch 信号的改变影响多种生物过程，包括细胞增殖、侵袭、细胞周期进展、免疫逃避、耐药性和干性维持。了解消化系统癌症中的Notch信号转导机制对于开发新型靶向疗法至关重要。目前，许多Notch通路靶向药物正在进行临床前研究，无论是作为单一疗法还是与传统抗癌疗法联合使用，都显示出良好的疗效。本综述总结了近期关于 Notch 信号参与消化系统癌症的高质量研究成果，重点关注其失调成分的表达变化和病理机制。文章特别强调了将Notch靶向方法转化为治疗策略的潜力，这些方法有望克服现有治疗方法的局限性并改善与这些癌症相关的不良预后。

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引用次数: 0

HKDC1 promotes autophagy and proliferation in pancreatic adenocarcinoma through interaction with PARP1 and poly(ADP-ribosyl)ation HKDC1 通过与 PARP1 和聚（ADP-核糖基）的相互作用促进胰腺癌的自噬和增殖。

IF 4.4 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2024-10-16 DOI: 10.1016/j.cellsig.2024.111474

Qiang Pang , Shansong Huang , Huiying Wang , Jiaqing Cao

Background

HKDC1 has been shown to play an important role in promoting malignant progression of pancreatic adenocarcinoma (PAAD), but the exact mechanism is unclear. This study aimed to investigate the function of HKDC1 in autophagy activation and cell proliferation.

Methods

By GSEA analysis of TCGA data of PAAD, we found that HKDC1 was closely associated with autophagy. We evaluated the effects of HKDC1 knockdown and overexpression on the expression of LC3B, an autophagy marker, and Cyclin D1 and PCNA, cell proliferation-associated proteins, by Western blotting (WB) and transmission electron microscopy (TEM) analysis.

Results

Knockdown of HKDC1 decreased LC3B expression and led to a decrease in the accumulation of autophagic vesicles and autophagic lysosomes, while overexpression of HKDC1 produced the opposite effect. Meanwhile, HKDC1 overexpression significantly promoted the proliferation of PAAD cells and increased the expression levels of Cyclin D1 and PCNA. Further studies showed that HKDC1 enhanced PARP1's own poly ADP-ribosylation (PARylation) activity by interacting with PARP1, which in turn promoted autophagy. In vivo experiments showed that knockdown of HKDC1 significantly inhibited the growth of pancreatic cancer cells in nude mice in vivo, reduced tumor volume and weight, and down-regulated the expression of PARP1, LC3, Cyclin D1 and PCNA.

Conclusion

HKDC1 plays a critical role in the malignant progression of PAAD by activating autophagy and promoting cell proliferation. Our findings suggest that targeting HKDC1 and its downstream signaling pathways may provide novel strategies for PAAD treatment.

背景：已有研究表明，HKDC1在促进胰腺腺癌（PAAD）恶性进展方面发挥着重要作用，但其确切机制尚不清楚。本研究旨在探讨HKDC1在自噬激活和细胞增殖中的功能：通过对 PAAD 的 TCGA 数据进行 GSEA 分析，我们发现 HKDC1 与自噬密切相关。我们通过Western印迹（WB）和透射电子显微镜（TEM）分析评估了HKDC1敲除和过表达对自噬标记物LC3B以及细胞增殖相关蛋白Cyclin D1和PCNA表达的影响：结果：敲除HKDC1会降低LC3B的表达，并导致自噬小泡和自噬溶酶体的积累减少，而过表达HKDC1则产生相反的效果。同时，过表达HKDC1能显著促进PAAD细胞的增殖，并增加细胞周期蛋白D1和PCNA的表达水平。进一步的研究表明，HKDC1通过与PARP1相互作用，增强了PARP1自身的多聚ADP-核糖基化（PARylation）活性，进而促进了自噬。体内实验表明，敲除 HKDC1 能显著抑制裸鼠体内胰腺癌细胞的生长，减少肿瘤体积和重量，并下调 PARP1、LC3、Cyclin D1 和 PCNA 的表达：结论：HKDC1通过激活自噬和促进细胞增殖，在PAAD的恶性进展过程中发挥着关键作用。我们的研究结果表明，靶向 HKDC1 及其下游信号通路可为 PAAD 治疗提供新策略。

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引用次数: 0

Glycolytic reprogramming in microglia: A potential therapeutic target for ischemic stroke 小胶质细胞中的糖酵解重编程：缺血性中风的潜在治疗靶点

IF 4.4 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2024-10-15 DOI: 10.1016/j.cellsig.2024.111466

Guangming Zhang , Anliu Zhao , Xiaolu Zhang , Miao Zeng , Huayuan Wei , Xu Yan , Jie Wang , Xijuan Jiang , Yongna Dai

Ischemic stroke is currently the second leading cause of mortality worldwide, with limited treatment options available. As resident immune cells, microglia promptly respond to cerebral ischemic injury, influencing neuroinflammatory damage and neurorepair. Studies suggest that microglia undergo metabolic reprogramming from mitochondrial oxidative phosphorylation to glycolysis in response to ischemia, significantly impacting their function during ischemic stroke. Therefore, this study aims to investigate the roles and regulatory mechanisms involved in this process, aiming to identify a new therapeutic target or potential drug candidate.

