title: A CCL2/ROS autoregulation loop is critical for cancer-associated fibroblasts-enhanced tumor growth of oral squamous cell carcinoma.
abstract: Cancer-associated fibroblasts (CAFs) have been described to play critical roles in initiation, progression and metastasis of various cancers. However, the involvement of CAFs in oral cancer (OC) has not been well addressed. In this study, we demonstrate that CAFs, when cocultured with OC cells (OCCs), produce high levels of chemokine (C-C motif) ligand 2 (CCL2) and, subsequently, enhance endogenous reactive oxygen species production in cells. Oxidative stress stimulates expression of cell cycle progression proteins in OCCs, leading to promotion of OCC proliferation, migration, invasion and, OC tumor growth. On the other hand, oxidative stress triggered the activation of nuclear factor-kappaB (NF-κB) and STAT3 in CAFs, resulting in accelerating CCL2 expression. In this way, CAFs-OCCs coculture creates a favorable cytokine-rich microenvironment, beneficial for both CAFs and OCCs. In addition, upregulation of CCL2 expression has been observed in oral squamous cell carcinoma tumors and patient plasma. We also showed that inhibition of CCL2 reduced OC tumor burden in mice. Therefore, our data suggested that CCL2 represents a potential therapeutic target for treatment of OC.
authors: Department of Stomatology, Medical College of FoShan University, Foshan 528000, People's Republic of China, dentistlx@163.com.
authors: Xia
authors: X
authors: Li
authors: Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors: Qing
authors: Q
authors: Xu
authors: Department of Breast, Xiangya Hospital, Central South University, Changsha 410008, People's Republic of China.
authors: Yuhui
authors: Y
authors: Wu
authors: Department of Head and Neck Surgery, Hunan provincial Tumor Hospital, Changsha 410013, People's Republic of China.
authors: Jinyun
authors: J
authors: Li
authors: Department of Biochemistry, Medical College of Foshan University, Foshan 528000, People's Republic of China.
authors: Dongsheng
authors: D
authors: Tang
authors: Department of periodontal and oral mucosal diseases, Foshan Stomatology Hospital, Foshan 528000, People's Republic of China.
authors: Lu
authors: L
authors: Han
authors: Department of Hepatobiliary Surgery, cancer center, Chenzhou No.1 People'S Hospital, Chenzhou 423000, People's Republic of China dentistlx@163.com fanqinqiao001@163.com.
authors: Qinqiao
authors: Q
authors: Fan
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism*; D018920:Coculture Techniques; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000378:metabolism*; D015870:Gene Expression; D064593:Heterografts; D006801:Humans; D051379:Mice; D009062:Mouth Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D016328:NF-kappa B / Q000378:metabolism; D009361:Neoplasm Invasiveness; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D047368:Tumor Burden / Q000235:genetics
chemical_list: D018932:Chemokine CCL2; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D050796:STAT3 Transcription Factor; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt