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

• Published in: Oncotarget Vol. 6; no. 9; pp. 6627 - 6640
• Main Authors: Cao, Lei, Fan, Xiaoyu, Jing, Wei, Liang, Yingchao, Chen, Rui, Liu, Yingying, Zhu, Minhui, Jia, Rongjie, Wang, Hao, Zhang, Xueguang, Zhang, Yanyun, Zhou, Xuyu, Zhao, Jian, Guo, Yajun
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 30-03-2015
• Subjects: Animals; Antineoplastic Agents - pharmacology; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Cell Line, Tumor; Cell Proliferation; Disease-Free Survival; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Neoplastic; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Integrin alphaVbeta3 - metabolism; Integrin beta3 - metabolism; Kaplan-Meier Estimate; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Liver Neoplasms - mortality; Liver Neoplasms - pathology; Male; Mice, Nude; Middle Aged; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; NF-kappa B - genetics; NF-kappa B - metabolism; Osteopontin - genetics; Osteopontin - metabolism; Phenotype; Polycomb Repressive Complex 1 - genetics; Polycomb Repressive Complex 1 - metabolism; Research Paper; Side-Population Cells - drug effects; Side-Population Cells - metabolism; Side-Population Cells - pathology; Signal Transduction; Spheroids, Cellular; Time Factors; Transfection; cancer stem cell; osteopontin; hepatocellular carcinoma; stemness
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.3113

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.