缺血性中风是目前全球第二大死亡原因，但可供选择的治疗方法却很有限。作为常驻免疫细胞，小胶质细胞会对脑缺血损伤做出迅速反应，影响神经炎症损伤和神经修复。研究表明，小胶质细胞在缺血时会发生新陈代谢重编程，从线粒体氧化磷酸化转变为糖酵解，从而显著影响其在缺血性卒中期间的功能。因此，本研究旨在探讨这一过程中的作用和调控机制，从而确定新的治疗靶点或潜在候选药物。

引用次数: 0

ARL8B promotes hepatocellular carcinoma progression and inhibits antitumor activity of lenvatinib via MAPK/ERK signaling by interacting with RAB2A ARL8B 与 RAB2A 相互作用，通过 MAPK/ERK 信号转导促进肝细胞癌的进展并抑制来伐替尼的抗肿瘤活性。

IF 4.4 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2024-10-15 DOI: 10.1016/j.cellsig.2024.111470

Mo-Mo Cao , Yi-Ming Li , Xiang Ding , Feng Fang , Lian-Yue Yang

Tumor recurrence and metastasis are important factors affecting postoperative survival in hepatocellular carcinoma (HCC) patients. ADP Ribosylation factor-like GTPase 8B (ARL8B) plays a crucial role in many biological processes, including lysosomal function, immune response, and cellular communication, all of which are related to the occurrence and development of tumors. However, its role in HCC remains unclear. Herein, we revealed that ARL8B is consistently elevated in HCC tissues compared to normal liver tissues, suggesting an unfavorable outcome in HCC patients. Increased ARL8B levels promoted the malignant phenotype of HCC in vitro and in vivo. Notably, ARL8B also induced epithelial-to-mesenchymal transition (EMT) in HCC cells. Mechanistically, the results of bioinformatics analysis combined with mass spectrometry revealed the potential downstream target molecule RAB2A of ARL8B. ARL8B directly interacted with RAB2A and increased the levels of GTP-bound RAB2A, thereby contributing to the activation of the extracellular signal-regulated kinase (ERK) signaling pathway. Interestingly, knockout of ARL8B in Hep3B cells enhanced the antitumor activity of lenvatinib in vitro and in vivo. Furthermore, AAV-shARL8B enhanced the inhibition of HCC growth through lenvatinib, providing new insights into its mechanism of action in lenvatinib-insensitive patients. In conclusion, ARL8B promotes the malignant phenotype of HCC and EMT via RAB2A mediated activation of the MAPK/ERK signaling pathway and is expected to be a valuable prognostic indicator and therapeutic target for HCC patients.

肿瘤复发和转移是影响肝细胞癌（HCC）患者术后生存的重要因素。ADP 核糖基化因子样 GTPase 8B（ARL8B）在溶酶体功能、免疫反应和细胞通讯等许多生物过程中发挥着至关重要的作用，所有这些过程都与肿瘤的发生和发展有关。然而，它在 HCC 中的作用仍不清楚。在本文中，我们发现与正常肝组织相比，ARL8B 在 HCC 组织中持续升高，这表明 HCC 患者的预后不利。ARL8B 水平的升高促进了 HCC 在体外和体内的恶性表型。值得注意的是，ARL8B 还能诱导 HCC 细胞的上皮细胞向间质转化（EMT）。从机理上讲，生物信息学分析结合质谱分析的结果揭示了ARL8B的潜在下游靶分子RAB2A。ARL8B直接与RAB2A相互作用，增加了GTP结合的RAB2A的水平，从而促进了细胞外信号调节激酶（ERK）信号通路的激活。有趣的是，在Hep3B细胞中敲除ARL8B能增强来伐替尼在体外和体内的抗肿瘤活性。此外，AAV-shARL8B通过来伐替尼增强了对HCC生长的抑制作用，这为来伐替尼不敏感患者了解其作用机制提供了新的视角。总之，ARL8B通过RAB2A介导的MAPK/ERK信号通路激活促进了HCC的恶性表型和EMT，有望成为HCC患者有价值的预后指标和治疗靶点。

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