更新于：2024-05-01

SLC39A8

solute carrier family 39 member 8

更新于：2024-05-01

基本信息

别名

BCG-induced integral membrane protein in monocyte clone 103 protein、BIGM103、LIV-1 subfamily of ZIP zinc transporter 6

+ [9]

简介

Electroneutral divalent metal cation:bicarbonate symporter of the plasma membrane mediating the cellular uptake of zinc and manganese, two divalent metal cations important for development, tissue homeostasis and immunity (PubMed:12504855, PubMed:22898811, PubMed:23403290, PubMed:29337306, PubMed:26637978, PubMed:29453449). Transports an electroneutral complex composed of a divalent metal cation and two bicarbonate anions or alternatively a bicarbonate and a selenite anion (PubMed:27166256, PubMed:31699897). Thereby, it also contributes to the cellular uptake of selenium, an essential trace metal and micronutrient (PubMed:27166256). Also imports cadmium a non-essential metal which is cytotoxic and carcinogenic (PubMed:27466201). May also transport iron and cobalt through membranes (PubMed:22898811). Through zinc import, indirectly regulates the metal-dependent transcription factor MTF1 and the expression of some metalloproteases involved in cartilage catabolism and also probably heart development (PubMed:29337306). Also indirectly regulates the expression of proteins involved in cell morphology and cytoskeleton organization (PubMed:29927450). Indirectly controls innate immune function and inflammatory response by regulating zinc cellular uptake which in turn modulates the expression of genes specific of these processes (PubMed:23403290, PubMed:28056086). Protects, for instance, cells from injury and death at the onset of inflammation (PubMed:18390834). By regulating zinc influx into monocytes also directly modulates their adhesion to endothelial cells and arteries (By similarity). Reclaims manganese from the bile at the apical membrane of hepatocytes, thereby regulating the activity of the manganese-dependent enzymes through the systemic levels of the nutrient (PubMed:28481222). Also participates in manganese reabsorption in the proximal tubule of the kidney (PubMed:26637978). By mediating the extracellular uptake of manganese by cells of the blood-brain barrier, may also play a role in the transport of the micronutrient to the brain (PubMed:26637978, PubMed:31699897). With manganese cellular uptake also participates in mitochondrial proper function (PubMed:29453449). Finally, also probably functions intracellularly, translocating zinc from lysosome to cytosol to indirectly enhance the expression of specific genes during TCR-mediated T cell activation (PubMed:19401385).

关联

100 项与 SLC39A8 相关的临床结果

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100 项与 SLC39A8 相关的转化医学

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0 项与 SLC39A8 相关的专利（医药）

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324

项与 SLC39A8 相关的文献（医药）

2024-02-23·Scientific reports

Comprehensive analyses of solute carrier family members identify SLC12A2 as a novel therapy target for colorectal cancer.

Article

作者: Dan-Yang Chen ; Yang-Yang Zhang ; Hai-Hang Nie ; Hai-Zhou Wang ; Pei-Shan Qiu ; Fan Wang ; Ya-Nan Peng ; Fei Xu ; Qiu Zhao ; Meng Zhang

As the largest transporter family impacting on tumor genesis and development, the prognostic value of solute carrier (SLC) members has not been elucidated in colorectal cancer (CRC). We aimed to identify a prognostic signature from the SLC members and comprehensively analyze their roles in CRC. Firstly, we downloaded transcriptome data and clinical information of CRC samples from GEO (GSE39582) and TCGA as training and testing dataset, respectively. We extracted the expression matrix of SLC genes and established a prognostic model by univariate and multivariate Cox regression. Afterwards, the low-risk and high-risk group were identified. Then, the differences of prognosis traits, transcriptome features, clinical characteristics, immune infiltration and drug sensitivity between the two groups were explored. Furthermore, molecular subtyping was also implemented by non-negative matrix factorization (NMF). Finally, we studied the expression of the screened SLC genes in CRC tumor tissues and normal tissues as well as investigated the role of SLC12A2 by loss of function and gain of function. As a result, we developed a prognostic risk model based on the screened 6-SLC genes (SLC39A8, SLC2A3, SLC39A13, SLC35B1, SLC4A3, SLC12A2). Both in the training and testing sets, CRC patients in the high-risk group had the poorer prognosis and were in the more advanced pathological stage. What's more, the high-risk group were enriched with CRC progression signatures and immune infiltration. Two groups showed different drug sensitivity. On the other hand, two distinct subclasses (C1 and C2) were identified based on the 6 SLC genes. CRC patients in the high-risk group and C1 subtype had a worse prognosis. Furthermore, we found and validated that SLC12A2 was steadily upregulated in CRC. A loss-of-function study showed that knockdown of SLC12A2 expression restrained proliferation and stemness of CRC cells while a gain-of-function study showed the contrary results. Hence, we provided a 6-SLC gene signature for prognosis prediction of CRC patients. At the same time, we identified that SLC12A2 could promote tumor progression in CRC, which may serve as a potential therapeutic target.

