IQGAP3 in clear cell renal cell carcinoma contributes to drug resistance and genome stability

Abstract

Background Clear cell renal clear cell carcinoma (ccRCC) is resistant to most chemotherapeutic drugs and the molecular mechanisms have not been fully revealed. Genomic instability and the abnormal activation of bypass DNA repair pathway is the potential cause of tumor resistance to radiotherapy and chemotherapy. IQ-motif GTPase activating protein 3 (IQGAP3) regulates cell migration and intercellular adhesion. This study aims to analysis the effects of IQGAP3 expression on cell survival, genome stability and clinical prognosis in ccRCC. Methods Multiple bioinformatics analysis based on TCGA database and IHC analysis on clinical specimens were included. Quantitative real-time polymerase chain reaction (qRT-PCR) and western blot (WB) were used to determine protein expression level. MTT assay and 3D spheroid cell growth assay were used to assess cell proliferation and drug resistance in RNAi transfected ccRCC cells. Cell invasion capacity was evaluated by transwell assay. The influence of IQGAP3 on genome instability was revealed by micronuclei number and γ H2AX recruitment test. Results The highly expressed IQGAP3 in multiple subtypes of renal cell carcinoma has a clear prognostic value. Deletion of IQGAP3 inhibits cell growth in 3D Matrigel. IQGAP3 depletion lso increases accumulated DNA damage, and improves cell sensitivity to ionizing radiation and chemotherapeutic drugs. Therefore, targeting DNA damage repair function of IQGAP3 in tumorigenesis can provide ideas for the development of new targets for early diagnosis.

Keywords

• Clear cell renal clear cell carcinoma
• IQGAP3
• Drug resistance
• Genomic stability
• DNA damage repair