Downregulation of Astrocyte Elevated Gene-1 Expression Combined with All-Trans Retinoic Acid Inhibits Development of Vasculogenic Mimicry and Angiogenesis in Glioma

Objective This study aimed to investigate the effects of downregulating astrocyte elevated gene-1(AEG-1)expression combined with all-trans retinoic acid(ATRA)on vasculogenic mimicry(VM)formation and angiogenesis in glioma.Methods U87 glioma cells were transfected with AEG-1 shRNA lentiviral vectors(U87-siAEG-1)and incubated in a medium containing 20µmol/L ATRA.Matrigel-based tube formation assay was performed to evaluate VM formation,and the cell counting kit-8(CCK-8)assay was used to analyze the proliferation of glioma cells in vitro.Reverse transcription-quantitative polymerase chain reaction and Western blot analysis were used to investigate the mRNA and protein expression of related genes,respectively.Glioma xenograft models were generated via subcutaneous implantation of glioma cells in nude mice.Tumor-bearing mice received an intraperitoneal injection of ATRA(10 mg/kg per day).Immunohistochemistry was used to evaluate the expression of related genes and the microvessel density(MVD)in glioma xenograft models.CD34/periodic acid-Schiff double staining was performed to detect VM channels in vivo.The volume and weight of tumors were measured,and a tumor growth curve was drawn to evaluate tumor growth.Results A combination of ATRA intervention and downregulation of AEG-1 expression significantly inhibited the proliferation of glioma cells in vitro and glioma VM formation in vitro and in vivo.It also significantly decreased MVD and inhibited tumor growth.Further,the expression levels of matrix metalloproteinase(MMP)-2,MMP-9,vascular endothelial-cadherin(VE-cadherin),and vascular endothelial growth factor(VEGF)in glioma significantly decreased in vivo and in vivo.Conclusion Hence,a combinatorial approach might be effective in treating glioma through regulating MMP-2,MMP-9,VEGF,and VE-cadherin expression.

Metadherin-driven promotion of cancer stem cell phenotypes and its effect on immunity in hepatocellular carcinoma

In this editorial we provide commentary on the article published by Wang et al,featured in the recent issue of the World Journal of Gastroenterology in 2024.We focus on the metadherin(MTDH),also known as astrocyte elevated gene-1 or lysine rich CEACAM1,and its effects on cancer stem cells(CSCs)and immunity in hepatocellular carcinoma(HCC).HCC is the most common primary liver cancer and one of the leading causes of cancer-related deaths worldwide.Most HCC cases develop in the context of liver cirrhosis.Among the pivotal mechanisms of carcinogenesis are gene mutations,dysregulation of diverse signaling pathways,epigenetic alterations,hepatitis B virus-induced hepatocarcinogenesis,chronic inflammation,impact of tumor microenvironment,oxidative stress.Over the years,extensive research has been conducted on the MTDH role in various tumor pathologies,such as lung,breast,ovarian,gastric,hepatocellular,colorectal,renal carcinoma,neuroblastoma,melanoma,and leukemias.Specifically,its involvement in tumor development processes including transformation,apoptosis evasion,angiogenesis,invasion,and metastasis via multiple signaling pathways.It has been demonstrated that knockdown or knockout of MTDH disrupt tumor development and metastasis.In addition,numerous reports have been carried out regarding the MTDH influence on HCC,demonstrating its role as a predictor of poor prognosis,aggressive tumor phenotypes prone to metastasis and recurrence,and exhibiting significant potential for therapy resistance.Finally,more studies finely investigated the influence of MTDH on CSCs.The CSCs are a small subpopulation of tumor cells that sharing traits with normal stem cells like self-renewal and differentiation abilities,alongside a high plasticity that alters their phenotype.Beyond their presumed role in tumor initiation,they can drive also disease relapse,metastasis,and resistance to chemo and radiotherapy.

Astrocyte elevated gene-1 induces breast cancer proliferation and invasion through upregulating HER2/neu expression

Background Astrocyte elevated gene-1 （AEG-1）, primarily identified as a late response gene induced by HIV-1 infection, plays multiple roles in the process of oncogenesis. This novel gene has been demonstrated to be involved in the several potent carcinogenic pathways, including PI3K/Akt pathway, nuclear factor （NF）-KB pathway, and Wnt/13-catenin pathway. Although the function of AEG-1 has been intensively investigated in recent years, the molecular mechanism underlying its oncogenic role is largely unknown. The aim of this research was to explore the potential function of AEG-1 in breast cancer development and progression. Methods AEG-1 was ectopically overexpressed in breast cancer MCF-7 cells and its biological effects on the proliferation and invasion of MCF-7 cells were studied by 3-（4,5-dimethylthiazol-2-yl）-2,5-diphenyltetrazolium bromide （MTT） and invasion assays. The expression of HER2/neu, a crucial oncogene involving in breast cancer carcinogenesis, was also determined. Results Overexpression of the AEG-1 promoted the proliferation and invasion ability of breast cancer cells, and upregulated the expression of HER2/neu, a crucial oncogene involving in breast cancer carcinogenesis. Conclusion AEG-1 might facilitate the proliferation and invasion of breast cancer cells by upregulating HER2/neu expression, which provides a potential target for breast cancer therapy.

