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ADAR2 functions as a tumor suppressor via editing IGFBP7 in esophageal squamous cell carcinoma
Yuan-Bin Chen1, Xiao-Yu Liao1, Jiang-Bo Zhang1
1State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China.
Abstract:
Esophageal squamous cell carcinoma (ESCC), one of the most aggressive cancers, is characterized by heterogeneous genetic and epigenetic changes. Recently, A-to-I RNA editing, catalyzed by adenosine deaminases acting on RNA (ADARs), was found to be aberrantly regulated during tumorigenesis. We previously reported that ADAR2 was downregulated in ESCC but its role was unclear. Thus, we report here that overexpression of ADAR2 can induce apoptosis in ESCC cell lines and inhibit tumor growth in vitro and in vivo. ADAR2 knockdown inhibited apoptosis in ADAR2 highly expressing tumor cells. RNA-seq assay showed that ADAR2, not ADAR1 or active-site-mutated ADAR2, could edit insulin-like growth factor binding protein 7 (IGFBP7) mRNA in ESCC. IGFBP7 knockdown or ADAR2 catalytic activity destruction abolished the pro-apoptotic function of ADAR2. Mechanistically, RNA editing may stabilize IGFBP7 protein by changing the protease recognition site of matriptase and this is essential for IGFBP7 to induce apoptosis. Western blotting revealed that ADAR2 overexpression could induce IGFBP7-dependent inhibition of Akt signaling. Thus, our data indicate that ADAR2 suppresses tumor growth and induces apoptosis by editing and stabilizing IGFBP7 in ESCC, and this may represent a novel therapeutic target for treating ESCC.
Insights
Adenosine deaminase acting on RNA 2 (ADAR2) suppresses esophageal squamous cell carcinoma (ESCC) growth by editing and stabilizing insulin-like growth factor binding protein 7 (IGFBP7), promoting apoptosis and inhibiting tumor progression.
Area of Science:
- Oncology
- Molecular Biology
- RNA Biology
Background:
- Esophageal squamous cell carcinoma (ESCC) is an aggressive cancer with complex genetic alterations.
- Aberrant RNA editing by adenosine deaminases acting on RNA (ADARs) is implicated in tumorigenesis.
- Previous studies showed ADAR2 downregulation in ESCC, but its specific role remained unclear.
Purpose of the Study:
- To investigate the role of ADAR2 in ESCC tumorigenesis.
- To elucidate the molecular mechanism by which ADAR2 affects ESCC progression.
- To explore ADAR2 as a potential therapeutic target for ESCC.
Main Methods:
- Overexpression and knockdown of ADAR2 in ESCC cell lines.
- In vitro and in vivo tumor growth assays.
- RNA sequencing (RNA-seq) to identify ADAR2 targets.
- Western blotting to assess protein levels and signaling pathways.
- Analysis of insulin-like growth factor binding protein 7 (IGFBP7) editing and function.
Main Results:
- ADAR2 overexpression induced apoptosis and inhibited tumor growth in ESCC models.
- ADAR2 specifically edited IGFBP7 mRNA, stabilizing its protein.
- IGFBP7 stabilization by ADAR2 was crucial for its pro-apoptotic function.
- ADAR2-mediated IGFBP7 upregulation inhibited Akt signaling.
Conclusions:
- ADAR2 acts as a tumor suppressor in ESCC by editing and stabilizing IGFBP7.
- This mechanism involves enhanced apoptosis and suppressed tumor growth.
- ADAR2-IGFBP7 axis represents a potential novel therapeutic strategy for ESCC.
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