Liver stem cells and hepatocellular carcinoma

Mishra, Lopa; Banker, Tanuj; Murray, Joseph C.; Byers, Stephen W.; Thenappan, Arun; He, Aiwu Ruth; Shetty, Kirti; Johnson, Lynt B.; Reddy, E. Premkumar

doi:10.1002/hep.22704

Cited by 304 publications

(281 citation statements)

References 122 publications

(100 reference statements)

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“…However, more and more evidence favors the hypothesis of liver T-ICs, which occupy a rare subpopulation within hepatocellular carcinoma, are responsible for hepatocellular carcinoma initiation and progression (34,35). Numerous studies have evidenced the existence of liver T-ICs which display distinct surface marker pattern, and have indicated their significance in prognosis and treatment of the patients.…”

Section: Discussionmentioning

confidence: 99%

Cyclin G1 Expands Liver Tumor-Initiating Cells by Sox2 Induction via Akt/mTOR Signaling

Wen

Han

Chen

et al. 2013

Molecular Cancer Therapeutics

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Recurrence and chemoresistance of liver cancer has been attributed to the existence of liver tumor-initiating cells (T-ICs). It is important to decipher the molecular mechanism for acquisition of drug resistance and to design combinatorial therapeutic strategies. Cyclin G1 has been shown to play a pivotal role in initiation and metastasis of hepatocellular carcinoma. In this study, we found that enhanced cyclin G1 expression was associated with drug resistance of hepatoma cells and higher recurrence rate in hepatocellular carcinoma patients. Expression of cyclin G1 was elevated in liver T-ICs and closely correlated with the expression of liver T-IC markers. Forced cyclin G1 expression remarkably enhanced self-renewal and tumorigenicity of hepatoma cells. Cyclin G1 overexpression dramatically upregulated the expression of Sox2 both in vitro and in vivo, which was impaired by chemical inhibitors of Akt/mTOR signaling. Furthermore, blockade of Akt/mTOR signaling or interference of Sox2 expression suppressed cyclin G1-enhanced self-renewal, chemoresistance, and tumorigenicity of hepatoma cells, indicating that cyclin G1 expands liver T-ICs through Sox2 induction via Akt/mTOR signaling pathway. These results suggest that cyclin G1-induced liver T-IC expansion contributes to the recurrence and chemoresistance of hepatoma, and cyclin G1 may be a promising biomarker for individualized therapy of hepatocellular carcinoma patients. Mol Cancer Ther; 12(9); 1796-804. Ó2013 AACR.

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Section: Discussionmentioning

confidence: 99%

Cyclin G1 Expands Liver Tumor-Initiating Cells by Sox2 Induction via Akt/mTOR Signaling

Wen

Han

Chen

et al. 2013

Molecular Cancer Therapeutics

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“…3 Recent evidence obtained using stem cell biologybased approaches implies that a rare population of cells in tumors, termed cancer stem cells, possess extreme tumorigenic potential and share several distinctive molecular mechanisms concerning self-renewal, differentiation, and proliferation. 2,4 Of note, it has been demonstrated that Bmi1 is necessary for the maintenance of not only leukemic stem cells but also cancer stem cells in solid tumors. 5,6 Considering that high expression levels of Bmi1 are reported in a wide range of malignancies, Bmi1 could be a general regulator of cancer stem cells as in normal stem cells.…”

mentioning

confidence: 99%

Bmi1promotes hepatic stem cell expansion and tumorigenicity in bothInk4a/Arf-dependent and -independent manners in Mice

et al. 2010

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We previously reported that forced expression of Bmi1 (B lymphoma Moloney murine leukemia virus insertion region 1 homolog) in murine hepatic stem/progenitor cells purified from fetal liver enhances their self-renewal and drives cancer initiation. In the present study, we examined the contribution of the Ink4a/Arf tumor suppressor gene locus, one of the major targets of Bmi1, to stem cell expansion and cancer initiation. Bmi1 2/2 Deltalike protein (Dlk) 1 hepatic stem/progenitor cells showed de-repression of the Ink4a/Arf locus and displayed impaired growth activity. In contrast, Ink4a/Arf 2/2 Dlk 1 cells gave rise to considerably larger colonies containing a greater number of bipotent cells than wild-type Dlk 1 cells. Although Ink4a/Arf 2/2 Dlk 1 cells did not initiate tumors in recipient nonobese diabetic/severe combined immunodeficiency mice, enforced expression of Bmi1 in Ink4a/Arf 2/2 Dlk 1 cells further augmented their self-renewal capacity and resulted in tumor formation in vivo. Microarray analyses successfully identified five downregulated genes as candidate downstream targets for Bmi1 in hepatic stem/progenitor cells. Of these genes, enforced expression of sex determining region Y-box 17 (Sox17) in Dlk 1 cells strongly suppressed colony propagation and tumor growth. Conclusion: These results indicate that repression of targets of Bmi1 other than the Ink4a/Arf locus plays a crucial role in the oncogenic transformation of hepatic stem/progenitor cells. Functional analyses of Bmi1 target genes would be of importance to elucidate the molecular machinery underlying hepatic stem cell system and explore therapeutic approaches for the eradication of liver cancer stem cells.

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“…These markers included EPCAM, a surface marker of both human hepatic progenitor cells [48] and newly-derived hepatocytes [49]; NCAM2, known as a liver progenitor cell marker and also expressed in acute and chronic damaged livers [50]; PROM1 and KIT, both having been reported as markers for liver progenitor cells [51]. Markers, such as SMAD4 and THY1 have also been shown to be expressed in liver progenitor cells [51][52][53][54]. TLR4 is known to be involved in liver fibrogenesis [55] and SOCS3 in hematopoiesis in fetal liver [56].…”

Section: Rodrigues Et Almentioning

confidence: 99%

Human skin-derived stem cells as a novel cell source for in vitro hepatotoxicity screening of pharmaceuticals

et al. 2015

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Liver stem cells and hepatocellular carcinoma

Cited by 304 publications

References 122 publications

Cyclin G1 Expands Liver Tumor-Initiating Cells by Sox2 Induction via Akt/mTOR Signaling

Cyclin G1 Expands Liver Tumor-Initiating Cells by Sox2 Induction via Akt/mTOR Signaling

Bmi1promotes hepatic stem cell expansion and tumorigenicity in bothInk4a/Arf-dependent and -independent manners in Mice

Human skin-derived stem cells as a novel cell source for in vitro hepatotoxicity screening of pharmaceuticals

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