褪黑素通过降低 IL-8 表达和逆转上皮间质转化来削弱癌症相关成纤维细胞的促肿瘤作用。

Melatonin blunts the tumor-promoting effect of cancer-associated fibroblasts by reducing IL-8 expression and reversing epithelial-mesenchymal transition.

机构信息

Department of General Surgery, The First Medical Center of Chinese PLA General Hospital, Beijing 100853, China; The Second School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China.

Zhujiang Hospital, Southern Medical University, Guangzhou 510515, China.

出版信息

Int Immunopharmacol. 2023 Jun;119:110194. doi: 10.1016/j.intimp.2023.110194. Epub 2023 Apr 18.

DOI:10.1016/j.intimp.2023.110194

PMID:37080066

Abstract

BACKGROUND

Most studies on melatonin have focused on tumor cells but have ignored the tumor microenvironment (TME), especially one of its important components, the cancer-associated fibroblasts (CAFs). Therefore, we attempted to explore the role of melatonin in TME.

METHODS

We investigated the regulatory role of melatonin in the tumor-promoting effect of CAFs and its underlying mechanism by using cell and animal models.

RESULTS

CAFs promoted tumor progression, but melatonin weakened the tumor-promoting effect of CAFs. Compared with tumor cells, IL-8 was mainly expressed in CAFs. CAFs-overexpressing IL-8 induced the epithelial-mesenchymal transition (EMT) of tumor cells, and a positive crosstalk was observed between CAFs and tumor cells undergoing EMT, thereby further promoting the IL-8 expression. Melatonin suppressed this crosstalk by inhibiting the NF-κB pathway, thereby impeding the IL-8 expression from CAFs. Importantly, melatonin reversed CAFs-derived IL-8-mediated EMT by inhibiting the AKT pathway. Melatonin was found to directly and indirectly inhibit tumor progression.

CONCLUSION

Our research reveals the potential action mechanism of melatonin in regulating the CAF-tumor cell interaction and suggests the potential of melatonin as an adjuvant of tumor therapy.

摘要

背景

大多数关于褪黑素的研究都集中在肿瘤细胞上，但忽略了肿瘤微环境（TME），特别是其重要组成部分之一——癌相关成纤维细胞（CAFs）。因此，我们试图探讨褪黑素在 TME 中的作用。

方法

我们通过细胞和动物模型研究了褪黑素在 CAFs 促进肿瘤作用中的调节作用及其潜在机制。

结果

CAFs 促进肿瘤进展，但褪黑素削弱了 CAFs 的促肿瘤作用。与肿瘤细胞相比，IL-8 主要在 CAFs 中表达。CAFs 过表达 IL-8 诱导肿瘤细胞发生上皮间质转化（EMT），并且观察到 EMT 过程中的 CAFs 和肿瘤细胞之间存在正相互作用，从而进一步促进了 IL-8 的表达。褪黑素通过抑制 NF-κB 通路抑制这种相互作用，从而抑制 CAFs 中的 IL-8 表达。重要的是，褪黑素通过抑制 AKT 通路逆转了 CAFs 衍生的 IL-8 介导的 EMT。褪黑素被发现可以直接和间接地抑制肿瘤进展。