Journal
INTERNATIONAL JOURNAL OF CANCER
Volume 146, Issue 6, Pages 1700-1716Publisher
WILEY
DOI: 10.1002/ijc.32608
Keywords
colorectal cancer; long noncoding RNAs; chemoresistance; cancer-associated fibroblasts; exosomes
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Funding
- Program of Shanghai Academic/Technology Research Leader [18XD1400900]
- Program for Shanghai Municipal Leading Talent (2015)
- Innovation Group Project of Shanghai Municipal Health Commission [2019CXJQ03]
- National Natural Scienceik Foundation of China [81672105]
- Shanghai Changning District Science and Technology Commission Key Project [CNKW2016Z01]
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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 beta-catenin pathway in vitro and in vivo. Mechanistically, CCAL interacts directly with mRNA stabilizing protein HuR (human antigen R) to increase beta-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.
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