AZIN1 RNA editing confers cancer stemness and enhances oncogenic potential in colorectal cancer

Shigeyasu, Kunitoshi; Okugawa, Yoshinaga; Toden, Shusuke; Miyoshi, Jinsei; Toiyama, Yuji; Nagasaka, Takeshi; Takahashi, Naoki; Kusunoki, Masato; Takayama, Tetsuji; Yamada, Yasuhide; Fujiwara, Toshiyoshi; Chen, Leilei; Goel, Ajay

doi:10.1172/jci.insight.99976

Cited by 100 publications

(101 citation statements)

References 38 publications

(43 reference statements)

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“…All cell lines were cultured according to the manufacturer's specifications. All cell lines were tested and authenticated every few months using a panel of established genetic markers [12]. All experiments were performed using cells that did not exceed 15-20 passages.…”

Section: Cell Linesmentioning

confidence: 99%

“…RNA editing is a recently identified epigenetic mechanism that regulates posttranscriptional activity of key oncogenes by altering their amino acid sequence and leading to changes in oncogenic function [8]. For example, recent studies have determined that dysregulation of RNA editing is involved in the development of hepatocellular carcinoma (HCC), gastric cancer, and colorectal cancer (CRC) [9][10][11][12]. Such a RNA editing process, wherein the conversion of an adenosine (A) to inosine (I) in primary RNA transcripts (A-to-I editing) is mediated by Adenosine Deaminase family Acting on RNA (ADAR), leading to diversification of the transcriptome in human cells [13].…”

Section: Introductionmentioning

confidence: 99%

“…One of the targets of RNA editing, Antizyme inhibitor 1 (AZIN1), confers a gain-of-function phenotype frequently through A-to-I conversions, which can promote ornithine decarboxylase (ODC) and polyamines accumulation − conditions that are associated with aggressive tumors [9,10]. Intriguingly, AZIN1 is also an important target of ADAR1 in various cancers [9][10][11][12].…”

Section: Introductionmentioning

confidence: 99%

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Activation of AZIN1 RNA editing is a novel mechanism that promotes invasive potential of cancer-associated fibroblasts in colorectal cancer

et al. 2019

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Adenosine-to-inosine (A-to-I) RNA editing is a recently described epigenetic modification, which is believed to constitute a key oncogenic mechanism in human cancers. However, its functional role in cancer-associated fibroblasts (CAFs) within the tumor microenvironment (TME) and its clinical significance remains unclear. Herein, we systematically analyzed a large cohort of 627 colorectal cancer (CRC) specimens, and investigated the expression pattern of ADAR1 and its biological significance on the antizyme inhibitor 1 (AZIN1) RNA editing levels. Both ADAR1 expression and AZIN1 RNA editing levels were significantly elevated in CRC tissues vs. normal mucosa, and these findings correlated with the increased expression of mesenchymal markers, Vimentin (ρ = 0.44) and Fibroblast activation protein (ρ = 0.38). Intriguingly, ADAR1 expression was specifically upregulated in both cancer cells and fibroblasts from cancerous lesions. Conditioned medium from cancer cells led to induction of ADAR1 expression and activation of AZIN1 RNA editing in fibroblasts (p < 0.05). Additionally, edited AZIN1 enhanced the invasive potential of fibroblasts. In conclusion, we provide novel evidence that hyper-editing of AZIN1 enhances the invasive potential of CAFs within the TME in colon and is an important predictor of tumor invasiveness in CRC.

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Section: Cell Linesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Activation of AZIN1 RNA editing is a novel mechanism that promotes invasive potential of cancer-associated fibroblasts in colorectal cancer

et al. 2019

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“…The association between the tumor aggressiveness and the overexpression of ADAR has also been demonstrated in hepatocellular carcinoma and colorectal cancer [26,27]. Based on available evidences, the molecular mechanisms of how ADAR promotes GC cell growth and migration might be explained by its role in the regulation of mTOR signaling pathway.…”

Section: Discussionmentioning

confidence: 93%

ADAR expression and copy number variation in patients with advanced gastric cancer

Behroozi

Shahbazi²,

Bakhtiarizadeh

et al. 2020

Preprint

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Background Gastric cancer (GC) is a world health problem and it is the third leading cause of cancer deaths worldwide. The current practice for prognosis assessment in GC is based on radiological and pathological criteria and they may not result in an accurate prognosis. The aim of this study is to evaluate expression and copy number variation of the ADAR gene in advanced GC and clarify its correlation with survival and histopathological characteristics. Methods Forty two patients with stage III and IV GC were included in this study. ADAR gene expression and copy number variation were measured by real-time PCR and Quantitative multiplex ﬂuorescent-PCR, respectively. Survival analysis performed based on the Kaplan–Meier method and Mantel–Cox test. Results ADAR mRNA was significantly overexpressed in the tumor tissues when compared to the adjacent normal tissues (p <0.01). Also, ADAR expression level in stage IV was higher than stage III. 40% of patients showed amplification in ADAR gene and there was a positive correlation between ADAR copy number and expression. Increased ADAR expression was clearly correlated with poorer survival outcomes and Mantel–Cox test showed statistically significant differences between low and high expression groups (p <0.0001). ADAR overexpression and amplification were significantly associated with metastasis, size and stage of tumor. Conclusions Together, our data indicate that amplification leads to over expression of ADAR and it could be used as a prognostic biomarker for disease progression, especially for the metastatic process in GC. Keywords Gastric cancer, ADAR gene, Overexpression, Amplification, Prognosis

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“…High levels of AZIN1 RNA editing have been observed in several cancer types [120,[131][132][133][134][135]. In addition, AZIN1 RNA editing has been shown to be a potential prognostic biomarker for overall survival and an independent risk factor for lymph node and distant metastasis in some cancers [131][132][133]. Moreover, Han et al [126] found a correlation between RNA editing with drug sensitivity, in which the sensitivities of paclitaxel, irinotecan, and topotecan are associated with editing in AZIN1.…”

Section: Rna Editing Rewires Rna Communication Networkmentioning

confidence: 99%

The Butterfly Effect of RNA Alterations on Transcriptomic Equilibrium

Desi

Tay

2019

Cells

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Post-transcriptional regulation plays a key role in modulating gene expression, and the perturbation of transcriptomic equilibrium has been shown to drive the development of multiple diseases including cancer. Recent studies have revealed the existence of multiple post-transcriptional processes that coordinatively regulate the expression and function of each RNA transcript. In this review, we summarize the latest research describing various mechanisms by which small alterations in RNA processing or function can potentially reshape the transcriptomic landscape, and the impact that this may have on cancer development.

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AZIN1 RNA editing confers cancer stemness and enhances oncogenic potential in colorectal cancer

Cited by 100 publications

References 38 publications

Activation of AZIN1 RNA editing is a novel mechanism that promotes invasive potential of cancer-associated fibroblasts in colorectal cancer

Activation of AZIN1 RNA editing is a novel mechanism that promotes invasive potential of cancer-associated fibroblasts in colorectal cancer

ADAR expression and copy number variation in patients with advanced gastric cancer

The Butterfly Effect of RNA Alterations on Transcriptomic Equilibrium

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