Objective

Dietary patterns are believed to regulate tumor progression by altering the tumor microenvironment. Of note, a high salt diet is a risk factor for various diseases. However, the role of high salt intake in the progression of cancers remains unknown.

Methods

We constructed an in vivo high salt diet model in MMTV-PyVT mice with spontaneous tumor-forming properties to explore the role of a high salt diet in the progression of breast cancer as well as the modulation of the tumor microenvironment. Also, in vitro experiments were performed to understand the mechanism.

Results

High salt diet accelerated the development (P < 0.05) and lung metastasis (P < 0.05) of breast cancer in MMTV-PyVT mice, compared to the normal diet model. Moreover, higher frequency of Th17 cells in circulation, tumor tissue and draining lymph node tissue were observed in the high salt diet model (P < 0.05 for all). In vitro, co-culture with Th17 cells facilitated the proliferation, migration and invasion of MCF-7 human breast cancer cells, while these enhanced aggressive behaviors could be reversed by application of 1,25-vitamin D₃ which could inhibit the differentiation of Th17 cells (P < 0.001 for all). In vitro, co-culture with Th17 cells activated MAPK signaling in MCF-7 cells (P < 0.001 for all). Consistently, activated MAPK/ERK signaling was observed by immunohistochemistry in breast cancer cell nodes in the high salt diet model (P < 0.05 for all). Mechanistically, higher level of IL-17F could be detected in breast tumors and serum from the high salt diet model through qRT-PCR and ELISA (P < 0.05 for all). IL-17F treatment facilitated the proliferation, migration and invasion of MCF-7 human breast cancer cells and activated MAPK/ERK signaling in MCF-7 cells (P < 0.001 for all). Moreover, the tumor-promoting function induced by Th17 cells and IL-17F could be inhibited by the administration of ERK inhibitor (sch772894) (P < 0.001 for all). Lastly, high concentration NaCl-induced Th17 cells promoted the proliferation, migration and invasion of MCF-7 human breast cancer cells and activated MAPK/ERK signaling in MCF-7 cells which could be inhibited by neutralizing anti-IL-17F (P < 0.001 for all).

Conclusion

High salt intake accelerates the growth of breast cancer and facilitates lung metastasis, as well as increases the level of Th17 cells. Increased Th17 cells might promote the growth of breast cancer via the secretion of IL-17F to activate the MAPK signaling pathway in breast cancer cells.

中文翻译：

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高盐饮食可以通过引发免疫反应来促进乳腺肿瘤的进展。

目的

据信饮食模式通过改变肿瘤微环境来调节肿瘤进展。值得注意的是，高盐饮食是多种疾病的危险因素。然而，高盐摄入量在癌症进展中的作用仍然未知。

方法

我们构建了具有自发肿瘤形成特性的MMTV-PyVT小鼠体内高盐饮食模型，以探索高盐饮食在乳腺癌进展以及肿瘤微环境调节中的作用。另外，进行了体外实验以了解其机理。

结果

 与正常饮食模型相比，高盐饮食能促进MMTV-PyVT小鼠乳腺癌的发展（P  <0.05）和肺转移（P <0.05）。此外，在高盐饮食模型中观察到循环中的Th17细胞，肿瘤组织和引流淋巴结组织的频率更高（ 所有P均<0.05）。在体外，与Th17细胞共培养可促进MCF-7人乳腺癌细胞的增殖，迁移和侵袭，而通过应用可抑制Th17分化的1,25-维生素D ₃可以逆转这些增强的侵袭行为。细胞（ 所有P均<0.001）。体外，与Th17细胞共培养可激活MCF-7细胞中的MAPK信号传导（ 所有P均<0.001）。一致地，在高盐饮食模型中，通过免疫组织化学在乳腺癌细胞淋巴结中观察到了活化的MAPK / ERK信号传导（全部P  <0.05）。从机理上讲，高盐饮食模型通过qRT-PCR和ELISA可以在乳腺肿瘤和血清中检测到更高水平的IL-17F（ 所有P均<0.05）。IL-17F治疗促进了MCF-7人乳腺癌细胞的增殖，迁移和侵袭，并激活了MCF-7细胞中的MAPK / ERK信号传导（ 所有P均<0.001）。此外，通过施用ERK抑制剂（sch772894）可以抑制Th17细胞和IL-17F诱导的促肿瘤功能（P 均<0.001）。最后，高浓度NaCl诱导的Th17细胞促进MCF-7人乳腺癌细胞的增殖，迁移和侵袭，并激活MCF-7细胞中的MAPK / ERK信号传导，这可以通过中和抗IL-17F来抑制（P  <0.001对所有人）。

结论

高盐摄入量会加速乳腺癌的生长并促进肺转移，并增加Th17细胞的水平。增加的Th17细胞可能通过分泌IL-17F激活乳腺癌细胞中的MAPK信号通路来促进乳腺癌的生长。