Osteopontin promotes a cancer stem cell-like phenotype in hepatocellular carcinoma cells via an integrin-NF-κB–HIF-1α pathway

Abstract

There is increasing evidence to suggest that hepatocellular carcinomas (HCCs) are sustained by a distinct subpopulation of self-renewing cells known as cancer stem cells. However, the precise signals required for maintenance of stemness-like properties of these cells are yet to be elucidated. Here, we demonstrated that the level of oncoprotein osteopontin (OPN) in tumor cells of the edge of bulk tumors was significantly correlated with the clinical prognosis of patients with HCC. OPN was highly expressed in side population fractions of HCC cell lines, as well as in dormant cells, spheroids and chemo-resistant cancer cells, all of which are considered as having stemness-like cellular features. Depletion of OPN in HCC cell lines resulted in a reduction in the proportion of side population fractions, formation of hepato-spheroids, expression of stem-cell-associated genes and decreased tumorigenecity in immunodeficient mice. Mechanistically, OPN was demonstrated to bind to integrin αvβ3 and activate the transcription factor NF-κB, which resulted in upregulation of HIF-1α transcription and its downstream gene, BMI1, to mediate maintenance of the stemness-like phenotype. Suppression of the αvβ3–NF-κB–HIF-1α pathway decreased OPN-mediated self-renewal capabilities. Levels of OPN protein expression were significantly correlated with HIF-1α protein levels in HCC tumor tissue samples. OPN might promote a cancer stem cell-like phenotype via the αvβ3–NF-κB–HIF-1α pathway. Our findings offer strong support for OPN requirement in maintaining stem-like properties in HCC cells.

Matrix stiffness-mediated effects on stemness characteristics occurring in HCC cells

“…Nevertheless, information is lacking on the relationship between matrix stiffness stimuli and HCC stem characteristic. Lately, OPN is found to promote a cancer stem cell-like phenotype in HCC cells via an integrin NF-κB-HIF-1α pathway [61]. Intriguingly, our previous data also suggested that higher matrix stiffness upregulated OPN expression in HCC cells [17], which implies a linkage between matrix stiffness and HCC stemness.…”

Radiation Resistance in KRAS-Mutated Lung Cancer Is Enabled by Stem-like Properties Mediated by an Osteopontin–EGFR Pathway

“…3,4). However, several recent reports highlight their importance for stem-like properties, while the role of EGFR in this regard is less clear (46–50). Osteopontin is an upstream activator of Src and EGFR signaling (38, 47, 51).…”

High expression of estrogen-related receptor α is significantly associated with poor prognosis in patients with colorectal cancer

“…A previous study revealed that ERRα, combined with PGC1α, activates the promoter of osteopontin (OPN) gene and leads to elevated OPN expression in CRC cells (29). OPN is a glycoprotein secreted by a variety of tissues and enhances cancer stem cell phenotypes in various cancer types (30,31). Higher levels of OPN are produced by macrophages when co-cultured with cluster of differentiation 44-positive CRC stem cells, subsequently increasing the tumorigenicity of the CRC cells (32).…”