title: miR-33a expression sensitizes Lgr5+ HCC-CSCs to doxorubicin via ABCA1.
abstract: Cancer stem cells (CSCs) are responsible for the unrestrained cell growth and chemo-resistance of malignant tumors. Reports about miR-33a in different type of cancer are limited, and it remains elusive whether there is a link between miR-33a and chemo-resistance of CSCs. Here we report that Lgr5+ hepatocellular carcinoma (HCC) cells from primary tissues and cell lines behave similarly to CSCs and are chemo-resistant to doxorubicin. Significantly, reduced miR-33a expression is associated with the chemo-resistance of Lgr5+ HCC-CSCs, accompanied by an overexpression of ABCA1 which is identiﬁed as target of miR-33a by mainly using miRNA luciferase assay and western-blotting. We demonstrate that down-regulation of miR-33a expression directly contributes to chemo-resistance of Lgr5+ HCC-CSCs, and restoring miR-33a expression sensitizes them to doxorubicin via apoptosis by mainly using TUNEL assay, soft agar colony formation assay and xenograft assay. Additionally, reduced miR-33a expression in HCC tissues is associated with chemo-response and poor patient survival, which suggests the therapeutic potential of miR-33a. In conclusion, our work indicates that ectopic miR-33a expression sensitizes Lgr5+ HCC-CSCs to doxorubicin via direct targeting ABCA1, which sheds new light on understanding the mechanism of chemo-resistance in HCC-CSCs and contributes to development of potential therapeutics against HCC.
authors.forename: H
authors.initials: H
authors.lastname: Hou
authors.forename: Y
authors.initials: Y
authors.lastname: Kang
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.forename: Y
authors.initials: Y
authors.lastname: Zeng
authors.forename: G
authors.initials: G
authors.lastname: Ding
authors.forename: J
authors.initials: J
authors.lastname: Shang
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000235:genetics*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics*; D035683:MicroRNAs / Q000235:genetics*; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; C116884:LGR5 protein, human; C550416:MIRN33a microRNA, human; D035683:MicroRNAs; D043562:Receptors, G-Protein-Coupled; D004317:Doxorubicin
keywords: ABCA1; Lgr5; cancer stem cells chemo-resistance hepatocellular carcinoma.; miR-33a