miR-122 is a unique molecule with great potential in diagnosis, prognosis of liver disease, and therapy both as miRNA mimic and antimir

Abstract

miR-122, a completely conserved liver-specific miRNA in vertebrates, is essential for the maintenance of liver homeostasis. This 22 nucleotide RNA regulates diverse functions such as cholesterol, glucose and iron homeostasis, lipid metabolism and infection of hepatitis C virus (HCV) and of the parasitic protozoa, Leishmania donovani. It is the first miRNA that underwent successful clinical trials in HCV infected patients. In contrast, miR-122 expression is reduced in nonalcoholic steatohepatitis (NASH) patients, and in a subset of hepatocellular carcinoma (HCC) patients including hepatitis B virus (HBV) positive patients with highly invasive and metastatic cancer. Studies in mice genetically depleted of miR-122 have highlighted its critical role in liver biology. These mice progressively develop steatohepatitis, fibrosis and hepatocellular cancer, establishing it as a bona fide tumor suppressor. Additionally, delivery of miR-122 using a viral vector or liposomal nanoparticles resulted in liver tumor suppression in animal models. These results suggest miR-122 supplementation might be beneficial in NASH or HBV positive HCC patients. Furthermore, circulating miR-122 has emerged as a sensitive biomarker for liver injury. The ability of miR-122 to promote differentiation of embryonic and adult stem cells to hepatocyte-like cells in vitro suggests its potential role in driving the hepatic differentiation program. In this review, we will discuss the role of miR-122 in liver physiology and the deleterious consequences of its loss of function, its role as a sensitive biomarker for liver injury and therapeutic target. Development of novel technologies for targeted delivery of miR-122 to tumor cells and for direct monitoring of miR-122 in biological fluids is urgently needed for translating the basic research to the bedside. This review focuses on miR-122, the most abundant hepatic miRNA, in the context of liver health and diseases.

Fig. (1)

Northern blot analysis of hepatic miRNAs in the wild type and miR-122 knockout livers (from reference [16]).

Fig. (2)

miR-122 liver specific (LKO) and germ-line (KO) mice develop spontaneous HCC and metastatic lung cancer after 12 months. Representative photographs are shown (from reference [16]).

Fig. (3)

A. Schematic representation of the recombinant scAAV harboring miR-122 minigene that generates miR-122. B. Timing of AAV8-miR-122 delivery after c-myc induction by doxycycline withdrawal) in Tet-O-Myc;LAP-tTA mice. C. Representative images of livers from AAV8, sh-luc-AAV8 and miR-122-AAV8 delivered mice (from reference [16]).

Fig. (4)

In vivo delivery of miR-122 mimic-loaded LNP-DP1 in DEN-induced HCCs developed in miR-122 KO mice (from reference [55]). A. The structure of the cationic lipid DODMA. B. The schematic representation of miRNA encapsulated by PEG modified LNP-DP1. C. Confocal microscopic imaging of Cy3-labeled siRNA formulated in LNP-DP1 in the benign liver and tumor tissues in a tumor-bearing miR-122 KO mouse. Four hours after intravenous administration of Cy3-labeled siRNA (2.5 mg/kg) tissues were processed for confocal microscopy. Red: Cy3-labeled siRNA; Green: cell outline (Phalloidin stained actin filament); Blue (DAPI): nucleus. Scale bars: 40μm. Red: Cy3-labeled siRNA; Yellow: collagen fibers; Blue: nucleus. Scale bars: 40μm. D. Growth curves of HCC xenograft tumors in nude mice intra-tumorally injected twice a week with LNP-DP1 loaded with NC miRNA (LNP-DP1/NC) or miR-122 (LNP-DP1/miR-122) at 10 μg per injection. P-value: *, P < .05; **, P < .01; ***, P < .001.