Abstract
Quaking homolog (QKI) is a member of the RNA‐binding signal transduction and activator of proteins family. Previous studies showed that QKI possesses the tumour suppressor activity in human cancers by interacting with the 3'‐untraslated region (3'‐UTR) of various gene transcripts via the STAR domain. This study first assessed the association of QKI‐6 expression with clinicopathological and survival data from bladder cancer patients and then investigated the underlying molecular mechanisms. Bladder cancer tissues (n = 223) were subjected to immunohistochemistry, and tumour cell lines and nude mice were used for different in vitro and in vivo assays following QKI‐6 overexpression or knockdown. QKI‐6 down‐regulation was associated with advanced tumour TNM stages and poor patient overall survival. QKI‐6 overexpression inhibited bladder cancer cell growth and invasion capacity, but induced tumour cell apoptosis and cell cycle arrest. Furthermore, ectopic expression of QKI‐6 reduced tumour xenograft growth and expression of proliferation markers, Ki67 and PCNA. However, knockdown of QKI‐6 expression had opposite effects in vitro and in vivo. QKI‐6 inhibited expression of E2 transcription factor 3 (E2F3) by directly binding to the E2F3 3'‐UTR, whereas E2F3 induced QKI‐6 transcription by binding to the QKI‐6 promoter in negative feedback mechanism. QKI‐6 expression also suppressed activity and expression of nuclear factor‐κB (NF‐κB) signalling proteins in vitro, implying a novel multilevel regulatory network downstream of QKI‐6. In conclusion, QKI‐6 down‐regulation contributes to bladder cancer development and progression.
Highlights
Bladder cancer remains a significant health problem in both men and women worldwide.[1]
We found that E2 transcription factor 3 (E2F3) enhanced Quaking homologue (QKI)‐6 promoter luciferase activity (Figure 7H)
We found that 20 μmol of pyrrolidin‐ edithiocarbamate (PDTC) treatment for 6 hours significantly down‐regulated p‐nuclear factor‐κB (NF‐κB) in both the T24 vector and QKI‐6 group and in the 5637 sh‐NC and sh‐QKI‐6 group (Figure 9A,B)
Summary
Bladder cancer remains a significant health problem in both men and women worldwide.[1]. Risk factors for de‐ veloping bladder cancer include tobacco smoking and occupational exposure to carcinogens (like benzidine).[6] These risk factors can alter gene expression and promote bladder carcinogenesis.[6]. More recent studies demonstrated that QKI pos‐ sesses tumour suppressor activity in various human cancers, includ‐ ing glioblastoma, and prostate, colon, lung, gastric, oral and kidney cancers.[9,11,14-18]. E2 transcription factor 3 (E2F3) is localized at chromosome 6p22, where gene amplification occurs in approximately 9% of bladder can‐ cers and is associated with a higher bladder tumour stage and grade, suggesting that E2F3 is an oncogene.[19]. Our findings provide novel insight into the role of QKI‐6 in bladder cancer development and progression and postulate that targeting the QKI‐6‐E2F3 interaction and NF‐κB signalling pathway could serve as a therapeutic strategy to clinically control bladder cancer
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