Involvement of c-Fos in the Promotion of Cancer Stem-like Cell Properties in Head and Neck Squamous Cell Carcinoma

Abstract

Purpose Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Although improvements in surgical techniques, chemotherapy and radiation delivery, and supportive care have improved quality of life for patients with HNSCC, regional and distant recurrence remain common. Recent evidence suggests that cancer stem-like cells (CSCs) play a significant role in recurrence and chemo-resistant. We previously observed that c-Fos was highly up-regulated in the HNSCC sphere forming cells. Consequences of c-Fos upregulation for the biology of HNSCC-CSCs are poorly understood. In this study, we investigated the role of c-Fos in renewal of stemness of HNSCC and tumor growth. Experimental Design and Results We generated stable HNSCC cell lines ectopically expressing the c-Fos gene. Exogenous expression of c-Fos in non-tumorigenic MDA1386Tu cells makes these cells tumorigenic in nude mice. Further, subcutaneous transplantation of c-Fos overexpressing Cal27 cells (tumorigenic) into immunocompromised mice enhanced tumor growth as compared to parental cells. Mechanistic investigations demonstrated that c-Fos overexpression enhanced the epithelial mesenchymal transition (EMT) state and expression of CSC markers (Nanog, c-Myc, Sox2 and Notch1). Ectopic expression of c-Fos in HNSCC cells also display increased number of sphere formation. We further observed that overexpression of c-Fos increased the expression of pERK and cyclin D1 in HNSCC cells. Conclusion Together, our results strongly suggest a novel role of c-Fos as a regulator of EMT and cancer stem cell reprogramming in HNSCC cells, which may hold potential as a CSC-directed therapeutic approach to improve HNSCC treatment.

Targeting the Formyl Peptide Receptor type 1 to prevent the adhesion of ovarian cancer cells onto mesothelium and subsequent invasion

“…Among the signaling pathways active to control metastatic spread of cancers are the members of activator protein-1 (AP-1) family transcription factors, including c-Fos [51]. This transcriptional activator binds to AP-1 motifs localized also in the uPA and uPAR promoter regions, upregulating their mRNA synthesis [14]..…”

Mechanisms of the Epithelial–Mesenchymal Transition and Tumor Microenvironment in Helicobacter pylori-Induced Gastric Cancer

“…As a physiological process, EMT is observed during organogenesis, tissue development, remodeling, and wound healing [52][53][54]; contrarily, any deregulations might induce carcinogenesis [55,56]. EMT-induced carcinogenesis is the prevalent cause of various malignancies including head and neck squamous cell carcinoma, papillary thyroid carcinoma, lung, pancreatic, gastric, ovarian, prostate, and breast cancer [57][58][59][60][61][62][63][64][65][66][67][68].…”

Sialidase NEU1 suppresses progression of human bladder cancer cells by inhibiting fibronectin-integrin α5β1 interaction and Akt signaling pathway

“…Epithelial-mesenchymal transition (EMT) is a biological conversion process of polarized epithelial cells to mesenchymal phenotype, characterized by loss of cell-cell adhesion and epithelial polarity as well as the acquisition of migratory and invasive properties. EMT is regulated by multiple signaling networks, including extracellular signalregulated protein kinases (ERKs), mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K)/ Akt, Smads, RhoB, β-catenin and c-fos [12][13][14][15]. Other than these signaling factors, aberrant expression and high sensitivity of sialic acid as a tumor marker have been reported in a variety of cancerous conditions, and in many EMT models [16][17][18].…”