FAS receptor regulates NOTCH activity through ERK-JAG1 axis activation and controls oral cancer stemness ability and pulmonary metastasis

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.

Revealing spatial multimodal heterogeneity in tissues with SpaTrio

“…Stimulation of T cells by EGFR may affect the activity of the NOTCH pathway in PVL cells. 63 At the same time, FASLG on the surface of T cells and the FAS of PVL cells interacted, and the FAS receptor regulated NOTCH pathway signaling by activating the ERK-JAG1 axis, 64 which provides further evidence of the effect of T cells on PVL cells ( Figure 6 K). The NOTCH pathway promotes angiogenesis and breast cancer metastasis.…”

JAG1 is associated with the prognosis and metastasis in breast cancer

“…The JAG1-Notch pathway facilitates tumor metastasis via various carcinogenic mechanisms [22][23][24] . Cohen et al 25 found that cyclin D1 is a downstream transcription target of the JAG1-Notch pathway, and knockdown of the JAG1 gene decreases cyclin D1 level, arresting the cell cycle in the G1 phase.…”

JAG1 is associated with the prognosis and metastasis in breast cancer

“…The JAG1-Notch pathway facilitates tumor metastasis via various carcinogenic mechanisms [22][23][24] . Cohen et al found that cyclin D1 is a downstream transcription target of the JAG1-Notch pathway, and knockdown of the JAG1 gene decreases cyclin D1 level, arresting cell cycle in G1 phase 25 .…”