Abstract 66P
Background
Damage specific DNA binding protein 2 (DDB2) is originally implied in the recognition of ultraviolet-induced DNA damage and the initiation of nucleotide excision repair (NER) process. This protein also demonstrated dual roles in several cancers, acting either as an oncogene or a tumor suppressor gene depending on cancer localization. In this study, we investigated the unresolved role of DDB2 in pancreatic ductal adenocarcinoma (PDAC).
Methods
The expression level of DDB2 in pancreatic cancer tissues and its correlation with patient survival were evaluated using publicly available data. Two PDAC cell models with CRISPR-modified DDB2 expression were developed: DDB2 was repressed in DDB2-high T3M4 cells (T3M4 KO) while DDB2 was overexpressed in DDB2-low Capan-2 cells (Capan-2 ACT). Immunofluorescence and qPCR assays were used to investigate epithelial-to-mesenchymal transition (EMT) in these models. Migration and invasion properties of the cells were also determined using wound healing and transwell assays. Sensitivity to 5-fluorouracil (5-FU), oxaliplatin, irinotecan and gemcitabine were finally investigated by crystal violet assays.
Results
DDB2 expression level was reduced in PDAC tissues compared to normal ones and DDB2-low levels were correlated to shorter disease-free survival in PDAC patients. DDB2 knockout in T3M4 cells enhanced the transcription of SNAIL, ZEB1 and TWIST EMT transcription factors (EMT-TFs), increased the expression of the N-cadherin mesenchymal marker and decreased the levels of the E-cadherin epithelial marker. Conversely, DDB2 overexpression in Capan-2 cells increased E-cadherin levels and decreased N-cadherin levels. The migration and invasion properties were negatively correlated with DDB2 expression in both cell models. DDB2 has no effect on T3M4 cell sensitivity to chemotherapy but sensitized Capan-2 cells to 5-FU, oxaliplatin and gemcitabine.
Conclusions
Our study highlights the potential tumor-suppressive effects of DDB2 on PDAC progression. DDB2 could thus represent a promising therapeutic target and a prognosis and predictive biomarker in patients with PDAC.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.