2024-02-12·Ecotoxicology and environmental safety

Zinc glycinate alleviates LPS-induced inflammation and intestinal barrier disruption in chicken embryos by regulating zinc homeostasis and TLR4/NF-κB pathway.

Article

作者: Chuanpi Xiao ; Luke Comer ; Xue Pan ; Nadia Everaert ; Martine Schroyen ; Zhigang Song

The effect of an immune challenge induced by a lipopolysaccharide (LPS) exposure on systemic zinc homeostasis and the modulation of zinc glycinate (Zn-Gly) was investigated using a chicken embryo model. 160 Arbor Acres broiler fertilized eggs were randomly divided into 4 groups: CON (control group, injected with saline), LPS (LPS group, injected with 32 µg of LPS saline solution), Zn-Gly (zinc glycinate group, injected with 80 µg of zinc glycinate saline solution) and Zn-Gly+LPS (zinc glycinate and LPS group, injected with the same content of zinc glycinate and LPS saline solution). Each treatment consisted of eight replicates of five eggs each. An in ovo feeding procedure was performed at 17.5 embryonic day and samples were collected after 12 hours. The results showed that Zn-Gly attenuated the effects of LPS challenge-induced upregulation of pro-inflammatory factor interleukin 1β (IL-1β) level (P =0.003). The LPS challenge mediated zinc transporter proteins and metallothionein (MT) to regulate systemic zinc homeostasis, with increased expression of the jejunum zinc export gene zinc transporter protein 1 (ZnT-1) and elevated expression of the import genes divalent metal transporter 1 (DMT1), Zrt- and Irt-like protein 3 (Zip3), Zip8 and Zip14 (P < 0.05). A similar trend could be observed for the zinc transporter genes in the liver, which for ZnT-1 mitigated by Zn-Gly supplementation (P =0.01). Liver MT gene expression was downregulated in response to the LPS challenge (P =0.004). These alterations caused by LPS resulted in decreased serum and liver zinc levels and increased small intestinal, muscle and tibial zinc levels. Zn-Gly reversed the elevated expression of the liver zinc finger protein A20 induced by the LPS challenge (P =0.025), while Zn-Gly reduced the gene expression of the pro-inflammatory factors IL-1β and IL-6, decreased toll-like receptor 4 (TLR4) and nuclear factor kappa-B p65 (NF-κB p65) (P < 0.05). Zn-Gly also alleviated the LPS-induced downregulation of the intestinal barrier gene Claudin-1. Thus, LPS exposure prompted the mobilization of zinc transporter proteins and MT to perform the remodeling of systemic zinc homeostasis, Zn-Gly participated in the regulation of zinc homeostasis and inhibited the production of pro-inflammatory factors through the TLR4/NF-κB pathway, attenuating the inflammatory response and intestinal barrier damage caused by an immune challenge.

2024-02-01·Free radical biology & medicine

Targeting ZIP8 mediated ferroptosis as a novel strategy to protect against the retinal pigment epithelial degeneration.

