Oncoprotein BMI-1 induces the malignant transformation of HaCaT cells

Department of Cell Biology, Second Military Medical University, Shanghai 200433, PR China.
Journal of Cellular Biochemistry (Impact Factor: 3.37). 01/2009; 106(1):16-24. DOI: 10.1002/jcb.21969
Source: PubMed

ABSTRACT BMI-1 (B-cell-specific Moloney murine leukemia virus integration site 1), a novel oncogene, has attracted much attention in recent years for its involvement in the initiation of a variety of tumors. Recent evidence showed that BMI-1 was highly expressed in neoplastic skin lesions. However, whether dysregulated BMI-1 expression is causal for the transformation of skin cells remains unknown. In this study, we stably expressed BMI-1 in a human keratinocyte cell line, HaCaT. The expression of wild-type BMI-1 induced the malignant transformation of HaCaT cells in vitro. More importantly, we found that expression of BMI-1 promoted formation of squamous cell carcinomas in vivo. Furthermore, we showed that BMI-1 expression led to the downregulation of tumor suppressors, such as p16INK4a and p14ARF, cell adhesion molecules, such as E-Cadherin, and differentiation related factor, such as KRT6. Therefore, our findings demonstrated that dysregulated BMI-1 could indeed lead to keratinocytes transformation and tumorigenesis, potentially through promoting cell cycle progression and increasing cell mobility.

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    ABSTRACT: Artemisinin and its derivatives are well known antimalaria drugs, particularly useful for the treatment of infection of Plasmodium falciparum malaria parasites resistant to traditional antimalarial pharmaceuticals. Artemisinin has inhibitory effects on cancer cell growth and anti-angiogenetic activity, including many drug- and radiation-resistant cancer cell lines. Moloney murine leukemia virus insertion site 1 (BMI-1) has been shown to regulate proliferation by inhibiting p16(ink4a) transcription. It is well known that BMI-1 over-expression was found in nasopharyngeal carcinoma cell lines and correlated with advanced invasive stage of the tumor progression and poor prognosis. In the present investigation, we analyzed the inhibitory effects of artemisinin on proliferation of nasopharyngeal carcinoma cell lines (CNE-1 and CNE-2, well-differentiated cells, and poorly differentiated cells). We demonstrated that artemisinin induced G1 cell cycle arrest in CNE-1 and CNE-2 cells. Artemisinin inhibited BMI-1 both in protein and transcript levels. BMI-1 knockdown made the cells more sensitive to artemisinin with an increase in G1 phase, but over-expression of BMI-1 partially reversed the artemisinin-induced G1 cell cycle arrest. Depletion of BMI-1 was able to intensifying the increment of p16 and the reduction of CDK4 induced by artemisinin. In addition, over-expression of BMI-1 was capable of attenuating the increasing p16 and decreasing CDK4 in cells treated with artemisinin. Taking together, the BMI1-p16/CDK4 axis was involved in the artemisinin-driven G1 arrest in nasopharyngeal carcinoma cells, and these results indicated that a potential treatment that the combination of artemisinin and BMI-1 downregulation could enhance the growth inhibitory affects on nasopharyngeal carcinoma cells.
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