Abstract
BackgroundDNA repair pathways are used by cancer cells to overcome many standard anticancer treatments, causing therapy resistance. Here, we investigated the role of XRCC4-like factor (XLF), a core member of the non-homologous end joining (NHEJ) repair pathway, in chemoresistance in hepatocellular carcinoma (HCC).MethodsqRT-PCR analysis and western blotting were performed to detect expression levels of genes and proteins related to NHEJ. NHEJ repair capacity was assessed in vitro (cell-free) and in vivo by monitoring the activity of the NHEJ pathway. Cell viability and IC50 assays were used to measure sensitivity to drug therapy. A xenograft HCC model was used to develop methods of targeting XLF-induced chemosensitization. Clinicopathological analysis was conducted on patients with HCC treated with transarterial chemoembolization (TACE).ResultsMany conventional cancer chemotherapeutics induce DNA double-strand breaks (DSBs). HCC cells respond to these breaks by increasing their NHEJ activity, resulting in resistance. XLF-knockdown cells show an inhibition of NHEJ activity in both cell-free and live-cell assays as well as a high level of unrepaired cellular DSBs. These results indicate that XLF facilitates DNA end-joining and therefore promotes NHEJ activity in cancer cells. Consequently, knockdown of XLF significantly chemosensitized resistant cells both in vitro and in xenograft tumors. A low rate of XLF genomic alteration was found in patients with primary HCC, but XLF expression was induced after drug treatment. Clinically, a high level of XLF expression is significantly associated with advanced HCC and shorter overall survival.ConclusionChemotherapy-induced overexpression of XLF and XLF-mediated enhancements in NHEJ activity contribute to chemoresistance in HCC cells and patients with HCC. Targeting XLF to modulate DSB repair could enhance drug sensitivity and may be a therapeutically useful addition to conventional therapy.
Highlights
DNA repair pathways are used by cancer cells to overcome many standard anticancer treatments, causing therapy resistance
Therapy sensitivity is associated with non-homologous end joining (NHEJ) activity To better understand how DNA damage repair contributes to hepatocellular carcinoma (HCC) therapy resistance, we first investigated the correlation between the presence of DNA lesions induced by chemotherapeutic drugs and cellular sensitivity
Given that XLFmediated induction of NHEJ activity in HCC cells is associated with chemotherapeutic drug sensitivity (Figs. 1 and 2), we investigated the incidence of X-ray-cross-complementation gene 4 (XRCC4)-like factor (XLF) gene alterations using bioinformatic analysis
Summary
DNA repair pathways are used by cancer cells to overcome many standard anticancer treatments, causing therapy resistance. Druginduced DNA lesions are recognized by DNA damage response (DDR) factors, which activate cell cycle checkpoints and direct DNA repair pathways. These events enable tumor cells to survive chemotherapy. The effectiveness of DNA-damaging drugs largely depends on the DNA damage repair capacity of a cancer cell. Using a combination of DNA-damaging drugs and drugs targeting DDR and DNA damage repair pathways is an obvious. Cancers often develop defects in genes associated with DNA repair pathways.
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