Astrocyte elevated gene-1 regulates hepatocellular carcinoma development and progression

Abstract

Hepatocellular carcinoma (HCC) is a highly aggressive vascular cancer characterized by diverse etiology, activation of multiple signal transduction pathways, and various gene mutations. Here, we have determined a specific role for astrocyte elevated gene-1 (AEG1) in HCC pathogenesis. Expression of AEG1 was extremely low in human hepatocytes, but its levels were significantly increased in human HCC. Stable overexpression of AEG1 converted nontumorigenic human HCC cells into highly aggressive vascular tumors, and inhibition of AEG1 abrogated tumorigenesis by aggressive HCC cells in a xenograft model of nude mice. In human HCC, AEG1 overexpression was associated with elevated copy numbers. Microarray analysis revealed that AEG1 modulated the expression of genes associated with invasion, metastasis, chemoresistance, angiogenesis, and senescence. AEG1 also was found to activate Wnt/β-catenin signaling via ERK42/44 activation and upregulated lymphoidenhancing factor 1/T cell factor 1 (LEF1/TCF1), the ultimate executor of the Wnt pathway, important for HCC progression. Inhibition studies further demonstrated that activation of Wnt signaling played a key role in mediating AEG1 function. AEG1 also activated the NF-κB pathway, which may play a role in the chronic inflammatory changes preceding HCC development. These data indicate that AEG1 plays a central role in regulating diverse aspects of HCC pathogenesis. Targeted inhibition of AEG1 might lead to the shutdown of key elemental characteristics of HCC and could lead to an effective therapeutic strategy for HCC.

Establishment and Characterization of MTDH Knockdown by Artificial Micro RNA Interference - Functions as a Potential Tumor Suppressor in Breast Cancer

“…Moreover, the expression of MTDH increases in malignant glioma and MTDH regulates in vitro invasion and migration of malignant glioma cells by activating the nuclear NF-kappaB signaling pathway (Sarkar et al, 2008). In addition, MTDH was also found to activate Wnt/ beta-catenin signaling pathway via ERK42/44 activation and upregulated lymphoid-enhancing factor 1/T cell factor 1 (LEF1/TCF1), the ultimate executor of the Wnt pathway, important for Hepatocellular carcinoma progression (Yoo et al, 2009). Further more, Microarray analysis of breast cancer cells revealed that MTDH knockdown led to decreased expression of chemoresistance genes ALDH3A1, MET, HSP90, AND HMOX1, and increased expression of pro-apoptotic genes BNIP3 and TRAIL MTDH was thought to be a potential focus for targeted therapy based on its multi-facet roles in regulating cancer apoptosis, invasion, metastasis, and chemoresistance.…”

AEG‐1 induces gastric cancer metastasis by upregulation of eIF4E expression

“…AEG‐1/MTDH was subsequently found to mediate the metastasis of breast cancer 8. In recent years, AEG‐1 expression was found to be elevated and correlated with clinical tumour type, stage, metastasis and prognosis in a variety of cancers, including breast 9, lung 10, colorectal 11, cervical 12, 13, head and neck 14, hepatocellular 15 and gastric cancers 16, 17. AEG‐1 has been shown to be transcriptionally up‐regulated by Ha‐Ras‐activated PI3K and c‐Myc 18.…”

Deregulation of MTDH Gene Expression in Gastric Cancer

“…The relationship between localization of MTDH and its function is not clear. While in breast cancer (Li et al, 2008), HCC (Yoo et al, 2009) and melanoma (Sarkar et al, 2009) increased MTDH nuclear staining is associated with advanced disease, in prostate cancer (Thirkettle et al, 2009), decreased nuclear staining is related to poor prognosis.…”

“…Activation of NF-κB , PI3K/AKT (Lee et al, 2006), MAP kinase and Wnt/β-catenin (Yoo et al, 2009) signal tarnsduction pathways by MTDH induces specific phenotypes including cell survival, anti-apoptosis, angiogenesis, migration and invasion in various cell types (Sarkar et al, 2009). More recently, Li et al have shown that over-expression of MTDH leads to increased acquisition of cancer stem cell markers in breast cancer cells (Li et al, 2011).…”

“…Intriguingly, expression analysis in cell lines and in patient-derived tumor samples revealed that MTDH significantly elevated in breast carcinoma (Li et al, 2008), HCC (Yoo et al, 2009), neuroblastoma , and malignant glioma (Liu et al, 2010) cell lines and tumor samples compared with their normal counterparts. Furthermore, it has been reported that MTDH plays important roles in multiple biological processes in the course of tumorigenesis via modulating of multiple signalling pathways (Lee et al, …”