Li Xia, Fan Qinqiao, Li Jinyun, Song Jing, Gu Yangcong
Department of Stomatology, School of Stomatology and medicine, Foshan Stomatology Hospital, Foshan University, Foshan 528000, PR China.
Department of Hepatobiliary Surgery, Cancer Center, Chenzhou No.1 People's Hospital, Chenzhou 423000, PR China.
Exp Cell Res. 2017 Feb 1;351(1):100-108. doi: 10.1016/j.yexcr.2017.01.001. Epub 2017 Jan 8.
Cancer associated fibroblasts (CAFs) are known to be involved in initiation, progression and metastasis of various cancers. However, the molecular mechanism of how CAFs affects the biological function of oral cancer (OC) has not been fully-addressed. In this study, we demonstrated that miR-124 was downregulated in oral CAFs and oral cancer cells (OCCs) when compared with matched normal fibroblasts (NFs). Hypermethylation in the promoter region of miR-124 genes was accounted for its downregulation. Interestingly, CAFs but not NFs exerted promotion effect on OCCs cell proliferation, migration and tumor growth in CAFs/NFs-OCCs co-culture. Furthermore, we identified Chemokine (C-C motif) ligand 2 (CCL2) and Interleukin 8 (IL-8) as two direct targets of miR-124. Over-expression of miR-124 in CAFs-OCCs co-culture abrogated CAFs-promoted OCCs cell growth and migration, and this inhibitory effect can be rescued by addition of CCL2 and IL-8. Finally, we showed that restoration of miR-124 expression by lentiviral infection or formulated miR-124 injection inhibited oral tumor growth in vivo suggesting miR-124 rescue could be a potential rationale for therapeutic applications in oral cancer in the future.
已知癌症相关成纤维细胞（CAFs）参与多种癌症的起始、进展和转移。然而，CAFs如何影响口腔癌（OC）生物学功能的分子机制尚未完全阐明。在本研究中，我们发现与配对的正常成纤维细胞（NFs）相比，miR-124在口腔CAFs和口腔癌细胞（OCCs）中表达下调。miR-124基因启动子区域的高甲基化是其表达下调的原因。有趣的是，在CAFs/NFs-OCCs共培养中，CAFs而非NFs对OCCs细胞增殖、迁移和肿瘤生长具有促进作用。此外，我们确定趋化因子（C-C基序）配体2（CCL2）和白细胞介素8（IL-8）是miR-124的两个直接靶点。在CAFs-OCCs共培养中过表达miR-124可消除CAFs促进的OCCs细胞生长和迁移，并且添加CCL2和IL-8可挽救这种抑制作用。最后，我们表明通过慢病毒感染或配制的miR-124注射恢复miR-124表达可在体内抑制口腔肿瘤生长，这表明挽救miR-124可能是未来口腔癌治疗应用的潜在理论依据。
