HNF1A inhibition induces the resistance of pancreatic cancer cells to gemcitabine by targeting ABCB1

• Published in: EBioMedicine Vol. 44; pp. 403 - 418
• Main Authors: Lu, Yanan, Xu, Dongni, Peng, Jintao, Luo, Zhaofan, Chen, Chujie, Chen, Yuqing, Chen, Huimou, Zheng, Minghui, Yin, Peihong, Wang, Zhi
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01-06-2019; Elsevier
• Subjects: ABCB1; Adult; Aged; Animals; Antimetabolites, Antineoplastic - pharmacology; Apoptosis - drug effects; ATP Binding Cassette Transporter, Subfamily B - antagonists & inhibitors; ATP Binding Cassette Transporter, Subfamily B - genetics; ATP Binding Cassette Transporter, Subfamily B - metabolism; Cell Line, Tumor; Cell Proliferation; Chemotherapy resistance; Deoxycytidine - analogs & derivatives; Deoxycytidine - pharmacology; Disease Models, Animal; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; Female; Gemcitabine; Gene Expression; Hepatocyte Nuclear Factor 1-alpha - antagonists & inhibitors; Hepatocyte Nuclear Factor 1-alpha - genetics; Hepatocyte Nuclear Factor 1-alpha - metabolism; HNF1A; Humans; Immunohistochemistry; Male; Mice; Middle Aged; Neoplasm Grading; Neoplasm Metastasis; Neoplasm Staging; Pancreatic ductal adenocarcinoma; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - mortality; Pancreatic Neoplasms - pathology; Prognosis; Promoter Regions, Genetic; Protein Binding; Research paper; Chemotherapy resistance; ABCB1; HNF1A; Gemcitabine; Pancreatic ductal adenocarcinoma
• ISSN: 2352-3964; 2352-3964
• DOI: 10.1016/j.ebiom.2019.05.013

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with poor prognosis, and gemcitabine-based chemotherapy remains an effective option for the majority of PDAC patients. Hepatocyte nuclear factor 1α (HNF1A) is a tumor-suppressor in PDAC, but its role in gemcitabine chemoresistance of PDAC has not been clarified.
The function of HNF1A in gemcitabine was detected by overexpression and knockdown of HNF1A in vitro and in vitro. The regulatory network between HNF1A and ABCB1 was further demonstrated by luciferase assays, deletion/mutation reporter construct assays and CHIP assays.
Here, we found that HNF1A expression is significantly associated with gemcitabine sensitivity in PDAC cell lines. Moreover, we identified that HNF1A overexpression enhanced gemcitabine sensitivity of PDAC both in vitro and in vitro, while inhibition of HNF1A had the opposite effect. Furthermore, by inhibiting and overexpressing HNF1A, we revealed that HNF1A regulates the expression of MDR genes (ABCB1 and ABCC1) in PDAC cells. Mechanistically, we demonstrated that HNF1A regulates ABCB1 expression through binding to its specific promoter region and suppressing its transcription levels. Finally, the survival analyses revealed the clinical value of HNF1A in stratification of gemcitabine sensitive pancreatic cancer patients.
Our study paved the road for finding novel treatment combinations using conventional cytotoxic agents with functional restoration of the HNF1A protein, individualized treatment through HNF1A staining and improvement of the prognosis of PDAC patients.
National Natural Science Foundations of China and National Natural Science Foundation of Guangdong Province.