RAD51 is a potential marker for prognosis and regulates cell proliferation in pancreatic cancer

Xiaomeng Zhang,Shuo Li,Weiqiang Yao,Ningyi Ma,Zhigang Ren

doi:10.1186/s12935-019-1077-6

Abstract

BackgroundThe DNA damage and repair pathway is considered a promising target for developing strategies against cancer. RAD51, also known as RECA, is a recombinase that performs the critical step in homologous recombination. RAD51 has recently received considerable attention due to its function in tumor progression and its decisive role in tumor resistance to chemotherapy. However, its role in pancreatic cancer has seldom been investigated. In this report, we provide evidence that RAD51, regulated by KRAS, promotes pancreatic cancer cell proliferation. Furthermore, RAD51 regulated aerobic glycolysis by targeting hypoxia inducible factor 1α (HIF1α).MethodsTCGA (The Cancer Genome Atlas) dataset analysis was used to examine the impact of RAD51 expression on overall survival of pancreatic cancer patients. Lentivirus-mediated transduction was used to silence RAD51 and KRAS expression. Quantitative real-time PCR and western blot analysis validated the efficacy of the knockdown effect. Analysis of the glycolysis process in pancreatic cancer cells was also performed. Cell proliferation was determined using a CCK-8 (Cell Counting Kit-8) proliferation assay.ResultsPancreatic cancer patients with higher levels of RAD51 exhibited worse survival. In pancreatic cancer cells, RAD51 positively regulated cell proliferation, decreased intracellular reactive oxygen species (ROS) production and increased the HIF1α protein level. KRAS/MEK/ERK activation increased RAD51 expression. In addition, RAD51 was a positive regulator of aerobic glycolysis.ConclusionThe present study reveals novel roles for RAD51 in pancreatic cancer that are associated with overall survival prediction, possibly through a mechanism involving regulation of aerobic glycolysis. These findings may provide new predictive and treatment targets for pancreatic cancer.

Highlights

The DNA damage and repair pathway is considered a promising target for developing strategies against cancer
We examined the correlation between RAD51 and KRAS mutation and the impact of RAD51 on cell proliferation and glucose metabolism reprogramming in pancreatic cancer
RAD51 expression predicted prognosis in pancreatic cancer To validate the role of RAD51 expression in pancreatic cancer prognosis, we used The Cancer Genome Atlas (TCGA) database to examine the correlation between RAD51 expression and overall survival of pancreatic cancer patients

Summary

Introduction

The DNA damage and repair pathway is considered a promising target for developing strategies against cancer. It is well accepted that DNA damage is a recurring phenomenon in biology and plays an important role in cancer development [3, 4]. Germline mutations in some of the DNA repair machinery components have been discovered in pancreatic cancer, indicating the involvement of DNA damage response factors in pancreatic cancer development and progression [8, 9]. Approximately 10% of sporadic pancreatic adenocarcinoma patients harbor mutations of BRCA2, a tumor suppressor that plays important roles in DNA break repair and homologous recombination [10]. ATM and ATR (Ataxia Telangiectasia And Rad Related) can phosphorylate a number of substrates, including the checkpoint kinase CHK1 (Check point kinase 1), which mediates cell-cycle arrest to facilitate DNA repair [13]. Expression of CHK1 has been reported to be elevated in pancreatic cancer, and inhibitors targeting CHK1 have been shown to have clinical potential for treatment of pancreatic cancer [9, 14, 15]

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