Abstract
TACE (Transarterial Chemoembolization) is an essential current treatment for liver cancer. Resistance to doxorubicin, the chemotherapeutic component of TACE, poses a serious problem in this treatment, necessitating a deeper understanding of the underlying resistance mechanisms. Upregulation of the Forkhead box A1 transcription regulator in our model of doxorubicin-resistant liver cancer cell line suggested a role in resistance. To better understand the role of FOXA1 in resistance to doxorubicin, we inhibited its expression using siRNA or its miRNA-212-3p inhibitor then studied the effect on the cancer cell lines survival using SRB assay. The expression of several downstream epithelial-mesenchymal transition genes, namely SLUG, TWIST, CDH1 (E-Cadherin), was determined using quantitative real-time PCR. Our results showed a significant upregulation of FOXA1 and downregulation of miRNA-212-3p in doxorubicin-resistant cells. Manipulation of FOXA1 and miRNA-212-3p expressions restored sensitive cell characteristics. In addition, inhibition of FOXA1 increased apoptosis induction in resistant cells. Changes detected in the tested EMT genes point to progression toward more aggressive behavior in the doxorubicin-resistant liver cancer cell line that was reversed with inhibition of FOXA1. Our results suggest a possible role of FOXA1 and miRNA-212-3p in the development of resistance to chemotherapeutic drugs in liver cancer and the possibility of their use as prognostic and/or therapeutic targets.