Abstract 882: Genomics approach to identify drug transporter ABCF1 associated with liver cancer recurrence and chemo-resistance
Authors: Cheung Siu Tim , Cheung Phyllis FY , Cheng Christine KC , Fan Sheung Tat 
Published: August 2012

Background: Liver cancer is the third leading cause of cancer death globally. Surgery is the mainstay for early stage patients with the best survival outcome, but cancer recurrence is still common after curative surgery. Chemotherapy has been widely used to treat advanced liver cancer but with marginal efficacy. There is an urgent need to elucidate the key genes that regulate recurrence and chemo-resistance in the clinical situation. Recently, we have demonstrated that the novel growth factor granulin-epithelin precursor (GEP) is associated with chemo-resistance and recurrence-free survival. GEP has been identified as a potential therapeutic target for liver cancer in our earlier genomic studies. We demonstrated that GEP overexpressed in the majority of liver cancers, regulated proliferation, invasion and tumorigenicity. Importantly, the anti-GEP monoclonal antibody treatment inhibited the growth of in vivo human liver cancer. GEP modulated the expression of the drug transporter ABCB5, and blockage of ABCB5 sensitized the liver cancer cells to chemotherapeutic agents and attenuated the expression of hepatic cancer stem cell markers CD133 and EpCAM. Notably, GEP expression is detectable in all liver cancer tissues while only half show detectable ABCB5 transcript. Importantly, the majority of the patients were chemo-resistant. Therefore, there should be additional crucial drug transporters. Objective: To use genomics approach to systematically examine the drug transporters in association with GEP, recurrence-free survival outcome, and functional role on chemo-resistance. Methods: The liver cancer gene expression profiles reported previously were re-examined, and all the drug transporter family members were ranked in association with GEP expression patterns. The genes that have shown high correlation with GEP expressions in the microarray hybridization datasets were further validated in an independent cohort of clinical specimens using independent research platform real-time quantitative RT-PCR. Results: Here, we reported that the expression levels of drug transporter ABCF1 and GEP were significantly correlated in human liver tissues (P &lt; 0.001). ABCF1 was detectable in all tumor tissues, upregulated in the tumor as compared with the adjacent non-tumor liver (P &lt; 0.001), and that the increased ABCF1 level was associated with poor recurrence-free survival (log-rank test, P = 0.001). Functionally, GEP regulated ABCF1 expresson levels, and suppression of ABCF1 rendered the liver cancer cells sensitive to chemotherapeutic agents. Conclusion: 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 liver cancer cells.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 882. doi:1538-7445.AM2012-882