Di-methylation of CD147-K234 Promotes the Progression of NSCLC by Enhancing Lactate Export

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CD147的研究进展

CD147分子是一种广泛表达于人体多种组织的跨膜糖蛋白,属于免疫球蛋白超家族。CD147在多种肿瘤细胞和组织中高表达,通过诱导基质金属蛋白酶(MMP)的分泌促进了肿瘤的浸润、转移。同时,CD147与炎症反应如类风湿性关节炎、动脉粥样硬化,以及细胞、组织的分化和发育等密切相关。简要综述了CD147参与的多种生理、病理过程。     

Soluble CD147 (BSG) as a Prognostic Marker in Multiple Myeloma

CD147 (basigin, BSG) is a membrane-bound glycoprotein involved in energy metabolism that plays a role in cancer cell survival. Its soluble form is a promising marker of some diseases, but it is otherwise poorly studied. CD147 is overexpressed in multiple myeloma (MM) and is known to affect MM progression, while its genetic variants are associated with MM survival. In the present study, we aimed to assess serum soluble CD147 (sCD147) expression as a potential marker in MM. We found that sCD147 level was higher in MM patients compared to healthy individuals. It was also higher in patients with more advanced disease (ISS III) compared to both patients with less advanced MM and healthy individuals, while its level was observed to drop after positive response to treatment. Patients with high sCD147 were characterized by worse progression-free survival. sCD147 level did not directly correlate with bone marrow CD147 mRNA expression. In conclusion, this study suggests that serum sCD147 may be a prognostic marker in MM.     

CD147 regulates melanoma metastasis via the NFAT1‐MMP‐9 pathway

Although accumulating evidence had revealed that NFAT1 has oncogenic characteristics, the role of this molecule in melanoma cells remains unclear. Previous studies proved that CD147 plays a crucial function in melanoma cell metastasis and invasion through matrix metalloproteinase 9 (MMP‐9) expression; however, the details of how CD147 regulates MMP‐9 expression remain elusive. In this study, we demonstrated that CD147 and NFAT1 are overexpressed in the tissues of patients with primary and metastatic melanoma, which has shown a positive correlation. Further, we observed that CD147 regulates NFAT1 activation through the [Ca²⁺]i‐calcineurin pathway. Knockdown of NFAT1 significantly suppresses melanoma metastasis, and we demonstrated that CD147 affects melanoma metastasis in an NFAT1‐dependent manner. Moreover, we verified that NFAT1 directly binds to MMP‐9 promoter. Inhibition of CD147 expression significantly abrogates MMP‐9 promoter luciferase gene reporter activity as well as NFAT1 association with MMP‐9 promoter. Taken together, this study demonstrated that CD147 affects MMP‐9 expression through regulating NFAT1 activity and provided a novel mechanism by which NFAT1 contributes to melanoma metastasis through the regulation of MMP‐9.     

CD147在肿瘤发展和组织修复中的作用

CD147是一种广泛存在于细胞表面的糖蛋白,参与机体多种生理和病理的过程。CD147已被证实是一种在肿瘤细胞中高度表达的胞膜监视分子．能刺激肿瘤细胞周围的成纤维细胞及肿瘤细胞产生基质金属蛋白酶（matrix metalloproteinase,MMP）。正常组织中CD147的出现和调节也伴随着MMP表达的升高。这一现象提示,CD147介导的MMP诱导作用是非肿瘤生理或病理状态下的一种常见调节机制。该文介绍在各种生理和病理状态下,CD147的不同调节机制。     

癌相关分子CD147与肝癌靶向治疗

CD147是一种在肝癌细胞膜表面高表达的跨膜糖蛋白,能够调节肝癌细胞生长、诱导基质金属蛋白酶（matrix metalloprotei-nase,MMP）分泌、促进肝癌细胞侵袭和转移,并且参与肝癌血管生长和耐药性形成。以CD147为靶点的单克隆抗体治疗肝癌具有显著疗效。本文就肝癌细胞CD147的分子特点、功能与机理以及针对CD147的靶向治疗等方面研究进展作较全面的综述。     

miR-29b induces SOCS-1 expression by promoter demethylation and negatively regulates migration of multiple myeloma and endothelial cells

