Genetic Deletion of AEG-1 Prevents Hepatocarcinogenesis

Abstract

Activation of the oncogene AEG-1 (MTDH, LYRIC) has been implicated recently in the development of hepatocellular carcinoma (HCC). In mice, HCC can be initiated by exposure to the carcinogen DEN, which has been shown to rely upon activation of NF-κB in liver macrophages. Since AEG-1 is an essential component of NF-κB activation, we interrogated the susceptibility of mice lacking the AEG-1 gene to DEN-induced hepatocarcinogenesis. AEG-1-deficient mice displayed resistance to DEN-induced HCC and lung metastasis. No difference was observed in the response to growth factor signaling or activation of Akt, ERK and β-catenin, compared to wild-type control animals. However, AEG-1-deficient hepatocytes and macrophages exhibited a relative defect in NF-κB activation. Mechanistic investigations showed that IL-6 production and STAT-3 activation, two key mediators of HCC development, were also deficient along with other biological and epigenetics findings in the tumor microenvironment confirming that AEG-1 supports an NF-κB-mediated inflammatory state that drives HCC development. Overall, our findings offer in vivo proofs that AEG-1 is essential for NF-κB activation and hepatocarcinogenesis, and they reveal new roles for AEG-1 in shaping the tumor microenvironment for HCC development.

Distinctive properties of metastasis-initiating cells

“…Interestingly, other factors that support tumor initiation activity seem to work only in the malignant context and are not involved in the regulation of normal adult tissue stem cells. For example, MTDH, an essential factor to support tumor initiation and metastasis in breast, prostate, and liver cancers, is dispensable for embryonic and postnatal development (Robertson et al 2014;Wan et al 2014a,b). Such factors will be ideal candidates for therapeutic targeting to prevent metastasis initiation.…”

The emerging role of astrocyte-elevated gene-1 in hepatocellular carcinoma (Review)

“…Subsequently, a recent study using AEG-1-deficient mice found that AEG-1-deficient hepatocytes and macrophages exhibited a relative defect in NF-κB activation; and the IL-6 production and STAT-3 activation were also deficient along with other biological and epigenetic findings in the tumor microenvironment. This demonstrated that AEG-1 supports an NF-κB-mediated inflammatory state that drives HCC development (73).…”

Astrocyte Elevated Gene-1 (AEG-1) Contributes to Non-thyroidal Illness Syndrome (NTIS) Associated with Hepatocellular Carcinoma (HCC)

“…Alb/AEG-1 and AEG-1KO Mice-Generation and characterization of a hepatocyte-specific AEG-1 transgenic mouse (Alb/ AEG-1) and an AEG-1 knock-out (AEG-1KO) mouse have been described previously (12)(13)(14) Patient Samples-Serum samples were collected from hepatitis C virus-HCC patients (n ϭ 23) and 14 healthy volunteers. These studies are approved by the Institutional Review Board of the University of Virginia.…”

“…Conversely, knockdown of AEG-1 in highly aggressive QGY-7703 cells, expressing high levels of AEG-1, significantly abrogates in vivo tumorigenesis (7,10). As a corollary, an AEG-1 knockout (AEG-1KO) mouse shows profound resistance to diethylnitrosamine/phenobarbital-induced hepatocarcinogenesis and metastasis (14).…”

“…AEG-1, anchored on endoplasmic reticulum membrane, associates with upstream ubiquitinated activators of NF-B, such as RIP1 and TRAF2, facilitating their accumulation and subsequent NF-B activation by diverse stimuli (21). Indeed, lipopolysaccharide (LPS)-induced NF-B activation is markedly abrogated in AEG-1KO hepatocytes and macrophages when compared with wild type (WT) (14). Studies have shown that NF-B activation by inflammatory cytokines inhibits DIO1 expression and contributes to NTIS (22).…”