Genetic deletion of AEG-1 prevents hepatocarcinogenesis

Chadia L. Robertson, Jyoti Srivastava, Ayesha Siddiq, Rachel Gredler, Luni Emdad, Devaraja Rajasekaran, Maaged Akiel, Xue Ning Shen, Chunqing Guo, Shah Giashuddin, Xiang Yang Wang, Shobha Ghosh, Mark A. Subler, Jolene J. Windle, Paul B. Fisher, Devanand Sarkar

Research output: Contribution to journalArticlepeer-review

47 Scopus citations


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-kB in liver macrophages. Because AEG-1 is an essential component of NF-kB activation, we interrogated the susceptibility of mice lacking the AEG-1 gene to DEN-induced hepatocarcinogenesis. AEG-1deficient 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 with wild-type control animals. However, AEG-1deficient hepatocytes and macrophages exhibited a relative defect in NF-κB activation. Mechanistic investigations showed that IL6 production and STAT3 activation, two key mediators of HCC development, were also deficient along with other biologic and epigenetics findings in the tumor microenvironment, confirming that AEG-1 supports an NF-kBmediated inflammatory state that drives HCC development. Overall, our findings offer in vivo proofs that AEG-1 is essential for NF-kB activation and hepatocarcinogenesis, and they reveal new roles for AEG-1 in shaping the tumor microenvironment for HCC development.

Original languageEnglish
Pages (from-to)6184-6193
Number of pages10
JournalCancer Research
Issue number21
StatePublished - 1 Nov 2014
Externally publishedYes


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