AEG-1 participates in high glucose-induced activation of Rho kinase and epithelial-mesenchymal transition in proximal tubular epithelial cells

Objective:To prove whether astrocyte elevated gene-1(AEG-1) plays a role in high glucosestimulated Rho kinase activation and epithelial-mesenchymal transition(EMT) in human renal tubular epithelial(HK-2) cells.Methods:The protein levels of AEG-1,alpha-smooth muscle actin,E-cadherin and MYPT1 were determined by Western blot.Results:AEG-1 protein level was upregulated in HK-2 cells stimulated with high glucose.AEG-1 siRNA downregulated Rho kinase protein expression and blocked high glucose-induced EMT.Conclusions:Our results show that AEG-1 acts a key role in high glucoseinduced activation of Rho kinase and EMT in HK-2 cells.

AEG-1和SKA3在甲状腺微小乳头状癌组织中的表达及临床意义

目的探讨星形细胞上调基因-1(AEG-1)和纺锤体与着丝粒相关蛋白3(SKA3)的表达与甲状腺微小乳头状癌(PTMC)临床病理特征和预后的关系。方法收集2015年5月至2016年8月经病理学检查确诊的92例PTMC患者的癌组织及对应癌旁组织石蜡标本。采用免疫组化SP法检测组织标本中AEG-1和SKA3的表达,并分析其表达与PTMC临床病理特征的关系;采用Kaplan-Meier法分析AEG-1、SKA3表达与患者无复发生存时间(RFS)的关系,采用Cox比例风险模型分析影响PTMC患者RFS的因素。结果AEG-1在癌旁组织和PTMC组织中的阳性表达率分别为17.4%(16/92)和72.8%(67/92),差异有统计学意义(P=0.000);SKA3在癌旁组织中的阳性表达率为15.2%(14/92),在PTMC组织中为66.3%(61/92),差异有统计学意义(P=0.000)。AEG-1蛋白表达与临床分期、淋巴结转移和腺外侵犯有关(P<0.05);SKA3蛋白表达与临床分期和淋巴结转移有关(P<0.05)。Spearman等级相关分析显示,PTMC组织中AEG-1和SKA3蛋白表达呈正相关(r=0.489,P=0.025)。Kaplan-Meier生存分析显示,AEG-1阳性表达者的1、3、5年无复发生存率分别为98.5%、92.5%、83.6%,低于AEG-1阴性表达者的100.0%、96.0%和92.0%,两组比较差异有统计学意义(P=0.046)。SKA3阳性表达者的1、3、5年无复发生存率为98.4%、90.2%、80.3%,低于SKA3阴性表达者的100.0%、96.8%、96.8%,两组比较差异有统计学意义(P=0.032)。Cox多因素分析结果显示,临床分期、淋巴结转移、AEG-1和SKA3表达是影响PTMC患者RFS的独立因素(P<0.05)。结论PTMC组织中AEG-1、SKA3表达水平升高,AEG-1表达与临床分期、淋巴结转移和腺外侵犯有关,SKA3表达与临床分期和淋巴结转移有关,二者均为PTMC患者预后不良的影响因素。

Inhibition of osteosarcoma growth and metastasis using a polysaccharide derivative of Amy-g-PLLD for the delivery of AEG-1 siRNA

Osteosarcoma is the most common primary malignant neoplasm of the bone in children and adolescents and has a high risk of relapse and metastasis. Of the various methods to treat osteosarcoma, the use of genetic approaches to inhibit the rapid growth of osteosarcoma while limiting tumor metastasis has presented a challenge in its implementation. Here, we successfully synthesized a polysaccharide derivative （Amy-g-PLLD） for delivery of astrocyte elevated gene-1 （AEG-1） small-interfering RNA （siRNA） （siAEG-1）, and used it for the first time to suppress osteosarcoma tumors in vitro and in vivo. Amy-g-PLLD/ siAEG-1 complexes were delivered into 143B human osteosarcoma cells with low resultant cytotoxicity. Osteosarcoma tumor proliferation and invasion were inhibited in vitro. Intratumoral injection of Amy-g-PLLD/siAEG-1 complexes markedly inhibited tumor growth and lung metastasis in 143B tumor-bearing mice. This biocompatible and effective approach employing a natural material- siRNA complex should pave the way for more genetic research in treating osteosarcoma.