CD133 confers cancer stem-like cell properties by stabilizing EGFR-AKT signaling in hepatocellular carcinoma

Jang, Jae Woo; Song, Yeonhwa; Kim, Se Hyuk; Kim, Jin Sun; Kim, Kang Mo; Choi, Eun Kyung; Kim, Joon; Seo, Haeng Ran

doi:10.1016/j.canlet.2016.12.023

Cited by 85 publications

(70 citation statements)

References 37 publications

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“…Nevertheless, various lines of evidence suggest that CD133 is not only a surface marker but it also plays a causal role in CSC. For example, CD133 is required for the maintenance of glioblastoma stem cells [131] and confers stem-like properties and chemoresistance to other cancer cell types [133–135]. Experimental data implicated the PI3K/Akt pathway as a CD133 effector [133, 134, 136].…”

Section: Main Textmentioning

confidence: 99%

“…For example, CD133 is required for the maintenance of glioblastoma stem cells [131] and confers stem-like properties and chemoresistance to other cancer cell types [133–135]. Experimental data implicated the PI3K/Akt pathway as a CD133 effector [133, 134, 136]. Akt pathway inhibitors, are being actively investigated in ovarian cancer therapy [137].…”

Section: Main Textmentioning

confidence: 99%

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Ovarian cancer stem cells: still an elusive entity?

2017

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The cancer stem cell (CSC) model proposes that tumor development and progression are fueled and sustained by undifferentiated cancer cells, endowed with self-renewal and tumor-initiating capacity. Ovarian carcinoma, based on its biological features and clinical evolution, appears as a prototypical example of CSC-driven disease. Indeed, ovarian cancer stem cells (OCSC) would account not only for the primary tumor growth, the peritoneal spread and the relapse, but also for the development of chemoresistance, thus having profound implication for the treatment of this deadly disease. In the last decade, an increasing body of experimental evidence has supported the existence of OCSC and their pathogenic role in the disease. Nevertheless, the identification of OCSC and the definition of their phenotypical and functional traits have proven quite challenging, mainly because of the heterogeneity of the disease and of the difficulties in establishing reliable biological models. A deeper understanding of OCSC pathobiology will shed light on the mechanisms that underlie the clinical behaviour of OC. In addition, it will favour the design of innovative treatment regimens that, on one hand, would counteract the resistance to conventional chemotherapy, and, on the other, would aim at the eradication of OC through the elimination of its CSC component.

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Section: Main Textmentioning

confidence: 99%

Section: Main Textmentioning

confidence: 99%

Ovarian cancer stem cells: still an elusive entity?

2017

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“…These results suggest that miR-612 plays important role in regulating the multi-directional differentiation and drug resistance of HCSCs [32]. CD133, a surface marker of HCSC, is expressed in 1-5% of liver cancer cases, but it is not expressed in normal tissue [33]. Studies have shown that miR-142-3p regulates this transmembrane glycoprotein CD133 and thus reduces the self-renewal, migration, proliferation, carcinogenesis and drug resistance capacities of HCSCs [34].…”

Section: Introductionmentioning

confidence: 96%

Characterization of the Role of MicroRNAs in Hepatic Cancer Stem Cells

Daia¹,

Zhang²

2017

Chemotherapy (Los Angel)

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Liver cancer is one of the most malignant tumors and is prone to relapse, metastasis and drug resistance. These phenomena can be explained by the existence of cancer stem cells (CSCs). CSCs have a strong ability to proliferate, are highly carcinogenic, exhibit multi-directional differentiation, develop drug resistance, and play critical roles in tumor radiotherapy, chemotherapy and tumor recurrence. miRNAs exert effects on oncogenes and tumor suppressor genes. There are distinctive miRNA expression profiles in different types of tumors, and these profiles are closely related to tumorigenesis, differentiation, metastasis and prognosis. Studies have shown that miRNAs are abnormally expressed in hepatocellular carcinoma and have important regulatory effects on the self-renewal and differentiation of hepatic cancer stem cells (HCSCs) as well as on the initiation of tumorigenesis. Therefore, it is critical to understand the impact of miRNAs in HCSC and the associated molecular mechanisms to develop new methods for the clinical diagnosis and treatment of liver cancer.

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“…Moreover, the overexpression of CD133 in 127 HCC specimens was associated with a poor prognosis (Dai et al ., ). Recent results have shown that CD133 may interact with the regulatory subunit of PI3K, stabilizing AKT signalling and conferring CSC‐like properties to hepatocellular carcinoma (Jang et al ., ,). Our results are in good agreement with these observations, as CD133‐positive cells presented higher proliferative and tumourigenic potential.…”

Section: Discussionmentioning

confidence: 99%

Targeting AMP‐activated kinase impacts hepatocellular cancer stem cells induced by long‐term treatment with sorafenib

et al. 2019

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Hepatocellular carcinoma ( HCC ) is the third leading cause of cancer death worldwide. HCC treatment is hindered by the frequent emergence of chemoresistance to the multikinase inhibitor sorafenib, which has been related to the presence of cancer stem cells ( CSC s) that self‐renew and often escape therapy. The key metabolic sensor AMP ‐activated kinase ( AMPK ) has recently been recognized as a tumour growth regulator. In this study, we aimed to elucidate the role of AMPK in the development of a stem cell phenotype in HCC cells. To this end, we enriched the CSC population in HCC cell lines that showed increased expression of drug resistance ( ALDH 1A1, ABCB 1A) and stem cell ( CD 133, Nanog, Oct4, alpha fetoprotein) markers and demonstrated their stemness phenotype. These cells were refractory to sorafenib‐induced cell death. We report that sorafenib‐resistant cells had lower levels of total and phosphorylated AMPK as well as its downstream substrate, ACC , compared with the parental cells. Interestingly, AMPK knockdown with si RNA or inhibition with dorsomorphin increased the expression of stem cell markers in parental cells and blocked sorafenib‐induced cell death. Conversely, the upregulation of AMPK , either by transfection or by pharmacological activation with A‐769662, decreased the expression of ALDH 1A1, ABCB 1A, CD 133, Nanog, Oct4, and alpha fetoprotein, and restored sensitivity to sorafenib. Analysis of the underlying mechanism points to hypoxia‐inducible factor HIF ‐1α as a regulator of stemness. In vivo studies in a xenograft mouse model demonstrated that stem‐like cells have greater tumourigenic capacity. AMPK activation reduced xenograft tumour growth and decreased the expression of stem cell markers. Taken together, these results indicate that AMPK may serve as a novel target to overcome chemoresistance in HCC .

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CD133 confers cancer stem-like cell properties by stabilizing EGFR-AKT signaling in hepatocellular carcinoma

Cited by 85 publications

References 37 publications

Ovarian cancer stem cells: still an elusive entity?

Ovarian cancer stem cells: still an elusive entity?

Characterization of the Role of MicroRNAs in Hepatic Cancer Stem Cells

Targeting AMP‐activated kinase impacts hepatocellular cancer stem cells induced by long‐term treatment with sorafenib

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