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  • Germacrene D br Our study showed that the


    Our study showed that the pretherapeutic serum IL-8 level of ad-vanced gastric cancer patients was associated the response to platinum-based NAC negatively. Furthermore, the serum IL-8 level increased with NAC implementation in the chemoresistant patients, while it decreased  Cancer Letters 454 (2019) 37–43
    gradually in the chemosensitive patients. These results suggested that the IL-8 level may portend both intrinsic and acquired chemoresistance, and the serum IL-8 level may be a new potential marker to evaluate the chemotherapy response in gastric cancer. Importantly, the IL-8 level dropped dramatically one month post-operation in the chemoresistant patients. We inferred that the IL-8 may be produced by tumor tissues, and the immunohistochemisrty study confirmed this speculation. IL-8 was exclusively and highly expressed in CAFs in chemoresistant tumor, but there was no IL-8 immunoactivity in CAFs in nearly CR tumor al-though there were CAFs in tissues. The primary CAFs from gastric cancer tissues produced more IL-8 than the primary normal fibroblasts.
    The in vitro cell proliferation study showed that IL-8 treatment in-creased the IC50 of cisplatin in human gastric cancer cell lines. To in-vestigate the mechanisms underlying of IL-8 in gastric cancer che-moresistance, the human stomach fibroblast line Hs738 was introduced in this study. As anticipated, the conditioned media from human gastric cancer Germacrene D increased the α-SMA level in Hs738 cells, namely activated the fibroblasts [31]. The activated Hs738 cells also secreted more IL-8.
    Investigations into the mechanisms of IL-8 in regulating therapeutic response and resistance indicated that IL-8 activated AKT, IKb and p65 through phosphrylation in gastric cancer cells, namely activated NF-κB pathway. Furthermore, IL-8 up-regulated the expression of ABCB1, an important drug pump [26], in gastric cancer cells. We confirmed the overexpression of ABCB1 and p-p65 in the tumor tissues from che-moreisitant patients. Taken together, it could be concluded that CAFs derived IL-8 promotes chemoresistance in human gastric cancer via NF-κB activation and up-regulating ABCB1 (Fig. 4D).
    IL-8 usually functions in different biologic processes by binding its receptors, CXCR1 and CXCR2 [23]. CXCR1 has been demonstrated to promote gastric cancer cell proliferation, migration and invasion [36], and intratumoral CXCR2 expression is associated with the survival in gastric cancer patients [37]. Repertaxin, an inhibitor of CXCR1/2, has been demonstrated to inhibit malignant behavior of human gastric cancer cells in vitro and in vivo and to enhance efficacy of 5-FU [38]. However, whether CAFs-derived IL-8 mediates chemoresistance via its receptors remains unknown. We will continue to investigate the roles of the CXCR1/2 in IL-8 mediated chemoresistance in the tumor micro-environment.
    Certainly, there were some limits in this study. We just probed IL-6 and IL-8 in the serum of gastric cancer patients. Other cytokines derived from CAFs in the chemoresistance of gastric cancer, the dynamic IL-8 level variation and its functions in the gastric cancer progression, the other mechanisms involved in IL-8-mediated resistance to cisplatin, as well as whether IL-8 derived from CAFs leads to the circumvention of other cytotoxic drugs beside ciaplatin, remained to be intensively stu-died. There was no survival data for these patients due to short follow-up time.
    In short, this study highlights the importance and its underlying mechanisms of CAFs in gastric cancer chemoresistance, and provides serum IL-8 level as a new prognostic indicator for evaluating the re-sponse to chemotherapy in gastric cancer, as well as a novel strategy targeting IL-8 or CAFs to improve the chemotherapeutical efficacy and the overall survival of gastric cancer patients.
    Conflicts of interest
    The authors declare no conflict of interest.
    This work was supported by the National Natural Science Foundation of China (Grant Nos. 81272711 and 81871959), the Priority Academic Program Development of Jiangsu Higher Education Institutions of Jiangsu Higher Education Institutions (JX10231801), the Key Medical Talents Program of Jiangsu Province (ZDRCA2016014), the Key R&D Program of Jiangsu Province (Social Development,
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