Epigenetic silencing of tumor suppressor genes frequently occurs and may account for their inactivation in cancer cells. We previously demonstrated that miR-29b is a tumor suppressor microRNA (miRNA) that targets de novo DNA methyltransferases and reduces the global DNA methylation of multiple myeloma (MM) cells. Here, we provide evidence that epigenetic activity of miR-29b leads to promoter demethylation of suppressor of cytokine signaling-1 (SOCS-1), a hypermethylated tumor suppressor gene. Enforced expression of synthetic miR-29b mimics in MM cell lines resulted in SOCS-1 gene promoter demethylation, as assessed by Sequenom MassARRAY EpiTYPER analysis, and SOCS-1 protein upregulation. miR-29b-induced SOCS-1 demethylation was associated with reduced STAT3 phosphorylation and impaired NFκB activity. Downregulation of VEGF-A and IL-8 mRNAs could be detected in MM cells transfected with miR-29b mimics as well as in endothelial (HUVEC) or stromal (HS-5) cells treated with conditioned medium from miR-29b-transfected MM cells. Notably, enforced expression of miR-29b mimics increased adhesion of MM cells to HS-5 and reduced migration of both MM and HUVEC cells. These findings suggest that miR-29b is a negative regulator of either MM or endothelial cell migration. Finally, the proteasome inhibitor bortezomib, which induces the expression of miR-29b, decreased global DNA methylation by a miR-29b-dependent mechanism and induced SOCS-1 promoter demethylation and protein upregulation. In conclusion, our data indicate that miR-29b is endowed with epigenetic activity and mediates previously unknown functions of bortezomib in MM cells.     

EEN regulates the proliferation and survival of multiple myeloma cells by potentiating IGF-1 secretion

The molecular mechanisms of multiple myeloma are not well defined. EEN is an endocytosis-regulating molecule. Here we report that EEN regulates the proliferation and survival of multiple myeloma cells, by regulating IGF-1 secretion. In the present study, we observed that EEN expression paralleled with cell proliferation, EEN accelerated cell proliferation, facilitated cell cycle transition from G1 to S phase by regulating cyclin-dependent kinases (CDKs) pathway, and delayed cell apoptosis via Bcl2/Bax-mitochondrial pathway. Mechanistically, we found that EEN was indispensable for insulin-like growth factor-1 (IGF-1) secretion and the activation of protein kinase B-mammalian target of rapamycin (Akt-mTOR) pathway. Exogenous IGF-1 overcame the phenotype of EEN depletion, while IGF-1 neutralization overcame that of EEN over-expression. Collectively, these data suggest that EEN may play a pivotal role in excessive cell proliferation and insufficient cell apoptosis of bone marrow plasma cells in multiple myeloma. Therefore, EEN may represent a potential diagnostic marker or therapeutic target for multiple myeloma.     

PD-L1和CD147在口腔鳞癌中的表达与临床意义

目的:探讨口腔鳞癌组织中免疫共刺激分子PD-L1与细胞外基质蛋白酶诱导因子CD147的表达、两者的相关性及临床意义。方法:应用免疫组化技术检测66例口腔鳞癌组织及36例正常口腔黏膜组织中PD-L1和CD147的表达,分析PD-L1、CD147表达的相关性及二者与口腔鳞癌临床病理参数的关系。结果:PD-L1在口腔鳞癌组织中表达阳性率为68.18%(45/66),正常口腔黏膜组织中表达阳性率仅为16.67%(6/36);CD147在口腔鳞癌组织中表达阳性率为74.24%(49/66),明显高于其在正常口腔黏膜组织中的表达13.88%(5/36)。PD-L1和CD147两者在口腔鳞癌组织中阳性表达率与口腔黏膜组织相比均明显升高(P0.01)。统计学分析显示,PD-L1和CD147在口腔鳞癌组织中的高表达与患者的性别年龄、吸烟史及肿瘤的体积等因素无明显相关,但与TNM分期及鳞癌的组织分化程度紧密相关。口腔鳞癌组织中PD-L1与CD147两者相关性分析r=0.342,P值小于0.01,说明二者的表达呈显著正相关。结论:口腔鳞癌组织中PD-L1与CD147均呈高表达,并且二者的过度表达可能与口腔鳞癌的发生、发展关系密切,合并检测二者可能为OSCC的诊疗及预后指明新的方向,为口腔鳞癌的靶向治疗提供新的靶点。     

CD147 is tightly associated with lactate transporters MCT1 and MCT4 and facilitates their cell surface expression

