Abstract
miR122 is the prevalent miRNA in adult healthy liver and it is responsible for liver stem cell differentiation towards hepatocyte lineage. Its expression is frequently lost in hepatocellular carcinoma (HCC). We studied the effects of restoring miR122 expression in a distinctive cell line derived from human HCC-BCLC9 cells-with a solid stem-like cell profile, high tumor initiating ability and undetectable miR122 expression. We generated a stable BCLC9 cell line that expresses miR122 (BCLC9-miR122). Restitution of miR122 in BCLC9 cells, decreases cell proliferation rate and reduces significantly tumor size in vivo. BCLC9-miR122 cells down-regulate expression of MYC, KLF4, FOXM1, AKT2 and AKT3 genes and up-regulate FOXO1 and FOXO3A gene expression. In addition, miR122 transfected cells decreased AKT2 kinase activation while decreased FOXO1 and FOXO3A protein inactivation. Reduction in tumor size in BCLC9-miR122 associated with an increase in p38MAPK protein expression and activation leading to a low phospho-ERK1/2 to phospho-p38 ratio. Treatment of miR122 positive cells with an inhibitor of TGFBR1 activation, abolished tumor dormancy program and recovered cell proliferation rate through a Smad-independent TGF-β response.HCC stem-like cells can be directed towards cell differentiation and tumor dormancy by restoring miR122 expression. We demonstrate, for the first time, that dormancy program is achieved through a Smad-independent TGF-β pathway. Reestablishing miR122 expression is a promising therapeutic strategy that would work concurrently reducing tumor aggressiveness and decreasing disease recurrence.
Highlights
MicroRNAs are regulators of gene expression by destabilizing and inducing degradation of messenger RNAs and/or repressing their translation [1]. miRs are key in cancer biomarker research due to their tissue specificity [2]
BCLC9 cell line was established from a welldifferentiated human hepatocellular carcinoma (HCC) [12] and they show a stem cell phenotype characterized by gene and protein expression of a pool of pluripotency markers: OCT4, NANOG, SOX2, KLF4, CD133, EpCAM, KRT19 genes, and overexpression of MYC which is not due to MYC gene amplification (Supplementary Figure S1A–S1C)
BCLC9 cells have been authenticated by ATCC as human origin, and not a match for any other profile in the ATCC or DSMZ Short Tandem Repeat (STR) databases
Summary
MicroRNAs (miRs) are regulators of gene expression by destabilizing and inducing degradation of messenger RNAs (mRNA) and/or repressing their translation [1]. miRs are key in cancer biomarker research due to their tissue specificity [2]. MiRs are key in cancer biomarker research due to their tissue specificity [2]. MiR122 expression increases along with liver development. Besides the well-known role of miR122 in favoring hepatitis C virus replication in hepatocytes [4], its function in the normal adult liver is related to cholesterol and lipid homeostasis [5]. It reaches its maximum levels in adult healthy liver and is associated with hepatocyte differentiation. Several studies forcing expression of miR122 in HCC cell lines, describe miR122 as a liver tumor suppressor [8] and hepatocyte cell differentiation factor [9]
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