Abstract
Simple SummaryDDX11, a helicase involved in sister chromatid cohesion, was identified as a significant biomarker of aggressive renal cell carcinoma (RCC) in our previous studies. In this study, we evaluated the molecular pathways through which DDX11 is involved in RCC cell survival. Furthermore, we assessed the sensitivity of poly (ADP-ribose) polymerase (PARP) inhibitors, which have not been used in RCC treatment, in association with DDX11 expression. DDX11-deficient RCC inhibited RCC proliferation, caused defects in segregation, and increased apoptosis. DDX11-deficient RCC was associated with increased sensitivity to PARP inhibition. DDX11 could be a novel therapeutic and prognostic biomarker for RCC patients, and this study is the first to suggest the use of PARP inhibitors in DDX11-deficient RCC patients.Genes associated with the DEAD-box helicase DDX11 are significant biomarkers of aggressive renal cell carcinoma (RCC), but their molecular function is poorly understood. We analyzed the molecular pathways through which DDX11 is involved in RCC cell survival and poly (ADP-ribose) polymerase (PARP) inhibitor sensitivity. Immunohistochemistry and immunoblotting determined DDX11 expression in normal kidney tissues, benign renal tumors, and RCC tissues and cell lines. Quantitative polymerase chain reaction validated the downregulation of DDX11 in response to transfection with DDX11-specific small interfering RNA. Proliferation analysis and apoptosis assays were performed to determine the impact of DDX11 knockdown on RCC cells, and the relevant effects of sunitinib, olaparib, and sunitinib plus olaparib were evaluated. DDX11 was upregulated in high-grade, advanced RCC compared to low-grade, localized RCC, and DDX11 was not expressed in normal kidney tissues or benign renal tumors. DDX11 knockdown resulted in the inhibition of RCC cell proliferation, segregation defects, and rapid apoptosis. DDX11-deficient RCC cells exhibited significantly increased sensitivity to olaparib compared to sunitinib alone or sunitinib plus olaparib combination treatments. Moreover, DDX11 could determine PARP inhibitor sensitivity in RCC. DDX11 could serve as a novel therapeutic biomarker for RCC patients who are refractory to conventional targeted therapies and immunotherapies.
Highlights
The understanding of the biology of renal cell carcinoma (RCC), especially the perturbed pathways that lead to the development and growth of tumors and their multiple subtypes with distinct molecular abnormalities, has been steadily improving [1,2]
Immunohistochemistry analysis of cryopreserved tissue sections prepared from normal kidney, benign renal tumors, localized low-grade ccRCC, localized high-grade ccRCC, and advanced high-grade ccRCC using an antibody against human DDX11 revealed strong expression of DDX11 in advanced and high-grade ccRCC, whereas weak DDX11 expression was noted in localized and low-grade ccRCC (Figure 1A)
Subsequent immunoblot analysis revealed strong DDX11 expression in advanced and high-grade ccRCC, but no DDX11 expression was observed in normal kidney tissues or benign renal tumors (Figure 1B)
Summary
The understanding of the biology of renal cell carcinoma (RCC), especially the perturbed pathways that lead to the development and growth of tumors and their multiple subtypes with distinct molecular abnormalities, has been steadily improving [1,2]. Treatments for advanced RCC have become markedly advanced over the past 30 years due to significant improvements in our understanding of this cancer [2]. Multiple therapeutic agents with varying mechanisms are available, and combinatorial therapy using agents with different mechanisms is being explored. Appropriate therapeutic effects of a combinatorial regimen along with dosage optimization will need to be ascertained to avoid treatment discontinuation due to intolerable toxicity and ensure that a marked therapeutic outcome can be achieved [5]
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