Abstract
Pulmonary metastasis occurring via the colonization of circulating cancer stem cells is a major cause of oral squamous cell carcinoma (OSCC)-related death. Thus, understanding the mechanism of OSCC pulmonary metastasis may provide a new opportunity for OSCC treatment. FAS, a well-known apoptosis-inducing death receptor, has multiple nonapoptotic, protumorigenic functions. Previously, we found that SAS OSCC cells with FAS receptor knockout did not affect orthotopic tumor growth or cervical lymph node metastasis. However, FAS knockout cells could not colonize in distant organs to form metastases upon intravenous injection, which hinted at the cancer stemness function of the FAS receptor. Immunohistochemistry staining indicated that the FAS receptor serves as a poor prognosis marker in OSCC patients. FAS knockout inhibited in vitro cancer spheroid formation, migration and invasion, and prevented mesenchymal transition in OSCC cells and inhibited OSCC pulmonary metastasis in vivo. To determine the regulatory mechanism by which the FAS receptor exerts its oncogenic function, we utilized cDNA microarrays and phosphoprotein arrays to discover key candidate genes and signaling pathway regulators. JAG1 expression and NOTCH pathway activation were controlled by the FAS receptor through ERK phosphorylation. Both JAG1 and NOTCH1 silencing decreased in vitro cancer spheroid formation. In OSCC cells, FAS ligand or JAG1 protein treatment increased NOTCH pathway activity, which could be abolished by FAS receptor knockout. In FAS knockout cells, restoring the NOTCH1 intracellular domain stimulated cancer spheroid formation. Both JAG1 and NOTCH1 silencing decreased in vivo OSCC growth. In conclusion, we found a novel FAS-ERK-JAG1-NOTCH1 axis that may contribute to OSCC stemness and pulmonary metastasis.
Highlights
Oral squamous carcinoma (OSCC) is the fifth most common cancer in Taiwanese males and the eighth-most common cancer in the United States
We proved that extracellular signal-regulated kinase (ERK) phosphorylation is critical to JAG1 expression and NOTCH signaling pathway activation, which are involved in FAS-mediated regulation of OSCC stemness and pulmonary metastasis
Here, we demonstrate the oncogenic role of the death receptor FAS in OSCC pulmonary metastasis through ERK-JAG1-NOTCH signaling (Fig. 7D)
Summary
Oral squamous carcinoma (OSCC) is the fifth most common cancer in Taiwanese males and the eighth-most common cancer in the United States. We found that FAS knockout suppresses OSCC in a tail vein injection model mimicking OSCC distant metastasis, surprisingly, we found that the injection of FAS−/− SAS stemness ability by silencing JAG1-NOTCH1 pathway activity dramatically reduced the number of lung colonies and cancer regulated by ERK phosphorylation. This process is cell colonies in the intrafemoral region compared with that with closely associated with the mechanism of OSCC pulmonary the injection of control SAS cells (Fig. 1G). Cells induced aberrant pulmonary hemorrhage and led to diffuse cancer colonies under hematoxylin and eosin (H&E) staining (Fig. 1H upper), but FAS receptor knockout revealed
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