Long noncoding RNA CCAL transferred from fibroblasts by exosomes promotes chemoresistance of colorectal cancer cells
Long noncoding RNA CCAL transferred from fibroblasts by exosomes promotes chemoresistance of colorectal cancer cells
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外泌体从成纤维细胞转移的长非编码RNA CCAL促进结直肠癌细胞的化疗耐药性
DOI：
10.1002/ijc.32608
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发表时间：
2019-08-27
影响因子：
6.4
通讯作者：
Guan, Ming
中科院分区：
文献类型：
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作者：
Deng, Xuan;Ruan, Haoyu;Guan, Ming
长链非编码RNA（lncRNA）参与结直肠癌（CRC）的病理过程。目前根除CRC的努力主要集中在靶向快速生长的癌上皮细胞的增殖。这在很大程度上是无效的，大多数肿瘤在暴露于化疗后产生耐药性。尽管长期以来人们认识到肿瘤微环境中癌相关成纤维细胞（CAF）和癌细胞之间的串扰，但CAF如何导致邻近癌细胞的耐药性尚未得到很好的表征。在这里，我们表明lncRNA CCAL（结直肠癌相关lncRNA）促进CRC细胞的奥沙利铂（Oxa）耐药性。与CRC组织的癌巢相比，RNA-ISH显示在肿瘤间质中表达更高的CCAL。功能研究表明，CCAL通过exosomes从CAFs转移到癌细胞，在体外和体内抑制CRC细胞凋亡，赋予化疗抗性并激活β-catenin通路。从机制上讲，CCAL直接与mRNA稳定蛋白HuR（人抗原R）相互作用，以增加β-连环蛋白mRNA和蛋白水平。我们的研究结果表明，CCAL表达的CAFs的结直肠肿瘤间质有助于肿瘤化疗耐药性和CCAL可能作为一个潜在的治疗目标的Oxa耐药。
Long noncoding RNAs (lncRNAs) are involved in the pathology of colorectal cancer (CRC). Current efforts to eradicate CRC predominantly focused on targeting the proliferation of rapidly growing cancer epithelial cells. This is largely ineffective with resistance arising in most tumors after exposure to chemotherapy. Despite the long‐standing recognition of the crosstalk between carcinoma‐associated fibroblasts (CAFs) and cancer cells in the tumor microenvironment, how CAFs may contribute to drug resistance in neighboring cancer cells is not well characterized. Here, we show that lncRNA CCAL (colorectal cancer‐associated lncRNA) promotes oxaliplatin (Oxa) resistance of CRC cells. RNA‐ISH shows higher CCAL expressed in the tumor stroma compared to cancer nests of CRC tissues. Functional studies reveal that CCAL is transferred from CAFs to the cancer cells via exosomes, where it suppresses CRC cell apoptosis, confers chemoresistance and activates β‐catenin pathway in vitro and in vivo. Mechanistically, CCAL interacts directly with mRNA stabilizing protein HuR (human antigen R) to increase β‐catenin mRNA and protein levels. Our findings indicate that CCAL expressed by CAFs of the colorectal tumor stroma contributes to tumor chemoresistance and CCAL may serve as a potential therapeutic target for Oxa resistance.