Journal
GASTROENTEROLOGY
Volume 142, Issue 7, Pages 1547-+Publisher
W B SAUNDERS CO-ELSEVIER INC
DOI: 10.1053/j.gastro.2012.02.042
Keywords
Cancer Stem Cell; Liver Cancer; Self-Renewal; Response to Chemotherapy
Categories
Funding
- National Natural Science Foundation of China [30921006, 81071778, 81101714, 91029732, 30900770]
- State Key Project for Infectious Diseases [2012ZX10002-009, 011]
- National Key Basic Research Program [2012CB316503]
- State Key Laboratory of Oncogenes and Related Genes [91-10-02, 03]
- Key Program of Basic Research of Shanghai, China [10JC1418500, 11QA1408900]
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BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is believed to arise from tumor-initiating cells (T-ICs), although little is known about their stem cell-like properties. METHODS: We quantified levels of p28(GANK) (Gankyrin), OV6, and Oct4 in 130 human HCC samples using immunohistochemistry. Magnetic-activated cell sorting was used to isolate OV6(+) HCC cells. T-IC properties were evaluated by quantitative reverse-transcription polymerase chain reaction, flow cytometry, and spheroid formation. We used a coimmunoprecipitation assay to study interactions among p28(GANK), Oct4, and WWP2. Tumorigenicity and pulmonary metastasis were examined in nonobese diabetic and severe combined immunodeficient mice. RESULTS: In HCC samples, high levels of p28GANK correlated with expansion of OV6(+) tumor cells; the combination of high levels of p28(GANK) and OV6 was associated with progression of HCC. p28(GANK) was predominantly expressed in liver T-ICs, isolated by magnetic sorting, and undifferentiated primary HCC spheroids. Increased levels of p28(GANK) in T-ICs increased their percentages in HCC samples, expression of stem cell genes, self-renewal potential, chemoresistance in vitro, and tumorigenicity and ability to develop into pulmonary metastases in mice. Conversely, knockdown of p28(GANK) reduced their T-IC properties. p28(GANK) likely activates liver T-ICs by impeding ubiquitination and degradation of the transcription factor Oct4 by WWP2. In support of this concept, levels of p28(GANK) correlated with those of Oct4 in HCC samples. CONCLUSIONS: p28(GANK) activates and maintains liver T-ICs in HCCs by preventing degradation of Oct4. Inhibitors of p28(GANK) might therefore be developed to inactivate T-ICs and slow tumor progression.
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