Article

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.

0 Followers
 · 
163 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The BMI1 oncogene is overexpressed in several human malignancies including gastric cancer. In addition to BMI1, mammalian cells also express Mel-18, which is closely related to BMI1. We have reported that Mel-18 functions as a potential tumor suppressor by repressing the expression of BMI1 and consequent downregulation of activated AKT in breast cancer cells. However, the mechanisms of BMI1 overexpression and the role of Mel-18 in other cancers are still not clear. The purpose of this study is to investigate the role of BMI1 and Mel-18 in gastric cancer. BMI1 was found to be overexpressed in gastric cancer cell lines and gastric tumors. Overexpression of BMI1 correlated with advanced clinical stage and lymph node metastasis; while the expression of Mel-18 negatively correlated with BMI1. BMI1 but not Mel-18 was found to be an independent prognostic factor. Downregulation of BMI1 by Mel-18 overexpression or knockdown of BMI1 expression in gastric cancer cell lines led to upregulation of p16 (p16INK4a or CDKN2A) in p16 positive cell lines and reduction of phospho-AKT in both p16-positive and p16-negative cell lines. Downregulation of BMI1 was also accompanied by decreased transformed phenotype and migration in both p16- positive and p16-negative gastric cancer cell lines. In the context of gastric cancer, BMI1 acts as an oncogene and Mel-18 functions as a tumor suppressor via downregulation of BMI1. Mel-18 and BMI1 may regulate tumorigenesis, cell migration and cancer metastasis via both p16- and AKT-dependent growth regulatory pathways.
    Molecular Cancer 02/2010; 9:40. DOI:10.1186/1476-4598-9-40 · 5.40 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The Polycomb group (PcG) genes are a class of regulators responsible for maintaining homeotic gene expression throughout cell division. PcG expression is deregulated in some types of human cancer. Both Bmi-1 and Mel-18 are of the key PcG proteins. We investigate the expression and clinicopathological roles of Mel-18 and Bmi-1 mRNA in gastric cancer. The expression of Mel-18 and Bmi-1 in a series of 71 gastric cancer tissues and paired normal mucosal tissues distant from the tumorous lesion was assayed by quantitative real time RT-PCR. The correlation between Mel-18 and Bmi-1 mRNA expression, and between Mel-18 or Bmi-1 mRNA level and clinicopathological characteristics were analyzed. Expression of Mel-18 and Bmi-1 genes was variably detected, but overexpression of Bmi-1 mRNA and decreased expression of Mel-18 mRNA were the most frequent alteration. In addition, the expression of Bmi-1 and Mel-18 mRNA inversely correlates in gastric tumors. Moreover, a significant positive correlation between Bmi-1 overexpression and tumor size, depth of invasion, or lymph node metastasis, and a significant negative correlation between Mel-18 low-expression with lymph node metastasis or the clinical stage were observed. Our data suggest that Mel-18 and Bmi-1 may play crucial but opposite roles in gastric cancer. Decreased Mel-18 and increased Bmi-1 mRNA expression was associated with the carcinogenesis and progression of gastric cancer. It is possible to list Bmi-1 and Mel-18 as biomarkers for predicting the prognosis of gastric cancer.
    Journal of Experimental & Clinical Cancer Research 11/2010; 29(1):143. DOI:10.1186/1756-9966-29-143 · 3.27 Impact Factor
  • [Show abstract] [Hide abstract]
    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.
    Journal of Cellular Biochemistry 07/2011; 112(7):1938-48. DOI:10.1002/jcb.23114 · 3.37 Impact Factor