Flap endonuclease 1 is a promising candidate biomarker in gastric cancer and is involved in cell proliferation and apoptosis

Abstract

As a DNA repair protein, flap endonuclease 1 (FEN1), a structure-specific 5' nuclease, plays pivotal roles in the maturation of Okazaki fragments, long-patch base excision repair, restarting of stalled replication forks and telomere maintenance. FEN1 possesses 5' endonuclease, 5' exonuclease and gap-endonuclease activities, which render it an essential node in maintaining genome fidelity. The aim of this study was to investigate the association between the expression level of FEN1 and gastric cancer and to explore the role of FEN1 in carcinogenesis and the progression of gastric cancer. The mRNA and protein expression of FEN1 in 42 matched pairs of human gastric tumor tissues and corresponding normal tissues were measured by semiquantitative reverse transcription-PCR and immunohistochemical staining. FEN1 expression was downregulated in the SGC-7901 gastric cancer cells following transfection with siRNA targeting the FEN1 gene. Western blot analysis was used to evaluate the protein expression of FEN1 in SGC-7901 human gastric cancer cells in order to verify the transfection efficiency of FEN1 siRNA. Moreover, cell proliferation was analyzed by MTS assay. The apoptosis of the cells was determined by flow cytometry. Our results revealed that FEN1 was overexpressed in gastric cancer in comparison to the corresponding normal gastric tissues (P<0.01). We further confirmed that FEN1 expression has a positive correlation with the degree of differentiation (P=0.027), lymphatic metastasis (P=0.001), tumor size (P=0.026) and TNM stage (P=0.020) of gastric cancer. A high FEN1 expression in SGC-7901 cells can be effectively downregulated by siRNA constructed to target the FEN1 gene. Moreover, the inhibition of FEN1 expression suppressed the proliferation and induced the apoptosis of SGC-7901 cells. Taken together, our results indicate that FEN1 may be a promising biomarker for the diagnosis of gastric cancer and individual therapy.

Targeting DNA Flap Endonuclease 1 to Impede Breast Cancer Progression

“…Cancer cells are characterized by their ability to divide rapidly. As a critical enzyme for DNA replication, overexpression of FEN1 is believed to be a biomarker of cancer cells (Wang et al, 2014, Abdel-Fatah et al, 2014). Indeed, we and other groups demonstrated that FEN1 is overexpressed in various types of cancers (Fig.…”

“…Indeed, there is growing evidence that FEN1 expression is associated with the onset and progression of cancer. FEN1 is expressed at low levels in quiescent cells (Kim et al, 2000), but is highly expressed in proliferative tissues and cancers including lung (Nikolova et al, 2009), breast (Singh et al, 2008), gastric (Wang et al, 2014), prostate (Lam et al, 2006), pancreatic (Iacobuzio-Donahue et al, 2003) and brain cancers (Krause et al, 2005). Moreover, the level of FEN1 expression in cancer tissues has been correlated with increased cancer grade and aggressiveness (Abdel-Fatah et al, 2014).…”

DNA Repair Endonucleases: Physiological Roles and Potential as Drug Targets

“…47,48 For example in several cancer types, including, head and neck cancer, ovarian cancer, osteosarcoma, lung cancer, and melanoma, low APE1 expression has been shown to be a marker of better prognosis and positive response to both chemotherapy and radiotherapy. [49][50][51][52][53] In a screen of 103 patients with non-small cell lung cancer, more than 70% of patients displayed high APE1 expression. APE1 was expressed in both the nucleus and also cytoplasm in the majority of tumor samples in contrast to normal healthy lung tissue, where APE1 staining was mostly seen only in the nucleus.…”

“…[58][59][60][61][62] However, in human studies, FEN1 has frequently been shown to be overexpressed in a number of tumors, including breast, ovarian, colorectal, stomach, lung, and kidney cancers, and is associated with resistance to therapy due to increased DNA repair capacity. 50,57,63,64 It has recently been shown in a large cohort of patients with breast cancer that high FEN1 expression correlated to an aggressive phenotype and decreased overall survival. 63 FEN1 protein staining was observed in both the nucleus alone, cytoplasm alone, and both nucleus/cytoplasm.…”

FEN1 knockdown improves trastuzumab sensitivity in human epidermal growth factor 2-positive breast cancer cells

“…Although FEN1 is generally regarded as a tumor suppressor gene, many studies have reported that it is highly expressed in proliferative cancer cells and is essential for cell growth and proliferation in tumor tissues (9)(10)(11). Notably, FEN1 expression is significantly upregulated by chemotherapy (5) and other genotoxic stresses, such as DNA-alkylating drugs (12) and radiation treatment (13).…”