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

Abstract

Background 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. Methods 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. Findings 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. Interpretation 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. Fund National Natural Science Foundations of China and National Natural Science Foundation of Guangdong Province.

Elevated HNF1A expression promotes radiation-resistance via driving PI3K/AKT signaling pathway in esophageal squamous cell carcinoma cells

“…The recent study showed that patients with pancreatic ductal adenocarcinoma (PDAC) with the HNF1A-positive subtype had the best prognostic survival time [22]. In a separate study, patients of PDAC in high HNF1A group demonstrated an improvement in OS and DFS compared with the moderate/low HNF1A groups [9]. In contrast, the patients of ESCC with high expression of HNF1A had a poor OS and PFS through online analysing by GEPIA and Kaplan-Meier plotter.…”

“…Our results showed that the overexpression of HNF1A promoted the proliferation of ESCC cells. In several studies, HNF1A had been linked to resistance to chemical drugs, including colon cancer [24] and pancreatic cancer [8][9][10]. However, there was little research on its relationship with radiosensitivity.…”

“…The researchers identified HNF1A as a central transcriptional regulator of both pancreatic cancer stem cells (PCSC) properties and a new oncogene in pancreatic ductal adenocarcinoma (PDA) 7 . However, HNF1A is also reported to down-regulate the cell cycle and anti-apoptotic genes, and up-regulate the expression of apoptotic genes 8 , inhibits to induce the resistance of pancreatic cancer cells to gemcitabine by targeting ABCB1 9 , and regulates the proliferation activity of pancreatic cancer cells by increasing the PTEN/AKT signaling pathway 10 . These findings strongly support the role of HNF1A as a tumor suppressor in PC.…”

The Roles of Long Noncoding RNAs HNF1α-AS1 and HNF4α-AS1 in Drug Metabolism and Human Diseases

“…The dysfunction of pancreatic beta cells and impaired insulin secretion because of HNF1α or HNF4α mutations are believed to be the pathological mechanisms to this type of disease. In addition to MODY, HNF1α and HNF4α are involved in other type of diseases, including other metabolic diseases, inflammatory diseases, and cancer [52][53][54][55]. HNF1α and HNF4α are reported to play different roles based on cancer types.…”

ABCA8-mediated efflux of taurocholic acid contributes to gemcitabine insensitivity in human pancreatic cancer via the S1PR2-ERK pathway

“…The most extensively studied ABC transporters related to chemoresistance include ABCB1 (also named P-glycoprotein or multidrug resistant gene 1), ABCC1 (also named multidrug resistance protein 1), and ABCG2 (also named breast cancer resistance protein) 8 . These ABC transporters have been demonstrated to confer PC resistance to gemcitabine (GEM) 9 – 11 , which is the mainstay chemotherapeutic agent for PC. Several other members of ABCB or ABCC subfamily, such as ABCB2 12 and ABCC5 13 , have also been found to be associated with PC chemoresistance.…”