CD147 is a broadly expressed plasma membrane glycoprotein containing two immunoglobulin-like domains and a single charge-containing transmembrane domain. Here we use co-immunoprecipitation and chemical cross-linking to demonstrate that CD147 specifically interacts with MCT1 and MCT4, two members of the proton-linked monocarboxylate (lactate) transporter family that play a fundamental role in metabolism, but not with MCT2. Studies with a CD2-CD147 chimera implicate the transmembrane and cytoplasmic domains of CD147 in this interaction. In heart cells, CD147 and MCT1 co-localize, concentrating at the t-tubular and intercalated disk regions. In mammalian cell lines, expression is uniform but cross-linking with anti-CD147 antibodies caused MCT1, MCT4 and CD147, but not GLUT1 or MCT2, to redistribute together into 'caps'. In MCT-transfected cells, expressed protein accumulated in a perinuclear compartment, whereas co-transfection with CD147 enabled expression of active MCT1 or MCT4, but not MCT2, in the plasma membrane. We conclude that CD147 facilitates proper expression of MCT1 and MCT4 at the cell surface, where they remain tightly bound to each other. This association may also be important in determining their activity and location.     

人成骨肉瘤细胞CD147基因编码区的克隆和序列测定

克隆人成骨肉瘤细胞CD147基因编码区并进行序列测定。以人成骨肉瘤细胞系MG63的mRNA为模板,采用RT-PCR方法得到人CD147的编码区cDNA,克隆至载体pcDNA3．1( )中,酶切鉴定后进行序列分析。结果获得人CD147编码区基因和重组质粒pcDNA3．1( )／asCD147,并经DNA序列分析证实其序列和献报道一致。以上结果证明了CD147在成骨肉瘤细胞中也有表达,为进一步进行其结构和功能研究打下了基础。     

CD147与亲环蛋白的相互作用

CD147是一种属于免疫球蛋白超家族的跨膜糖蛋白,可参与多种生理和病理过程,在组织重构、精子发生、神经形成及肿瘤转移等过程中发挥作用,其高表达于某些免疫细胞和肿瘤细胞表面,作为受体可与亲环蛋白(Cyp)结合。Cyp遍布于原核及真核生物中,在人类正常和肿瘤组织中,均可发现亲环蛋白。CypA和CypB这两种亲环蛋白家族中最丰富的成员,在细胞内和细胞外均可发挥重要作用。亲环蛋白与CD147的相互作用在炎症性疾病、心血管疾病及肿瘤的发生发展中具有重要意义,本文对CD147和亲环蛋白这两种蛋白质及其相互作用的研究进展和前景做一综述。     

Lack of evidence for caveolin-1 and CD147 interaction before and after bleomycin-induced lung injury

Immunohistochemical and in vitro studies indicate that caveolin-1, which occurs abundantly in alveolar epithelial type I cells and microvascular endothelial cells of the lung, is selectively downregulated in the alveolar epithelium following exposure to bleomycin. Bleomycin is also known to enhance the expression levels of metalloproteinases and of the metalloproteinase inducer CD147/EMMPRIN in lung cells. Experimental in vitro data has showed that MMP-inducing activity of CD147 is under the control of caveolin-1. We studied the effects of bleomycin on the expression of caveolin-1, CD147 and metalloproteinases using an alveolar epithelial rat cell line R3/1 with properties of both alveolar type I and type II cells and explanted rat lung slices. In parallel, retrospective samples of bleomycin-induced fibrosis in rats and mice as well as samples of wild type and caveolin-1 knockout animals were included for immunohistochemical comparison with in vitro data. Here we report that treatment with bleomycin downregulates caveolin-1 and increases CD147 and MMP-2 and -9 expression/activity in R3/1 cells using RT-PCR, Western blot analysis, MMP-2 activity assay and immunocytochemistry. Immunofluorescence double labeling revealed that caveolin-1 and CD147 were not colocalized in vitro. The in vitro findings were confirmed through immunohistochemical studies of the proteins in paraffin embedded precision-cut rat lung slices and in fibrotic rat lung tissues. The caveolin-1-negative hyperplastic ATII cells exhibited enhanced immunoreactivity for CD147 and MMP-2. Caveolin-1-negative ATI cells of fibrotic samples were mostly CD147 negative. There were no differences in the pulmonary expression of CD147 between the normal and caveolin-1 deficient animals. The results demonstrate that bleomycin-induced lung injury is associated with an increase in CD147 expression and MMP activity, particularly in alveolar epithelial cells. In addition, our data exclude any functional interaction between CD147 and alveolar epithelial caveolin-1.     

