Expression of ATP-binding cassette transporter ABCF1 in fetal liver and liver cancer associated with cancer stem cell markers and chemo-resistance

Abstract

The importance of understanding stem cell biology in relation to cancer has been made clear since the cancer stem cells (CSCs) notion and recurring deregulated stem cell pathways reported in cancers. ATP-binding cassette (ABC) transporter ABCB1 (also named P-glycoprotein and MDR1) has shown to be CSC marker, mediate multidrug-resistance in model systems, yet, with controversial clinical relevance. Through systemic analysis on the expression profiles of ABC genes in hepatocellular carcinoma (HCC) clinical samples, ABCF1 was found significantly over-expressed in HCCs compared to the adjacent non-tumor liver tissues and associated with recurrence-free survival after curative partial hepatectomy. Recurrences have often been attributed to CSCs. We therefore further explored the significance of ABCF1 in both fetal liver and liver cancer cells in respect to stem cell features. Expression of ABCF1 in fetal, neonatal and adult mouse livers were examined by immunohistochemistry, western blot and flow cytometry. Consistently, elevated ABCF1 expression was demonstrated in early embryonic stages but rarely in neonates and adult livers. Also, ABCF1 co-stained with stem cell-related marker β-catenin and hepatic CSC markers CD133 and GEP in fetal hepatocytes and in HCC cells. ABCF1 suppression by siRNA enhanced chemo-sensitivity of the HCC cells Hep3B compared to control cells on cisplatin and 5-Fluorouracil. Overexpression of ABCF1, conversely, induced chemo-resistance to cisplatin, and doxorubicin efflux ability in Hep3B and HepG2 cells. The current study put together the functional significance of ABCF1 in liver development and liver cancer as a stem cell-related molecule regulating chemo-resistance.