HNF1A Inhibition Induces the Resistance of Pancreatic Cancer Cell to Gemcitabine by Targeting ABCB1

Background: Pancreatic adenocarcinoma (PDAC) is an aggressive disease with poor prognosis, and gemcitabine-based chemotherapy remains the effective option for major PDAC patients. However, most patients eventually develop gemcitabine resistance and little is known about the molecular mechanisms mediating it. HNF1A has been identified as a tumor-suppressor in PDAC, while its role in gemcitabine chemoresistance of PDAC has not been clarified. Methods: The function of HNF1A to gemcitabine was detected by overexpression and knockdown of HNF1A in vitro and in vivo. The regulatory network between HNF1A and ABCB1 was further demonstrated by luciferase assays, deletion/mutation reporter constructs assays and chromatin immunoprecipitation assays.   Findings: Here, we found that HNF1A expression is significantly associated with gemcitabine sensitivity of PDAC cell lines. Moreover, we identified that HNF1A overexpression enhanced gemcitabine sensitivity of PDAC both in vitro and in vivo, while inhibition of HNF1A had an opposite effect. Further, by inhibition and overexpression of HNF1A, we revealed that HNF1A regulates the expression of multidrug resistance genes (ABCB1 and ABCC1) in PDAC cells. Mechanistically, we demonstrated that HNF1A regulates ABCB1 expression through binding its specific promoter region and suppress its transcription levels. Finally, the survival analyses revealed a clinical value of HNF1A in stratification of gemcitabine sensitive pancreatic cancer patients. Interpretation: Our study paved the road for find novel treatment combinations using conventional cytotoxic agents with functional restoration of HNF1A protein, and individualize treatment through HNF1A staining and finally improve the prognosis of PDAC patients.   Funding Statement: This study was supported by grants from the National Natural Science Foundation of China (grant number 81571196，81702417 and 81672807, www.nsfc.gov.cn), the National Natural Science Foundation of Guangdong Province (grant number 2016A030311047, 2017A030313880, http://pro.gdstc.gov.cn), the Sun Yat-sen University Clinical Research 5010 Program (grant number 2012007). Declaration of Interests: The authors declare no conflict of interest. Ethics Approval Statement: The tissue samples using for the research were approved by ethics committee of Sun Yat-sen Memorial Hospital of Sun Yat-sen University. All cases obtained the informed consent from the patients. The protocols for animal experiments were approved by the Institutional Animal Care and Use Committee and Institutional Biosafety Committee of Sun Yat-sen University.