Wang Q, Li WL, You P et al.Oncoprotein BMI-1 induces the malignant transformation of HaCaT cells. J Cell Biochem 106:16-24

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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    • "Third, Bmi-1 and other PcG proteins are expressed at higher levels in tumors, both SCC (Reinisch et al., 2007; Balasubramanian et al., 2010), basal cell carcinoma (Reinisch et al., 2007) and melanoma (Bachmann et al., 2006; Mihic-Probst et al., 2007), although the Bmi-1 finding is somewhat controversial for melanoma, as one report describes reduced expression with clinical progression in malignant melanoma (Bachmann et al., 2008). Moreover, forced Bmi-1 expression in HaCaT cells causes transformation (Wang et al., 2009). This suggests that overexpression of these proteins may be one mechanism whereby tumor cells escape death through a mechanism that involves modulation of cell cycle and apoptotic processes (Lee et al., 2008; Balasubramanian et al., 2010). "
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    ABSTRACT: The Polycomb group (PcG) proteins are epigenetic suppressors of gene expression that function through modification of histones to change chromatin structure and modulate gene expression and cell behavior. Recent studies show that PcG proteins are expressed in epidermis, that their levels change during differentiation and in disease states, and that PcG expression is regulated by agents that influence cell proliferation and survival. The results indicate that PcG proteins regulate keratinocyte cell-cycle progression, apoptosis, senescence, and differentiation. These proteins are expressed in progenitor cells, in the basal layer, and in suprabasal keratinocytes, and the level, timing, and distribution of expression suggest that the PcG proteins have a central role in maintaining the balance between cell survival and death in multiple epidermal compartments. Additional studies indicate an important role in skin cancer progression.
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    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.
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    ABSTRACT: B-cell-specific Moloney murine leukemia virus insertion site 1 (BMI1) is a member of the polycomb group of transcriptional repressors. Until now, its expression and functional significance in pancreatic carcinogenesis was unknown. In the present study, we demonstrated that expression of BMI1 was markedly up-regulated in pancreatic cancer cell lines and surgically resected cancer specimens. In addition, BMI1 expression levels correlated positively with the presence of lymph node metastases and negatively with patient survival rates, suggesting a role for BMI1 in the progression of pancreatic cancer. Furthermore, stable down-regulation of BMI1 suppressed cell growth, delayed the G1/S transition, and enhanced the susceptibility of different pancreatic cell lines to apoptosis following expression of a lentiviral-mediated shRNA targeted for BMI1. Expression of the short-hairpin RNA also correlated with the up-regulation of p21 and Bax and the down-regulation of cyclin D1, cyclin-dependent kinase (CDK)-2 and -4, Bcl-2, and phospho-Akt. Finally, growth suppression following BMI1 depletion was confirmed in a nude mouse model. In conclusion, our findings indicate that BMI1 plays an important role in the late progression of pancreatic cancer and may represent a novel therapeutic target for the treatment of pancreatic cancer.
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