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

Sho Takeda, Kunitoshi Shigeyasu, Yoshinaga Okugawa, Kazuhiro Yoshida, Yoshiko Mori, Shuuya Yano, Kazuhiro Noma, Yuzo Umeda, Yoshitaka Kondo, Hiroyuki Kishimoto, Fuminori Teranishi, Takeshi Nagasaka, Hiroshi Tazawa, Shunsuke Kagawa, Toshiyoshi Fujiwara, Ajay Goel

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)127-135
Number of pages9
JournalCancer Letters
Volume444
DOIs
Publication statusPublished - Mar 1 2019

Fingerprint

RNA Editing
Colorectal Neoplasms
Fibroblasts
Tumor Microenvironment
Neoplasms
Inosine
Vimentin
Conditioned Culture Medium
Epigenomics
Adenosine
Colon
Mucous Membrane
Cancer-Associated Fibroblasts
Proteins

Keywords

  • ADAR1
  • AZIN1
  • Biomarker
  • Cancer associated fibroblasts
  • Colorectal cancer
  • RNA editing

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

@article{769b09fbbd7b435f85d1aaed81418e62,
title = "Activation of AZIN1 RNA editing is a novel mechanism that promotes invasive potential of cancer-associated fibroblasts in colorectal cancer",
abstract = "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.",
keywords = "ADAR1, AZIN1, Biomarker, Cancer associated fibroblasts, Colorectal cancer, RNA editing",
author = "Sho Takeda and Kunitoshi Shigeyasu and Yoshinaga Okugawa and Kazuhiro Yoshida and Yoshiko Mori and Shuuya Yano and Kazuhiro Noma and Yuzo Umeda and Yoshitaka Kondo and Hiroyuki Kishimoto and Fuminori Teranishi and Takeshi Nagasaka and Hiroshi Tazawa and Shunsuke Kagawa and Toshiyoshi Fujiwara and Ajay Goel",
year = "2019",
month = "3",
day = "1",
doi = "10.1016/j.canlet.2018.12.009",
language = "English",
volume = "444",
pages = "127--135",
journal = "Cancer Letters",
issn = "0304-3835",
publisher = "Elsevier Ireland Ltd",

}

TY - JOUR

T1 - Activation of AZIN1 RNA editing is a novel mechanism that promotes invasive potential of cancer-associated fibroblasts in colorectal cancer

AU - Takeda, Sho

AU - Shigeyasu, Kunitoshi

AU - Okugawa, Yoshinaga

AU - Yoshida, Kazuhiro

AU - Mori, Yoshiko

AU - Yano, Shuuya

AU - Noma, Kazuhiro

AU - Umeda, Yuzo

AU - Kondo, Yoshitaka

AU - Kishimoto, Hiroyuki

AU - Teranishi, Fuminori

AU - Nagasaka, Takeshi

AU - Tazawa, Hiroshi

AU - Kagawa, Shunsuke

AU - Fujiwara, Toshiyoshi

AU - Goel, Ajay

PY - 2019/3/1

Y1 - 2019/3/1

N2 - 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.

AB - 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.

KW - ADAR1

KW - AZIN1

KW - Biomarker

KW - Cancer associated fibroblasts

KW - Colorectal cancer

KW - RNA editing

UR - http://www.scopus.com/inward/record.url?scp=85059133645&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85059133645&partnerID=8YFLogxK

U2 - 10.1016/j.canlet.2018.12.009

DO - 10.1016/j.canlet.2018.12.009

M3 - Article

VL - 444

SP - 127

EP - 135

JO - Cancer Letters

JF - Cancer Letters

SN - 0304-3835

ER -