Article

作者: Ziling Liu ; Jianguo Huang ; Deshuang Li ; Chuanhe Zhang ; Huan Wan ; Bing Zeng ; Yao Tan ; Fuhua Zhong ; Hongxia Liao ; MuYun Liu ; Zhe-Sheng Chen ; Chang Zou ; Dongcheng Liu ; Bo Qin

The degeneration of retinal pigment epithelium (RPE) plays an important role in the development of age-related macular degeneration (AMD). However, the underlying mechanism remains elusive. In this study, we identified that ZIP8, a metal-ion transporter, plays a crucial role in the degeneration of RPE cells mediated by ferroptosis. ZIP8 was found to be upregulated in patients with AMD through transcriptome analysis. Upregulated ZIP8 was also observed in both oxidative-stressed RPE cells and AMD mouse model. Importantly, knockdown of ZIP8 significantly inhibited ferroptosis in RPE cells induced by sodium iodate-induced oxidative stress. Blocking ZIP8 with specific antibodies reversed RPE degeneration and restored retinal function, improving visual loss in a mouse model of NaIO₃-induced. Interestingly, the modification of the N-glycosylation sites N40, N72 and N88, but not N273, was essential for the intracellular iron accumulation mediated by ZIP8, which further led to increased lipid peroxidation and RPE death. These findings highlight the critical role of ZIP8 in RPE ferroptosis and provide a potential target for the treatment of diseases associated with retinal degeneration, including AMD.

