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Cancer tissues consist of cancer cells, surrounding stromal cells and the extracellular matrix. Cancer‐associated fibroblasts ( CAF ) are one of the key components of stromal cells.  CAF  have a great impact on the behavior of cancer cells, including proliferation, invasion, metastasis and chemoresistance in many ways. However, the underlying mechanism had not been fully elucidated. In this study, we investigated the role of  CAF  in cisplatin resistance of lung cancer cells. By using conditioned medium from  CAF  ( CAF ‐ CM ), we found that  CAF  decreased the sensitivity of lung cancer cells to cisplatin.  RNA  sequencing results showed that  CAF  expressed a higher level of Annexin A3 ( ANXA 3) than normal fibroblasts ( NF ), and  CAF ‐ CM  incubation increased the  ANXA 3 level in lung cancer cells. Overexpression of  ANXA 3 in lung cancer cells increased cisplatin resistance and activated c‐jun N‐terminal kinase ( JNK ), whereas knockdown of  ANXA 3 increased cisplatin sensitivity. Further study showed that  CAF ‐ CM  enhanced cisplatin resistance by inhibiting cisplatin‐induced apoptosis, determined by repression of caspase‐3 and caspase‐8, through activation of the  ANXA 3/ JNK  pathway. Conversely, suppression of  JNK  activation by specific inhibitor retarded the effect of  CAF ‐ CM  and  ANXA 3 on cisplatin sensitivity. Taken together, our study demonstrated that  CAF  potentiated chemoresistance of lung cancer cells through a novel  ANXA 3/ JNK  pathway both in vitro and in vivo, suggesting  ANXA 3 could be a potential therapeutic target for the treatment of chemoresistant cancer.

Cancer‐associated fibroblasts contribute to cisplatin resistance by modulating ANXA 3 in lung cancer cells