Abstract
Enhancers are cis-acting elements that can promote the expression of target genes and respond to estrogen to induce the transcription of eRNAs, which are closely associated with cancer development. Further study on eRNAs may lead to a better understanding of the significance of transcriptional regulation and the progression of malignant tumors. SMAD7 enhancer RNA (SMAD7e) is an estrogen-responsive eRNA. However, the relationship between SMAD7e and bladder cancer remains unclear. SMAD7e was significantly upregulated in bladder cancer tissues and estrogen-stimulated cells. Knockdown of SMAD7e by CRISPR-Cas13a suppressed cell proliferation and migration, and induced cell apoptosis and inhibited cell invasion. Estrogen caused overexpression of SMAD7e and played a facilitating role in bladder cancer cells. Furthermore, knockdown of SMAD7e by CRISPR-Cas13a prevented the cancer-promoting effects of estrogen on bladder cancer both in vitro and in vivo. The present study suggested the crucial role of SMAD7e in bladder cancer. Estrogen might promote the development of bladder cancer by inducing SMAD7e production. These findings may provide a potential target for CRISPR-mediated gene therapy for bladder cancer in the future.
Highlights
Estrogen is reported to be associated with the development of many cancers (Horie, 2010)
SMAD7 enhancer RNA (SMAD7e) may function as a oncogenic factor in bladder cancer
We measured SMAD7e expression levels after estrogen stimulation for 1 h in 5637 cells and T24 cells, using RT qPCR. These results indicated that SMAD7e expression was significantly increased in bladder cancer cells when stimulated by estrogen (Figure 2A)
Summary
Estrogen is reported to be associated with the development of many cancers (Horie, 2010). The sex difference in morbidity suggests the importance of estrogen for bladder cancer development. The molecular mechanisms of estrogen in bladder cancer remain unclear. Recent studies have shown that SMAD7 plays a role in breast cancer development and progression (Rahman et al, 2017). It would be interesting to determine if the SMAD7e mediates the effect of estrogen on bladder cancer. The effects of SMAD7e knockdown on the proliferation, migration, apoptosis, and invasion of bladder cancer cells were determined. We demonstrated that SMAD7e knockdown mediated by CRISPR-Cas13a reduced the cancer-promoting ability of estrogen on bladder cancer cells both in vitro and in vivo. This work suggested CRISPR-Cas13a as an effective tool to target one specific enhancer RNA- SMAD7e in bladder cancer and revealed its advantage in anticancer research
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