项与 SLC39A8 相关的新闻（医药）

2024-04-05

·佰傲谷BioValley

肿瘤中的关键炎症通路

J Hematol Oncol.(一) 类花生酸(Eicosanoid)信号通路：二十烷基硫酸酯信号通路在生理过程和病理过程中都起着关键作用，通过类花生酸将炎症与癌症联系起来。二十碳多不饱和脂肪酸(PUFAs)是由20碳多不饱和脂肪酸(PUFAs)氧化而成的具有高度生物活性的衍生物，可通过环氧合酶(COX)、脂氧合酶(LOX)和细胞色素P450途径产生。COX途径产生前列腺素(PGs)和血栓素A(TXs)，而LOX途径则产生白三烯(LTs)和脂氧素(LXs)。COX信号通路COX家族中，COX-2的表达会受到早期炎症(proinflammatory)的上调，并被发现和调控多种肿瘤的进展相关。在炎症反应的早期阶段，COX-2衍生的PG被认为具有促炎功能。前列腺素D2、前列腺素E2、前列腺素F2α、前列腺素I2和血栓素A2是通过COX通路衍生的五种关键 PG。COX/PEG2COX-2/CSK3β信号还和上皮-间充质转化有关，通过抑制GSK3β来促进E-钙粘蛋白、β-连环蛋白和p120连环蛋白的蛋白质稳定性。抑制COX-2可以下调E-钙黏蛋白导致细胞死亡。PGE2通过其两种E-前列腺素受体EP2和EP4提供信号传导来塑造DC功能。EP4调节CD80、CD86、CD83、MHC II等激活标志物上调以及IL-10和IL-23的产生，引导cDC2成熟，促进T细胞扩增，形成抑制性而非促炎性T细胞群富集。PGE2还可能通过E2调节NK细胞合成IFN-γ来诱导免疫抑制，从而促进肿瘤的发生。肿瘤来源的前列腺素E2(PGE2)介导MDSC分化和获得促肿瘤特征。在PGE2暴露期间，EP2/4联合阻断M-MDSCs可防止这些抑制特征的发生。双重 EP2/EP4 PGE2受体拮抗剂增加了肿瘤微环境淋巴细胞浸润，并显着降低了多种肿瘤模型中的疾病负担。前列腺素D2则是COX-2的另一种代谢物，可能在慢性炎症和癌症中发挥双重作用。PGD2与其受体PTGDR2之间的相互作用抑制了胃癌细胞的自我更新，并减弱了胃癌的生长和转移。脂氧合酶(LOX)信号通路LOX通路负责将花生四烯酸代谢为白三烯，包括白三烯A4(LTA4)、LTB4和LTD4等。炎症细胞(包括白细胞、巨噬细胞和肥大细胞)是白三烯的主要来源。抑制LTB4受体可抑制炎症相关肿瘤的进展，LTD4则在肝细胞癌和慢性乙型肝炎患者的循环中上调。LOX途径主要包括5-LOX、12-LOX和15-LOX。5-LOX在上皮性癌和淋巴瘤中高度表达，具有促血管生成和促肿瘤活性。12-LOX通过激活整合素连接的激酶/NF-κB途径来促进肿瘤的生长。而15-LOX的代谢产物被发现能增强肿瘤相关炎症，既有促肿瘤作用又有抗肿瘤作用。另一种由LOX衍生的类花生酸脂毒素(lipoxins， LXs)则具有抗肿瘤作用。在前列腺癌中，LXA4通过抑制METTL3和或FPR2/IRF4途径，以促进巨噬细胞M2样极化。LXA4对炎性巨噬细胞极化的抑制作用与p-NF-κB p65和IRF5活性的下调有关，从而降低了LPS诱导的M1巨噬细胞通过FPR2/IRF5信号通路的表型和功能极化。 J Hematol Oncol.(二)JAK/STAT信号通路STAT3在炎症反应和肿瘤进展中发挥着广泛的作用。多种生长因子和细胞因子参与典型的STAT3通路，调节细胞分化、血管生成和肿瘤形成。IL-6和STAT3是启动肿瘤的肠上皮细胞生存和增殖所必需的。此外，在设计肠道的肿瘤如前列腺癌中，肠道生物失调增加了肠道通透性，肿瘤内的内毒素通过NF-κB/IL 6/STAT3轴促进了肿瘤的进展。Int Immunopharmacol.影响JAK/STAT通路的药物种类复杂，包括植物化学物质、合成药物和生物分子等等。Int Immunopharmacol.(三)金属代谢铁和ROS氧化还原铁代谢失调是肿瘤细胞的一个重要标志，在肿瘤细胞中，恶性肿瘤细胞需要大量的铁来生存和增殖。细胞色素P450酶、一氧化氮合酶、NADPH氧化酶和脂氧合酶等铁依赖性酶参与ROS的产生。同时，谷胱甘肽过氧化物酶GPX4是一种铁死亡的中枢抑制剂，GPX4利用还原性谷胱甘肽将活性的PUFA-PL-OOH还原为非活性和非致死性的PUFA-PL-OH。抑制Gpx4可通过诱导铁性死亡而增强治疗的抗肿瘤效应。十年铁死亡：双向调控与药物开发锌和NF-κB通路锌与许多炎症性细胞因子的产生和信号传递有关。当对应激刺激做出急性反应时，血浆锌浓度迅速下降。人体的锌代谢与ZIP8等锌转运蛋白的活性密切相关。在感染过程中，激活的NF-κB增加ZIP8的表达，ZIP8定位于细胞膜并调节锌的摄取。锌抑制了IKKβ的活性，从而减弱了炎症反应。参考文献：1.Wang M, Chen S, He X, Yuan Y, Wei X. Targeting inflammation as cancer therapy. J Hematol Oncol. 2024 Mar 22;17(1):13. doi: 10.1186/s13045-024-01528-7.2.Balamurugan K,et al.Stabilization of E-cadherin adhesions by COX-2/GSK3β signaling is a targetable pathway in metastatic breast cancer. JCI Insight. 2023 Mar 22;8(6):e156057. doi: 10.1172/jci.insight.156057.3.Cuenca-Escalona J,et al.PGE2-EP4 signaling steers cDC2 maturation toward the induction of suppressive T-cell responses. Eur J Immunol. 2024 Mar;54(3):e2350770. doi: 10.1002/eji.202350770.4.Francica BJ,et al.Dual Blockade of EP2 and EP4 Signaling is Required for Optimal Immune Activation and Antitumor Activity Against Prostaglandin-Expressing Tumors. Cancer Res Commun. 2023 Aug 8;3(8):1486-1500. doi: 10.1158/2767-9764.CRC-23-0249.5.Yuan J, et al. Lipoxin A4 regulates M1/M2 macrophage polarization via FPR2-IRF pathway. Inflammopharmacology. 2022 Apr;30(2):487-498. doi: 10.1007/s10787-022-00942-y.6.Wang Y,et al. Deciphering JAK/STAT signaling pathway: A multifaceted approach to tumorigenesis, progression and therapeutic interventions. Int Immunopharmacol. 2024 Mar 22;131:111846. doi: 10.1016/j.intimp.2024.111846.·····

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