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New Data Reveal microRNA 'Sponge' Role for HCV in the Liver

NEW YORK (GenomeWeb) – A team led by Rockefeller University researchers this week reported new data showing that the hepatitis C virus acts like a "sponge" for a tumor-suppressing microRNA in the liver, offering new clues about the virus' well-established association with hepatocellular carcinoma.

MiR-122 is a liver-specific miRNA involved in fat and liver metabolism, but has also been shown to be a required host factor for HCV replication. Specifically, the virus recruits the RNAi protein Argonaute 2 (Ago2) to its 5' end, thereby stabilizing its RNA and slowing its decay in order to maintain infection.

Notably, miR-122 is also involved in tumor suppression, with in vivo studies demonstrating that its knockdown leads to sustained liver inflammation and tumor development.

With the growing availability of new methods for studying genome-wide miRNA/mRNA interaction networks, the Rockefeller team sought to examine the global effects of HCV infection on miR-122 targets during infection in vitro using high-throughput sequencing and cross-linking and immunoprecipitation, or HITS-CLIP.

As reported in Cell, the investigators observed Ago engagement at the HCV 5' UTR miR-122 sites, consistent with observations by other groups.

Surprisingly, on the human transcriptome they also saw reduced Ago binding and functional mRNA de-repression of miR-122 targets during HCV infection, indicating that HCV RNA functionally sequesters miR-122 — a miRNA "sponge" effect similar to that which has been proposed by others for competing endogenous RNAs (ceRNAs).

The study's authors noted, however, that ceRNAs do function differently from HCV RNA.

"HCV genomic RNA critically requires miR-122 interaction to stabilize the viral genome and stimulate translation and replication, while most cellular miRNA targets are degraded upon encountering a miRNA," they wrote. "Moreover, unlike cellular mRNA targets, HCV genomic RNA is its own substrate for replication, and thus constitutes a positive feedback loop to sequester additional miR-122."

In their report, the Rockefeller scientists also showed that HCV's miR-122 sponge activity could be redirected to the targets of another miRNA by changing the miRNA tropism of the virus, which suggests that this effect is "largely dispensable" for the virus, at least in the context of the highly permissive liver cell line used in the study.

Although miR-122 sequestration by HCV replication confers a slightly less pro-viral cellular environment, this may be a small tradeoff for the "hugely beneficial role miR-122 plays directly in the viral life cycle," they wrote.

Although additional work is required to better understand the effect of HCV's miR-122 sponge activity on hepatocytes, the researchers noted that it is "tantalizing to speculate that miR-122 sequestration in a chronic HCV infection may be a molecular link to the heterogeneous liver dysfunction that characterizes HCV-induced disease."

Indeed, a number of miR-122 targets confirmed or established using CLIP and reporter measurements are known to be upregulated in fibrosis or liver cancer, they added.

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