Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China.
Department of Pathology, Tianjin Chest Hospital, Tianjin, China.
Cancer Sci. 2019 May;110(5):1609-1620. doi: 10.1111/cas.13998. Epub 2019 Apr 9.
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 (ANXA3) than normal fibroblasts (NF), and CAF-CM incubation increased the ANXA3 level in lung cancer cells. Overexpression of ANXA3 in lung cancer cells increased cisplatin resistance and activated c-jun N-terminal kinase (JNK), whereas knockdown of ANXA3 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 ANXA3/JNK pathway. Conversely, suppression of JNK activation by specific inhibitor retarded the effect of CAF-CM and ANXA3 on cisplatin sensitivity. Taken together, our study demonstrated that CAF potentiated chemoresistance of lung cancer cells through a novel ANXA3/JNK pathway both in vitro and in vivo, suggesting ANXA3 could be a potential therapeutic target for the treatment of chemoresistant cancer.
肿瘤组织由癌细胞、周围的基质细胞和细胞外基质组成。癌症相关成纤维细胞（CAF）是基质细胞的关键组成部分之一。CAF 以多种方式对癌细胞的行为产生重大影响，包括增殖、侵袭、转移和化疗耐药性。然而，其潜在机制尚未完全阐明。在这项研究中，我们研究了 CAF 在肺癌细胞顺铂耐药中的作用。通过使用 CAF 的条件培养基（CAF-CM），我们发现 CAF 降低了肺癌细胞对顺铂的敏感性。RNA 测序结果表明，CAF 表达的 Annexin A3（ANXA3）水平高于正常成纤维细胞（NF），并且 CAF-CM 孵育增加了肺癌细胞中的 ANXA3 水平。肺癌细胞中 ANXA3 的过表达增加了顺铂耐药性，并激活了 c-jun N 末端激酶（JNK），而 ANXA3 的敲低则增加了顺铂敏感性。进一步的研究表明，CAF-CM 通过抑制 caspase-3 和 caspase-8 的表达，通过激活 ANXA3/JNK 通路，抑制顺铂诱导的细胞凋亡，从而增强肺癌细胞的顺铂耐药性。相反，通过特异性抑制剂抑制 JNK 激活会延迟 CAF-CM 和 ANXA3 对顺铂敏感性的影响。总之，我们的研究表明，CAF 通过一种新型的 ANXA3/JNK 通路在体外和体内增强了肺癌细胞的化疗耐药性，提示 ANXA3 可能成为治疗化疗耐药性癌症的潜在治疗靶点。
