Journal
CANCER LETTERS
Volume 454, Issue -, Pages 37-43Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2019.04.002
Keywords
Chemoresistance; Cancer-associated fibroblast; IL-8; NF-kappa B; ABCB1
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Funding
- National Natural Science Foundation of China [81272711, 81871959]
- Priority Academic Program Development of Jiangsu Higher Education Institutions of Jiangsu Higher Education Institutions [JX10231801]
- Key Medical Talents Program of Jiangsu Province [ZDRCA2016014]
- Key R&D Program of Jiangsu Province [BE2018758]
- Programs of Jiangsu Province Hospital of Chinese Medicine [Y2018RC14, Y2018CX71]
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Chemoresistance remains the major obstacle to achieve optimal prognosis in gastric cancer patients, and the underlying molecular mechanisms of cancer-associated fibroblasts (CAFs) in gastric cancer chemoresistance remain poorly understood. We identified the high pretherapeutical serum IL-8 level in gastric cancer patients was associated with poor response to platinum-based therapy, and it increased gradually during neoadjuvant chemotherapy and it decreased after radical surgery. Immunohistochemistry assays showed that IL-8 was highly expressed in gastric cancer tissues in chemoresistant patients, and located in CAFs. Primary CAFs produced more IL-8 than the corresponding normal fibroblasts, and human stomach fibroblast line Hs738 secreted more IL-8 after co-cultured with conditioned media from AGS or MGC-803 cells. IL-8 increased the IC50 of cisplatin (CDDP) in AGS or MGC-803 in vitro. Simultaneously, IL-8 treatment enhanced the expression of PI3K, phosphorylated-AKT (p-AKT), phosphorylated-IKb (p-IKb), phosphorylated-p65 (p-p65) and ABCB1, and ABCB1 and p-p65 were overexpressed in tumor tissues of chemoresistant patients. Collectively, CAFs derived IL-8 promotes chemoresistance in human gastric cancer via NF-kappa B activation and ABCB1 up-regulation. Our study provides a novel strategy to improve the chemotherapeutical efficacy and the prognosis of gastric cancer.
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