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.

SLC27A2 regulates miR-411 to affect chemo-resistance in ovarian cancer

“…This implies that low SLC27A2 expression level induces ABCG2 expression by down-regulating miR-411. The ABC transporter family has at least 48 members identified in humans, and 12 of these are recognized putative drug transporters [13][14][15]. When tumor patients have higher expression of ABC transporter pumps, they usually do not respond to chemotherapy because the ABC transporters located on the cytoplasm side of the resistant cell effluxes chemotherapeutic drugs out of the tumor cells, thus leading to chemo-resistance [16].…”

RNA-seq reveals distinctive RNA profiles of small extracellular vesicles from different human liver cancer cell lines

“…The leucine-rich, repeat-containing, G protein-coupled receptor 5 (LGR5), another marker of cell plasticity and stem cell potential in LC, is expressed only in HuH7- and HuH6-EVs. It has been suggested that LGR5-expressing HCC stem-like cells may play an important role for the pathogenesis and drug resistance of HCC [ 39 ]. It is possible that EpCAM-, E-cadherin- and LGR5-carrying EVs participate to the preparation of the microenvironment to accommodate the subpopulation of tumor stem like cells originating from the LCC.…”

Role of microRNA‑33a in malignant cells (Review)

“…1F). Similarly, Hou et al (37) have reported that miR-33a overexpression in Lgr5+ hepatoma-cancer stem cells decreases ATP-binding cassette transporter A1 (ABCA1) expression, thereby reducing the resistance of these cells to doxorubicin (Fig. 1G).…”