Effects of HNF1A inhibition on drug resistance of human pancreatic cancer PANC1 cells to gemcitabine plus abraxane

Objective To explore the effects of hepatocyte nuclear factor 1 homeobox A(HNF1A) on drug resistance of PANC1 cells to gemcitabine plus abaraxane and explore the potential mechanism. Methods 78 pancreatic cancer patients with locally advanced or distant metastasis who received gemcitabine plus abaraxane chemotherapy after surgery in Biliary and Pancreatic Surgery Department of Sun Yat-sen Memorial Hospital from March 2012 to May 2017 were enrolled. qPCR was used to detect HNF1A mRNA levels in pancreatic cancer tissue. The patients were divided into high-expression group (n=39) and low-expression group (n=39) according to the median expression level of HNF1A, and the correlation of HNF1A expression with cancer clinicopathologic parameters and survival was analyzed. qPCR was used to detect HNF1A mRNA of 3 drug-sensitive cell lines (BxPC-3, CFPAC-1 and L3.6pl) and 4 drug-resistant pancreatic cancer cell lines (PANC1, MIA PaCa-2, Hs766T and Mpanc96). Lentivirus with plasmids carrying HNF1AcDNA infection was used to establish HNF1A overexpressing PANC1 cells ( HNF1A group), and lentivirus with empty plasmids were used to infect PANC1 cells to construct the control group. The mRNA and protein expression of HNF1A and ATP binding cassette transporter family ABCC1 in HNF1A group and control group were measured by qPCR and Western Blot, respectively. The half inhibition concentration (IC50) of gemcitabine plus abaraxane was detected by MTT, and cell apoptosis was examined by flow cytometry. Results Pancreatic cancer patients with high HNF1A expression had a better overall survival than those with low HNF1A expression (17.9 months vs 12.4 months), and the difference was statistically significant (P<0.001). HNF1A low expression in pancreatic cancer tissue was significantly associated with advanced TNM stage, perineural invasion (PNI) and short overall survival. The expression level of HNF1A was significantly down-regulated in drug-resistant PANC1 cells compared to drug-sensitive BxPC-3 cells by an average fold change of 6.73, and the difference was statistically significant (P<0.001). In HNF1A group, the mRNA and protein levels of ABCC1 were significantly decreased compared with those in control group (0.012±0.004vs0.047±0.008, 0.281±0.040vs0.832±0.046, P=0.003, P<0.001). IC50 of HNF1A group to gemcitabine plus abraxane was decreased compared with that of control group [(26.31±2.91)μmol/L vs (72.63±4.07) μmol/L], and the cell apoptosis rate of HNF1A group was increased compared with that of control group [(40.18±1.64)% vs(21.31±1.98)%], and the differences were statistically significant (P<0.01). Conclusions HNF1A may induce resistance of pancreatic cancer cell to gemcitabine plus abraxane by downregulating ABCC1. Key words: Pancreatic neoplasms; Hepatocyte nuclear factor 1A; Chemistry therapy; Drug resistance, neoplasm