Genomics approach to identify growth factor and drug transporter associated with liver cancer recurrence and chemo-resistance

Abstract

Background: Liver cancer is the third leading cause of cancer death globally. Surgery is the mainstay for early stage patients but recurrence is still common. Chemotherapy has been widely used to treat advanced liver cancer but with marginal efficacy. Recent evidences have shown the role of tumor initiating cells on chemo-resistance and recurrence, however, the key genes remind inconclusive. Recently, we have demonstrated that the novel growth factor granulin-epithelin precursor (GEP) and drug transporter ABCB5 were associated with chemo-resistance and recurrence-free survival (Gastroenterology 2011). GEP has been identified as a potential therapeutic target for liver cancer in our earlier genomic studies. The aim of the study is to identify additional drug transporters with clinical relevance. Methods: The liver cancer gene expression profiles reported previously were re-examined for all the ATP-binding transporters. The gene of interest were further validated in an independent cohort using real-time quantitative RT-PCR. Results: ABCF1 was upregulated in tumor compared with non-tumor (P/0.001), and increased ABCF1 was associated with poor recurrence- free survival (log-rank test, P = 0.001). Functionally, suppression of ABCF1 rendered the liver cancer cells sensitive to chemotherapeutic agents. Liver cancer cells that were positive for GEP and ABCB5/ABCF1 showed enhanced expression of the stem cell related signaling molecules-catenin, Oct4 and Nanog. Conclusions: In summary, chemo-resistance and cancer recurrence are dictated by a subset of cells expressing GEP and ABC transporters. Targeting the novel growth factor GEP and drug transporters, in combination with chemotherapy, could provide novel treatment modalities to eradicate the aggressive hepatic tumor initiating cells.