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

Cao, Lei; Fan, Xiaoyu; Wei, Jing; Liang, Yingchao; Chen, Rui; Liu, Yingying; Zhu, Minhui; Jia, Rongjie; Wang, Hao; Zhang, Xueguang; Zhang, Yanyun; Zhou, Xuyu; Zhao, Jian; Guo, Yajun

doi:10.18632/oncotarget.3113

Cited by 69 publications

(69 citation statements)

References 47 publications

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“…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.…”

Section: Discussionmentioning

confidence: 97%

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

et al. 2016

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Matrix stiffness as an important physical attribute of extracellular matrix exerts significant impacts on biological behaviors of cancer cells such as growth, proliferation, motility, metabolism and invasion. However, its influence on cancer stemness still remains elusive. Here, we explore whether matrix stiffness-mediated effects on stemness characteristics occur in HCC cells. As the substrate stiffness increased, HCC cells exhibited high proportion of cells with CD133(+)/EpCAM(+), high expression levels of CD133, EpCAM, Nanog and SOX2, greater self-renewing ability and oxaliplatin resistance. Simultaneously, their phosphorylation levels of Akt and mTOR, as well as p-4E-BP and SOX2 expressions were also obviously upregulated. Conversely, knockdown of integrin β1 partially attenuated higher stiffness-mediated stemness characteristics in HCC cells, and reversed the phosphorylation levels of Akt and mTOR, and expressions of p-4E-BP and SOX2, suggesting that integrin β1 may deliver higher stiffness signal into HCC cells and activate mTOR signaling pathway. Additionally, mTOR inhibitor suppressed the mTOR phosphorylation level and expression levels of p-4E-BP and SOX2 in HCC cells grown on higher stiffness substrate, as well as depressed their stemness properties significantly, favoring a regulating role of mTOR signaling pathway in matrix stiffness-mediated effects on stemness. In summary, matrix stiffness may be involved in the process of stemness regulation via activating integrin β1/Akt/mTOR/SOX2 signaling pathway. To the best of our knowledge, this study first reveals a novel regulating pathway to direct the stemness characteristics in HCC cells.

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Section: Discussionmentioning

confidence: 97%

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

et al. 2016

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“…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).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2017

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Lung cancers with activating KRAS mutations are characterized by treatment resistance and poor prognosis. In particular, the basis for their resistance to radiation therapy is poorly understood. Here we describe a radiation resistance phenotype conferred by a stem-like subpopulation characterized by mitosis-like condensed chromatin (MLCC), high CD133 expression, invasive potential, and tumor-initiating properties. Mechanistic investigations defined a pathway involving osteopontin and the EGFR in promoting this phenotype. Osteopontin/EGFR-dependent MLCC protected cells against radiation-induced DNA double-strand breaks and repressed putative negative regulators of stem-like properties such as CRMP1 and BIM. The MLCC-positive phenotype defined a subset of KRAS-mutated lung cancers that were enriched for co-occurring genomic alterations in TP53 and CDKN2A. Our results illuminate the basis for the radiation resistance of KRAS-mutated lung cancers with possible implications for prognostic and therapeutic strategies.

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“…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).…”

Section: Errα Expression (N=128) ------------------------------------mentioning

confidence: 99%

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

et al. 2018

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Abstract. Colorectal cancer (CRC) is one of the most common types of malignancy with high morbidity and mortality rates worldwide. This biologically heterogeneous disease results in diverse therapeutic responses, thus, novel prognostic biomarkers are required to improve CRC treatment. Estrogen-related receptor α (ERRα) is a nuclear orphan receptor, which is associated with estrogen receptor α. The present study aimed to investigate the expression of ERRα in patients with CRC, and explore the association between ERRα expression and clinicopathological factors, local recurrence and prognosis. In the present study, ERRα expression was detected in 15 fresh CRC tissues using quantitative real-time polymerase chain reaction (RT-qPCR) and in 128 paraffin-embedded CRC tissues using immunohistochemistry. The associations between ERRα expression and prognosis of CRC patients were evaluated by univariate, and multivariate (Cox proportional hazards model) analysis. RT-qPCR demonstrated that the mRNA expression of ERRα in CRC tissues was significantly higher compared with that in matched normal tissues. Immunohistochemistry revealed that ERRα high expression was detected in the nuclei of cancer cells from 39.1% (50/128) of CRC tissues. ERRα expression based on immunohistochemical staining was significantly associated with tumor differentiation, tumor invasion, lymph node status and Dukes stage (all P<0.05). Furthermore, patients with high ERRα expression were significantly associated with an increased risk of recurrence and poor prognosis, compared with patients with low ERRα expression. ERRα expression was identified as an independent prognostic factor for patients with CRC. In conclusion, ERRα serves important roles in the progression of CRC and is a potential prognostic factor for patients with CRC.

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

Cited by 69 publications

References 47 publications

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

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

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

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

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