Role of Damage DNA-Binding Protein 1 in Pancreatic Cancer Progression and Chemoresistance.

Yiyin Zhang,Yubin Lei,Chen Liang,Qingcai Meng,Bo Zhang,Xianjun Yu,Jie Hua,Jin Xu,Jiang Liu,Si Shi

doi:10.3390/cancers11121998

Abstract

Damaged DNA-binding protein 1 (DDB1) recruits nucleotide excision pathway proteins to form the UV-damaged DNA-binding protein complex and is required for DNA repair. DDB1 was reported to participate in apoptosis and chemoresistance regulation in several cancers. However, little is known about the function of DDB1 in pancreatic adenocarcinoma (PDAC). In this study, we reported that DDB1 functions as a tumor-promoting factor in PDAC by regulating cancer cell proliferation, epithelial-mesenchymal transition (EMT) and chemoresistance. Compared to normal pancreatic tissues, PDAC tissues had high expression levels of DDB1, and this high expression was positively correlated with poor prognosis. Furthermore, reductions in cell proliferation and EMT were observed in DDB1-deficient PDAC cell lines. Intriguingly, we also found that abrogation of DDB1 expression increased PDAC cell sensitivity to gemcitabine (GEM). Mechanistically, DDB1 knockdown was associated with an increase in deoxycytidine kinase expression in vivo and in vitro. In summary, our work demonstrated that DDB1 promotes PDAC progression and chemoresistance and may serve as a potential predictive marker and therapeutic target for PDAC treatment.

Highlights

Despite the low incidence of pancreatic cancer, it still ranks as the fourth leading cause of cancer-related deaths in the United States [1]
Interactive Analysis (GEPIA) dataset, we found that Damaged DNA-binding protein 1 (DDB1) transcription was increased significantly in pancreatic cancer tissues and varied in different stages (Figure 1A,B); high mRNA expression of
This was consistent with the prognostic data from our center, as higher expression of DDB1 was detected in tumoral areas (Figure 1E), which was confirmed at the mRNA level from 45 paired samples

Summary

Introduction

Despite the low incidence of pancreatic cancer, it still ranks as the fourth leading cause of cancer-related deaths in the United States [1]. 80% of patients have metastatic disease when first diagnosed, and other than direct surgical resection, chemotherapy remains the main treatment for pancreatic ductal adenocarcinoma (PDAC). Gemcitabine (GEM), has been regarded as the cornerstone of chemotherapy for PDAC since 1997 and various GEM-based chemotherapy combinations have been developed in the past 2 decades [2,3]. The efficacy of either GEM monotherapy or combinations remains disappointing. It is of vital importance to explore the potential mechanism of GEM resistance and to invent new therapeutic strategies to conquer PDAC. GEM enters the cytosol mainly through the human equilibrative nucleoside transporter-1 [4] and is phosphorylated into difluorodeoxycytidine monophosphate (dFdCMP) by deoxycytidine kinase (dCK)

Methods

Results

Discussion

Conclusion