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Nanog regulates self-renewal of cancer stem cells through the insulin-like growth factor pathway in human hepatocellular carcinoma
Open accessAbstract
Hepatocellular carcinoma (HCC) exhibits cellular heterogeneity and embryonic stem-cell–related genes are preferentially overexpressed in a fraction of cancer cells of poorly differentiated tumors. However, it is not known whether or how these cancer cells contribute to tumor initiation and progression. Here, our data showed that increased expression of pluripotency transcription factor Nanog in cancer cells correlates with a worse clinical outcome in HCC. Using the Nanog promoter as a reporter system, we could successfully isolate a small subpopulation of Nanog-positive cells. We demonstrate that Nanog-positive cells exhibited enhanced ability of self-renewal, clonogenicity, and initiation of tumors, which are consistent with crucial hallmarks in the definition of cancer stem cells (CSCs). NanogPos CSCs could differentiate into mature cancer cells in in vitro and in vivo conditions. In addition, we found that NanogPos CSCs exhibited resistance to therapeutic agents (e.g., sorafenib and cisplatin) and have a high capacity for tumor invasion and metastasis. Knock-down expression of Nanog in NanogPos CSCs could decrease self-renewal accompanied with decreased expression of stem-cell–related genes and increased expression of mature hepatocyte-related genes. Overexpression of Nanog in NanogNeg cells could restore self-renewal. Furthermore, we found that insulin-like growth factor (IGF)2 and IGF receptor (IGF1R) were up-regulated in NanogPos CSCs. Knock-down expression of Nanog in NanogPos CSCs inhibited the expression of IGF1R, and overexpression of Nanog in NanogNeg cells increased the expression of IGF1R. A specific inhibitor of IGF1R signaling could significantly inhibit self-renewal and Nanog expression, indicating that IGF1R signaling participated in Nanog-mediated self-renewal. Conclusion : These data indicate that Nanog could be a novel biomarker for CSCs in HCC, and that Nanog could play a crucial role in maintaining the self-renewal of CSCs through the IGF1R-signaling pathway.
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“Human infections with V. vulnificus and their laboratory models often terminate in septic shock (Shan et al., 2012).”
From Hepcidin-Induced Hypoferremia Is a Critical Host Defense Mechanism against the Siderophilic Bacterium Vibrio vulnificus (2015) · cites this paper as Shan et al., 2012
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Metadata
- Authors
- Shan, J., Shen, J., Liu, L., Xia, F., Xu, C., Duan, G., Xu, Y., Ma, Q., Yang, Z., Zhang, Q., Ma, L., Liu, J., Xu, S., Yan, X., Bie, P., Cui, Y., Bian, X.-W., & Qian, C.
- Affiliations
- Army Medical University (CN)
- Corresponding author
- Qian, Cheng
- ORCID
- Venue
- Hepatology
- Published
- 2012-09
- Volume
- 56
- Issue
- 3
- Pages
- 1004-1014
- ISSN
- 0270-9139 (ISSN-L)
- OpenAlex
- W1963590109
- Cited by
- 296
- References
- 37
- Citations by year
- 2026: 3 · 2025: 12 · 2024: 8 · 2023: 11 · 2022: 16 · 2021: 22 · 2020: 15 · 2019: 28 · 2018: 24 · 2017: 33 · 2016: 38 · 2015: 40 · 2014: 21 · 2013: 20 · 2012: 5
- FWCI
- 13.61
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (973 Program, 81090423, 2010CB529406, 81101630)
- National Key Research and Development Program of China (2010CB529406)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
- Keywords
- Nanog, hepatocellular carcinoma, cancer stem cells, self-renewal, insulin-like growth factor II, IGF1R signaling, pluripotency transcription factors, tumor initiation, drug resistance, sorafenib, cisplatin, tumor invasion and metastasis, stem cell markers
- MeSH terms
- Nanog Homeobox Protein, Carcinoma, Hepatocellular, Humans, Liver Neoplasms, Neoplastic Stem Cells, Signal Transduction, Receptor, IGF Type 1, Homeodomain Proteins
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