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
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DOI：
10.1016/j.canlet.2018.12.009
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发表时间：
2019-01-01
期刊：
影响因子：
9.7
通讯作者：
Goel, Ajay
中科院分区：
文献类型：
--
作者：
Takeda, Sho;Shigeyasu, Kunitoshi;Goel, Ajay
腺苷转肌苷（Adenosine-to-inosine，A-to-I）RNA编辑是近年来发现的一种表观遗传修饰，被认为是人类肿瘤发生的重要机制之一。然而，其在肿瘤微环境（TME）内的癌症相关成纤维细胞（CAF）中的功能作用及其临床意义仍不清楚。本文系统分析了627例结直肠癌（CRC）标本，研究了ADAR 1在抗酶抑制剂1（AZIN 1）RNA编辑水平上的表达模式及其生物学意义。与正常粘膜相比，CRC组织中ADAR 1表达和AZIN 1 RNA编辑水平均显著升高，这些发现与间充质标志物波形蛋白（p = 0.44）和成纤维细胞活化蛋白（p = 0.38）的表达增加相关。有趣的是，ADAR 1表达在癌细胞和癌性病变的成纤维细胞中特异性上调。来自癌细胞的条件培养基导致成纤维细胞中ADAR 1表达的诱导和AZIN 1 RNA编辑的激活（p < 0.05）。此外，编辑的AZIN 1增强了成纤维细胞的侵袭潜力。总之，我们提供了新的证据，证明AZIN 1的超编辑增强了结肠TME内CAF的侵袭潜力，并且是CRC中肿瘤侵袭性的重要预测因子。
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 (p = 0.44) and Fibroblast activation protein (p = 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.