Abstract
Tumor breakthrough is driven by genetic or epigenetic variations which assist in initiation, migration, invasion and metastasis of tumors. Astrocyte elevated gene-1 (AEG-1) protein has risen recently as the crucial factor in malignancies and plays a potential role in diverse complex oncogenic signaling cascades. AEG-1 has multiple roles in tumor growth and development and is found to be involved in various signaling pathways of: (i) Ha-ras and PI3K/AKT; (ii) the NF-κB; (iii) the ERK or mitogen-activated protein kinase and Wnt or β-catenin and (iv) the Aurora-A kinase. Recent studies have confirmed that in all the hallmarks of cancers, AEG-1 plays a key functionality including progression, transformation, sustained angiogenesis, evading apoptosis, and invasion and metastasis. Clinical studies have supported that AEG-1 is actively intricated in tumor growth and progression which includes esophageal squamous cell, gastric, colorectal, hepatocellular, gallbladder, breast, prostate and non-small cell lung cancers, as well as renal cell carcinomas, melanoma, glioma, neuroblastoma and osteosarcoma. Existing studies have reported that AEG-1 expression has been induced by Ha-ras through intrication of PI3K/AKT signaling. Conversely, AEG-1 also activates PI3K/AKT pathway and modulates the defined subset of downstream target proteins via crosstalk between the PI3K/AKT/mTOR and Hedgehog signaling cascade which further plays a crucial role in metastasis. Thus, AEG-1 may be employed as a biomarker to discern the patients of those who are likely to get aid from AEG-1-targeted medication. AEG-1 may play as an effective target to repress tumor development, occlude metastasis, and magnify the effectiveness of treatments. In this review, we focus on the molecular mechanism of AEG-1 in the process of carcinogenesis and its involvement in regulation of crosstalk between the PI3K/AKT/mTOR and Hedgehog signaling. We also highlight the multifaceted functions, expression, clinicopathological significance and molecular inhibitors of AEG-1 in various cancer types.
Highlights
In humans is encoded by gene metadherin (MTDH); mapped in chromosome 8q22 is a prime oncogene, constituting about 528 amino acids, two nuclear localization sequences, an N terminal transmembrane region, a possible ATP or GTP-binding site and several putative phosphorylation sites [1], which is markedly overexpressed in several cancer types [2] as in esophageal squamous cell (ESCC) [3], gastric [4], colorectal [5], hepatocellular (HCC) [6,7], breast [8], prostate [9] and osteosarcoma [10]
AEG-1that helps in progression and development these cancers, andosteosarcoma further, it was Astrocyte elevated gene-1 (AEG-1) is nethe progression and development of these cancers, and further, it was found that AEG-1 cessitate in tissue proliferation, angiogenesis, invasion, metastasis and in reducing chemois necessitate in tissue proliferation, angiogenesis, invasion, metastasis and in reducing and radio-resistance
The predominant role of AEG-1 in controlling signaling pathways of several cancers displays that it has a major role in cancer progression and metastasis
Summary
Oncogene Ha-ras works in the background for activation of AEG-1 chemo- and radio-resistance. PI3K/AKT, which leads to AEG-1 transcriptional upregulation by c-Myc [11]. AEG-1 through PI3K/AKT, which leads to AEG-1 transcriptional upregulation by c-Myc. Once the is overexpressed, it can trigger diverse oncogenic in[11]. PI3K/AKT signaling, a pathway that controls the expression of several genes intricated signaling, a pathway that controls the expression of several genes intricated in cancer cell in cancer proliferation, cell survival, proliferation, and [11]. MTDH expression through the activation of PI3K/AKT pathway, which phosphorylates creases. PI3K/AKTand pathway, phosphorylates and and inactivates and subsequently elevates theofstabilization bindingwhich of c-Myc to the MTDH promoter. GSK-3β and can subsequently elevates and binding c-Mycproto the MTDH liferation, survival, and activate invasion.AKT, Solid arrows activation, bar-headed arrows indicate proliferation, inpromoter. Bar-headed arrows indicate inhibition and dotted arrows indicate probable mechanism of action) [17]
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