Osteopontin promotes a cancer stem cell-like phenotype in hepatocellular carcinoma cells via an integrin-NF-κB-HIF-1α pathway.
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.
School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, People's Republic of China.|International Joint Cancer Institute, The Second Military Medical University, Shanghai, 200433, People's Republic of China.|Clinical Immunology Laboratory, The First Affiliated Hospital of Suzhou University, Suzhou, 215007, Jiangsu, People's Republic of China.
Lei
L
Cao
International Joint Cancer Institute, The Second Military Medical University, Shanghai, 200433, People's Republic of China.
Xiaoyu
X
Fan
Changhai Hospital, The Second Military Medical University, Shanghai, 200433, People's Republic of China.
Wei
W
Jing
International Joint Cancer Institute, The Second Military Medical University, Shanghai, 200433, People's Republic of China.
Yingchao
Y
Liang
International Joint Cancer Institute, The Second Military Medical University, Shanghai, 200433, People's Republic of China.
Rui
R
Chen
International Joint Cancer Institute, The Second Military Medical University, Shanghai, 200433, People's Republic of China.|Changhai Hospital, The Second Military Medical University, Shanghai, 200433, People's Republic of China.
Yingying
Y
Liu
Changhai Hospital, The Second Military Medical University, Shanghai, 200433, People's Republic of China.
Minhui
M
Zhu
International Joint Cancer Institute, The Second Military Medical University, Shanghai, 200433, People's Republic of China.
Rongjie
R
Jia
International Joint Cancer Institute, The Second Military Medical University, Shanghai, 200433, People's Republic of China.
Hao
H
Wang
Clinical Immunology Laboratory, The First Affiliated Hospital of Suzhou University, Suzhou, 215007, Jiangsu, People's Republic of China.
Xueguang
X
Zhang
School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, People's Republic of China.
Yanyun
Y
Zhang
Changhai Hospital, The Second Military Medical University, Shanghai, 200433, People's Republic of China.
Xuyu
X
Zhou
International Joint Cancer Institute, The Second Military Medical University, Shanghai, 200433, People's Republic of China.|PLA General Hospital Cancer Center, PLA Postgraduate School of Medicine, Beijing, 100853, People's Republic of China.|Beijing Key Laboratory of Cell Engineering & Antibody, Beijing, 100853, People's Republic of China.
Jian
J
Zhao
International Joint Cancer Institute, The Second Military Medical University, Shanghai, 200433, People's Republic of China.|PLA General Hospital Cancer Center, PLA Postgraduate School of Medicine, Beijing, 100853, People's Republic of China.|Beijing Key Laboratory of Cell Engineering & Antibody, Beijing, 100853, People's Republic of China.
Yajun
Y
Guo
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D039661:Integrin beta3 / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D008297:Male; D008819:Mice, Nude; D008875:Middle Aged; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D053495:Osteopontin / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D063150:Polycomb Repressive Complex 1 / Q000235:genetics / Q000378:metabolism; D058985:Side-Population Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D018874:Spheroids, Cellular; D013997:Time Factors; D014162:Transfection
D000970:Antineoplastic Agents; C069077:BMI1 protein, human; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C061248:ITGB3 protein, human; D039302:Integrin alphaVbeta3; D039661:Integrin beta3; D016328:NF-kappa B; C506895:SPP1 protein, human; D053495:Osteopontin; D063150:Polycomb Repressive Complex 1
cancer stem cell; hepatocellular carcinoma; osteopontin; stemness