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Title: MiR-124 down-regulation is critical for cancer associated fibroblasts-enhanced tumor growth of oral carcinoma

Abstract

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. - Highlights: • miR-124 was downregulated in oral cancer cells and cancer associated fibroblasts. • Hypermethylation in the promoter region was accounted for miR-124 downregulation.more » • CCL2 and IL-8 are two direct targets of miR-124. • miR-124 rescue could be a potential rationale for oral cancer therapy.« less

Authors:
 [1];  [2];  [3]; ;  [1]
  1. Department of Stomatology, School of Stomatology and medicine, Foshan Stomatology Hospital, Foshan University, Foshan 528000 (China)
  2. Department of Hepatobiliary Surgery, Cancer Center, Chenzhou No.1 People's Hospital, Chenzhou 423000 (China)
  3. Department of Head and Neck Surgery, The Affiliated Cancer Hospital of Xiangya School of Medicine, Center South University, Changsha 410013 (China)
Publication Date:
OSTI Identifier:
22649822
Resource Type:
Journal Article
Resource Relation:
Journal Name: Experimental Cell Research; Journal Volume: 351; Journal Issue: 1; Other Information: Copyright (c) 2017 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; BIOLOGICAL FUNCTIONS; BIOLOGICAL RECOVERY; CARCINOMAS; CELL PROLIFERATION; FIBROBLASTS; GENES; IN VIVO; INDIUM 124; INJECTION; LIGANDS; LYMPHOKINES; METASTASES; PLANT GROWTH; THERAPY

Citation Formats

Li, Xia, E-mail: dentistlx@163.com, Fan, Qinqiao, Li, Jinyun, Song, Jing, and Gu, Yangcong. MiR-124 down-regulation is critical for cancer associated fibroblasts-enhanced tumor growth of oral carcinoma. United States: N. p., 2017. Web. doi:10.1016/J.YEXCR.2017.01.001.
Li, Xia, E-mail: dentistlx@163.com, Fan, Qinqiao, Li, Jinyun, Song, Jing, & Gu, Yangcong. MiR-124 down-regulation is critical for cancer associated fibroblasts-enhanced tumor growth of oral carcinoma. United States. doi:10.1016/J.YEXCR.2017.01.001.
Li, Xia, E-mail: dentistlx@163.com, Fan, Qinqiao, Li, Jinyun, Song, Jing, and Gu, Yangcong. Wed . "MiR-124 down-regulation is critical for cancer associated fibroblasts-enhanced tumor growth of oral carcinoma". United States. doi:10.1016/J.YEXCR.2017.01.001.
@article{osti_22649822,
title = {MiR-124 down-regulation is critical for cancer associated fibroblasts-enhanced tumor growth of oral carcinoma},
author = {Li, Xia, E-mail: dentistlx@163.com and Fan, Qinqiao and Li, Jinyun and Song, Jing and Gu, Yangcong},
abstractNote = {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. - Highlights: • miR-124 was downregulated in oral cancer cells and cancer associated fibroblasts. • Hypermethylation in the promoter region was accounted for miR-124 downregulation. • CCL2 and IL-8 are two direct targets of miR-124. • miR-124 rescue could be a potential rationale for oral cancer therapy.},
doi = {10.1016/J.YEXCR.2017.01.001},
journal = {Experimental Cell Research},
number = 1,
volume = 351,
place = {United States},
year = {Wed Feb 01 00:00:00 EST 2017},
month = {Wed Feb 01 00:00:00 EST 2017}
}
  • Oral squamous cell carcinoma (OSCC) is one of the most common cancers worldwide and the 5 years survival rate of the patients is about 60% in the USA, due to acquired chemotherapeutic resistance and metastasis of the disease. In this study, we found that tivantinib, a selective MET inhibitor, suppresses OCSS cell proliferation and colony formation, however, anti-tumor activities induced by tivantinib are independent of the inhibition of MET signaling pathway. In addition, tivantinib cause G2/M cell cycle arrest and caspases-dependent apoptosis in OSCC cell lines. We also found that tivantinib dose-dependently suppressed the activation and expression of FAK. Inmore » all, these data suggested that tivantinib may be developed as a chemotherapeutic agent to effectively treat certain cancers including OSCC. - Highlights: • Tivantinib suppresses OSCC cell growth independent of the inhibition of HGF/MET signaling pathway. • Tivantinib blocks cell cycle and induces caspases-mediated apoptosis. • Tivantinib elicits its anti-tumor activity with the inhibition of FAK signaling pathway.« less
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