Mature MiR-17-5p and passenger miR-17-3p induce hepatocellular carcinoma by targeting PTEN, GalNT7, and vimentin in different signal pathways

Abstract

SummaryTo study the physiological role of a single microRNA (miRNA), we generated transgenic mice expressing the miRNA precursor miR-17 and found that the mature miR-17-5p and the passenger strand miR-17-3p were abundantly expressed. We showed that mature miR-17-5p and passenger strand miR-17-3p could synergistically induce the development of hepatocellular carcinoma. The mature miR-17-5p exerted this function by repressing the expression of PTEN. In contrast, the passenger strand miR-17-3p repressed expression of vimentin, an intermediate filament with the ability to modulate metabolism, and GalNT7, an enzyme that regulates metabolism of liver toxin galactosamine. Hepatocellular carcinoma cells, HepG2, transfected with miR-17 formed larger tumors with more blood vessels and less tumor cell death than mock-treated cells. Expression of miR-17 precursor modulated HepG2 proliferation, migration, survival, morphogenesis and colony formation and inhibited endothelial tube formation. Silencing of PTEN, vimentin or GalNT7 with their respective siRNAs enhanced proliferation and migration. Re-expressing these molecules reversed their roles in proliferation, migration and tumorigenesis. Further experiments indicated that these three molecules do not interact with each other, but appear to function in different signaling pathways. Our results demonstrated that a mature miRNA can function synergistically with its passenger strand leading to the same phenotype but by regulating different targets located in different signaling pathways. We anticipate that our assay will serve as a helpful model for studying miRNA regulation.

MicroRNA-17-5p activates hepatic stellate cells through targeting of Smad7

“…13,14 miR-17-5p is reported to synergistically trigger HCC development via its target PTEN. 15 An earlier study by our group showed that high expression of serum miR-17-5p is associated with poor prognosis in HCC patients. 16 However, the precise roles of miR-17-5p in liver fibrosis remain obscure at present.…”

Exercise for cardiac health and regeneration: killing two birds with one stone

“…Each miRNA has numerous downstream targets, many still to be identified, that could lead to undesired side effects. In line with this, miR-17-3p has been clearly related to growth, proliferation, invasion, and survival of different types of tumor cells (12,13). Moreover, it has been shown to suppress the expression of mRNAs responsible for the synthesis of antioxidant enzymes in human peripheral blood mononuclear cells and endothelial cells (16).…”

“…This relatively novel class of molecules are being thoroughly investigated for its potential therapeutic use (10,11). Although miR-17-3p action inducing cell proliferation and survival had previously been described in murine prostate tumor (12,13), its role in cardiomyocytes and altered expression in response to exercise were first demonstrated by Shi and colleagues (3). The authors verified that miR-17-3p is downregulated in left ventricular samples of patients with dilated cardiomyopathy, and anticipated that with heart failure patients a single cardiopulmonary exercise test was able to increase serum miR-17-3p.…”

The effects of perfluorocarbon on ICAM-1 expression in LPS-induced A549 cells and the potential mechanism

“…Jiang and Li (46) confirmed that miR-17-3p expression is regulated by TNF-α and LPS in HeLa cells. In addition, miR-17-3p induces carcinoma by targeting vimentin (47), mediates stress responses by targeting MDM2 (48), and inhibits angiogenesis by downregulating fetal liver kinase-1 (49). In certain clinical studies, circulating miR-17-3p in serum has been indicated to be a potential non-invasive biomarker for colorectal cancer screening (50,51).…”