Cooperation between MYC and companion 8q genes in hepatocarcinogenesis
Authors: Scott Powers
Journal: Hepatology (2014)

Potential conflict of interest: Nothing to report. See Article on Page 915 In this issue of Hepatology, Devanand Sarkar and coworkers report that AEG‐1, a gene located at chromosomal region 8q22, cooperates with c‐MYC (8q24) to induce a highly metastatic form of hepatocellular carcinoma (HCC) in transgenic mice.1 The authors used the ALB (albumin) promoter to drive selective expression of these two 8q genes in mature hepatocytes, under conditions where MYC expression alone is sufficient to induce HCC, albeit a less‐aggressive form without distant metastasis. Interestingly, expression of AEG‐1 and MYC forms a positive feedback loop, in that each promotes the expression of the other, presumably playing a normal interacting role in liver development that is hijacked during hepatocarcinogenesis. Their oncogenic cooperation has an additional interesting feature in that the combination of AEG‐1 and MYC, but neither gene alone, induces expression of maternally imprinted long noncoding RNAs (lncRNAs) RIAN and MEG3. The authors go on to show that expression of these lncRNAs play a functional role in AEG‐1/MYC‐induced malignancy.1 As with the study of microRNAs a few years back, the study of lncRNAs is becoming increasingly central to current research in hepatocarcinogenesis. AEG‐1 (also known as LYRIC and MTDH) is an interesting gene in its own right, encoding a protein with several nuclear‐localization signals and a single transmembrane domain. There is evidence that it directly interacts with beta‐catenin and nuclear factor kappa B and that it activates both of these proteins, although the biochemical mechanism of activation has not been determined.2 A complex array of biochemical and oncogenic effects of AEG‐1 has been reported, but, as yet, no clear idea has emerged as to its normal biological function. Sarkar et al. as well as other groups will no doubt continue to place AEG‐1 as the central focus of their research, and hopefully some clear molecular understanding of its normal function, and how this is hijacked during cancer formation, will emerge. AEG‐1 and MYC also function in a broader context of 8q gain; a genetic event that occurs in roughly 50% of HCCs and that involves the increased expression of many genes besides AEG‐1 and MYC. There are several genes located on chromosomal arm 8q that have been shown to promote or maintain HCC, including COPS5, SGK3, GPAA1, CTHRC1, NDRG1, as well as MYC and AEG‐1/MDTH. COPS5 encodes a component of the signalosome that functions in the ubiquitin‐proteasome pathway and is part of a group of 8q genes, including MYC, that are up‐regulated during the critical transition of hepatic preneoplasms to early‐stage HCC.3SGK3 encodes a cytoplasmic kinase that, as with protein kinase B (Akt), is activated in response to growth factor simulation and that phosphorylates many of the same substrates as Akt.4GPAA1 encodes a subunit of the complex that catalyzes the attachment of glycosylphosphatidylinositol anchors to eukaryotic proteins.5CTHRC1 encodes a secreted glycoprotein that activates the planar cell polarity pathway of Wnt signaling.6NDRG1 encodes a hypoxia‐induced protein that, when suppressed by RNA interference, induces senescence in HCC cells.7 Understanding how these validated 8q driver genes and others yet to be discovered cooperate to promote human HCC development is a major challenge and a key obstacle to deeper understanding of the genesis of this highly lethal disease. Our ability to understand how the coordinated regulation of a large set of oncogenic and interacting genes affect the evolving tumor is limited both by a lack of experimental tools, models, and theoretical frameworks by which to think about biochemical mechanisms. Network biology can be used to look for relationships between 8q oncogenic drivers and key oncogenes and tumor suppressors and also may pinpoint other 8q genes that play an oncogenic role, as suggested by their placement within the network by previous knowledge of pathways and protein‐protein interactions (Fig. 1).Figure 1: Interacting network of 8q amplified driver genes, 8q candidate driver genes, and key tumor suppressors and oncogenes. Amplified HCC driver genes COPS5, SGK3, GPAA1, CTHRC1, NDRG1, MYC, and AEG‐1/MDTH were used as seeds to construct an interaction network using cBioPortal.10 With the exception of the key tumor‐suppressor genes (shaded blue) and oncogenes (shaded red violet) all genes not localized to 8q were removed. Lighter orange shading indicates a connected candidate 8q driver gene; darker orange shading indicates a validated 8q driver gene. Connecting lines indicate different lines of evidence of either direct protein‐protein interaction or pathway interaction. Validated 8q driver genes SGK3 and CTHRC1 did not form interactions with other members of the network. The network is displayed as a representation of the type of analysis that will be needed to fully understand the oncogenic interaction of the multitude of genes driving the selection of 8q gain.Perhaps one of the most significant leads about how to move forward with understanding this complex genetic event comes from the findings of Sarkar et al. that MYC and AEG‐1 form a self‐reinforcing system of gene activation. Such a self‐reinforcing system of gene activation was previously observed in HCC for the closely linked 11q13 driver genes, FGF19 and CCND1.8 Testing for such interactions among a large set of genes is much less resource intensive than looking for oncogenic cooperation between a large set of genes. An additional problem facing our ability to understand the malignant consequences of 8q gain is that there is not a corresponding normal function that is being hijacked. The ability to determine the normal function of individual cancer genes has helped us understand their function in cancer. Although it is conceivable that coordinated regulation of such a large group of linked genes serves some role during normal development, none have been reported to date. Rather than hijacking a normal function, the selective advantage of 8q gain may just be a consequence of the high ratio of growth‐promoting genes relative to growth‐suppressive genes (as hypothesized as a general explanation for the selective advantage of all large chromosomal alterations in cancer9). However, it seems likely that interactions between the various driver genes could play an equally important role. Regardless, our ability to design rational therapies to the major genetic events that drive HCC progression would be greatly enhanced by a deeper understanding of highly recurrent chromosomal alterations such as 8q gain.