LncRNA HOXB-AS1 promotes cell growth in multiple myeloma via FUT4 mRNA stability by ELAVL1

Multiple myeloma (MM) is defined as the second most common hematological tumor in the globe. Long noncoding RNAs (lncRNAs) have been reported to play stimulative or suppressive role in the progression of different carcinomas. The investigation of lncRNAs in MM is still inadequate. LncRNA HOXB cluster antisense RNA 1 (HOXB-AS1) was once revealed to facilitate glioma progression by affecting cellular activities of glioma cells. However, whether HOXB-AS1 participates in the development of MM still remains an enigma. In this study, we unveiled that HOXB-AS1 was highly expressed in MM and loss-of-function assays certified that HOXB-AS1 obstruction suppressed MM cell proliferation, and stimulated cell apoptosis. In addition, HOXB-AS1 could modulate fucosyltransferase 4 (FUT4) and FUT4-mediated Wnt/β-catenin pathway. In subsequence, it was observed from mechanism assays that HOXB-AS1 enhanced the interaction between ELAVL1 and FUT4 so as to stabilize FUT4 messenger RNA. In the end, rescue experiments affirmed that HOXB-AS1 affected the cell growth through FUT4 in MM. In conclusion, the whole modulation mechanism of HOXB-AS1/ELAVL1/FUT4 axis in MM was validated in this study, which suggested that HOXB-AS1 might function as a powerful and promising therapeutic biomarker for the clinical treatment of patients with MM.     

CD147相互作用蛋白及其细胞生物学功能

CD147（basigin、EMMPRIN、neurothelin、M6、HAb18G等）是一个跨膜糖蛋白家族,广泛表达于各种上皮细胞,但其表达在大鼠、小鼠、鸡和人等不同种属间存在很大差异性。CD147高表达于上皮来源的肿瘤细胞表面,如肺癌、乳腺癌和肝癌等。CD147抗原胞外段有2个IgSF结构域,跨膜区有一个带电谷氨酸（GIu）残基,胞内段含有40个氨基酸。CD147的结构特点提示其可能参与蛋白-蛋白相互作用。由于CD147分子的3D结构信息还没有获得,与其相互作用的分子还没有完全明确,但近来应用黏附、免疫共沉淀等实验方法,一些研究报道提示,CD147可与整合素（integrin）、环亲合素（cyclophilins）、单羧酸转运器（monocarboxylate transporter,MCT）等蛋白相互作用,而这些蛋白可能作为CD147分子的候选配体或受体,通过蛋白-蛋白相互作用,介导广泛的上皮细胞生物学功能。     

CD147 stimulates HIV-1 infection in a signal-independent fashion

CD147 is a type I transmembrane protein previously identified as a signal transducing receptor for extracellular cyclophilins. CD147-expressing cells exhibit a characteristic activation of extracellular-signal regulated kinase 1 and 2 (ERK1/2) in response to stimulation with cyclophilin A (CypA). CD147 was also shown to enhance HIV-1 infection in a CypA-dependent fashion, but the role of signaling in this activity of CD147 has not been investigated. In this report, we demonstrate that neither mutations incapacitating signaling response of CD147 to CypA stimulation, nor inhibitor of ERK activation, reduced susceptibility of cells to HIV-1 infection. Surprisingly, truncation of the cytoplasmic tail of CD147 did not abolish signaling response to CypA, but reduced infection by HIV-1 to the level observed in control cells. These results indicate that CD147 enhances HIV-1 replication in a signaling-independent fashion through specific events mediated by the cytoplasmic domain of the protein.     

Blocking CD147 induces cell death in cancer cells through impairment of glycolytic energy metabolism

CD147 is a multifunctional transmembrane protein and promotes cancer progression. We found that the anti-human CD147 mouse monoclonal antibody MEM-M6/1 strongly induces necrosis-like cell death in LoVo, HT-29, WiDr, and SW620 colon cancer cells and A2058 melanoma cells, but not in WI-38 and TIG-113 normal fibroblasts. Silencing or overexpression of CD147 in LoVo cells enhanced or decreased the MEM-M6/1 induced cell death, respectively. CD147 is known to form complex with proton-linked monocarboxylate transporters (MCTs), which is critical for lactate transport and intracellular pH (pHi) homeostasis. In LoVo cells, CD147 and MCT-1 co-localized on the cell surface, and MEM-M6/1 inhibited the association of these molecules. MEM-M6/1 inhibited lactate uptake, lactate release, and reduced pHi. Further, the induction of acidification was parallel to the decrease of the glycolytic flux and intracellular ATP levels. These effects were not found in the normal fibroblasts. As cancer cells depend on glycolysis for their energy production, CD147 inhibition might induce cell death specific to cancer cells.