Research Highlights
2010; Future Medicine; Volume: 2; Issue: 5 Linguagem: Inglês
10.2217/epi.10.52
ISSN1750-1911
AutoresKoji Itahana, Goberdhan P. Dimri,
Tópico(s)Advanced biosensing and bioanalysis techniques
ResumoEpigenomicsVol. 2, No. 5 News & ViewsFree AccessResearch HighlightsKoji Itahana & Goberdhan P DimriKoji ItahanaCancer & Stem Cell Biology Program, Duke-NUS Graduate Medical School Singapore, 169857, Singapore & Goberdhan P Dimri† Author for correspondenceDepartment of Biochemistry & Molecular Biology, The George Washington University Medical Center, Washington, DC 20037, USA. Published Online:9 Nov 2010https://doi.org/10.2217/epi.10.52AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInRedditEmail Evaluation of: Yang GF, He WP, Cai MY et al.: Intensive expression of Bmi-1 is a new independent predictor of poor outcome in patients with ovarian carcinoma. BMC Cancer 10, 133–141 (2010); Song W, Tao K, Li H et al.: Bmi-1 is related to proliferation, survival and poor prognosis in pancreatic cancer. Cancer Sci. 101(7), 1754–1760 (2010).Cancer is a deadly disease. Annually the treatment and management of cancer costs billions of US dollars worldwide. Hence, it is important to find reliable biomarkers for evaluating the possible outcome after therapy for different types of cancer. The BMI-1 oncogene was originally identified as a c-Myc-cooperating oncogene in murine B- and T-cell lymphomagenesis [1,2]. It is a transcriptional repressor belonging to the polycomb group gene family. Since overexpression of BMI-1 has been reported in many types of cancers [3], several studies have been performed to elucidate whether BMI-1 could be a reliable biomarker to predict poor prognosis. Indeed, overexpression of BMI-1 has been found to correlate with poor prognosis in various cancer types, such as nasopharyngeal cancer [4], hepatocellular cancer [5], bladder cancer [6], gastric cancer [7], oligodendrogliomas [8] and non-small-cell lung cancer [9]. However, recently a negative correlation between BMI-1 and poor prognosis was also reported in squamous cell cancer of the tongue [10]. Therefore, it is important to evaluate the potential of BMI-1 as a biomarker in all types of human cancer.Two recent studies provide evidence that BMI can be a poor prognosis marker in ovarian and pancreatic cancers. The correlation between BMI-1 expression and poor prognosis in these two types of cancers has not been explored in the past. First, Yang et al. studied BMI-1 expression and survival in a cohort of 179 patients with invasive ovarian carcinoma [11]. The authors found a significant association of expression of BMI-1 with shortened patient survival (mean: 49 vs 100 months; p < 0.001). They also found a positive association between BMI-1 expression and ascending histological grade of the tumors. Second, Song et al., studied survival of 72 patients with pancreatic cancer and found that the overexpression of BMI-1 was associated with a significantly shorter overall survival (p < 0.01) and presence of lymph node metastases [12]. They also demonstrated that the BMI-1 depletion in pancreatic cancer cell lines suppressed their proliferation, and sensitized cells to apoptosis and inhibition of tumor formation in nude mice. Although the authors analyzed expression of few proteins involved in the cell cycle, cell survival and apoptosis, and reported that BMI-1 downregulation correlated with upregulation of p21 and BAX, and the downregulation of cyclin D1, CDK2, CDK4, BCL-2 and phospho-AKT, the underlying mechanisms of apoptosis and inhibition of proliferation by BMI-1 depletion remain unclear in cancer cells. In conclusion, these two papers highlight the potential of BMI-1 as a poor prognosis marker in ovarian and pancreatic cancers. Similar studies involving larger patient populations should provide batteries of reliable markers to clinicians for predicting prognosis of different cancers.References1 van Lohuizen M, Verbeek S, Scheijen B et al.: Identification of cooperating oncogenes in E mu-myc transgenic mice by provirus tagging. Cell65(5),737–752 (1991).Crossref, Medline, CAS, Google Scholar2 Haupt Y, Alexander WS, Barri G et al.: Novel zinc finger gene implicated as myc collaborator by retrovirally accelerated lymphomagenesis in E mu-myc transgenic mice. Cell65(5),753–763 (1991).Crossref, Medline, CAS, Google Scholar3 Sparmann A, van Lohuizen M: Polycomb silencers control cell fate, development and cancer. Nat. Rev. Cancer6(11),846–856 (2006).Crossref, Medline, CAS, Google Scholar4 Song LB, Zeng MS, Liao WT et al.: Bmi-1 is a novel molecular marker of nasopharyngeal carcinoma progression and immortalizes primary human nasopharyngeal epithelial cells. Cancer Res.66(12),6225–6232 (2006).Crossref, Medline, CAS, Google Scholar5 Wang H, Pan K, Zhang HK et al.: Increased polycomb-group oncogene Bmi-1 expression correlates with poor prognosis in hepatocellular carcinoma. J. Cancer Res. Clin. Oncol.134(5),535–541 (2008).Crossref, Medline, CAS, Google Scholar6 Qin ZK, Yang JA, Ye YL et al.: Expression of Bmi-1 is a prognostic marker in bladder cancer. BMC Cancer9,61 (2009).Crossref, Medline, Google Scholar7 Zhang XW, Sheng YP, Li Q et al.: BMI1 and Mel-18 oppositely regulate carcinogenesis and progression of gastric cancer. Mol. Cancer9,40 (2010).Crossref, Medline, CAS, Google Scholar8 Hayry V, Tynninen O, Haapasalo HK et al.: Stem cell protein BMI-1 is an independent marker for poor prognosis in oligodendroglial tumours. Neuropathol. Appl. Neurobiol.34(5),555–563 (2008).Crossref, Medline, CAS, Google Scholar9 Vrzalikova K, Skarda J, Ehrmann J et al.: Prognostic value of Bmi-1 oncoprotein expression in NSCLC patients: a tissue microarray study. J. Cancer Res. Clin. Oncol.134(9),1037–1042 (2008).Crossref, Medline, CAS, Google Scholar10 Hayry V, Makinen LK, Atula T et al.: Bmi-1 expression predicts prognosis in squamous cell carcinoma of the tongue. Br. J. Cancer102(5),892–897 (2010).Crossref, Medline, CAS, Google Scholar11 Yang GF, He WP, Cai MY et al.: Intensive expression of Bmi-1 is a new independent predictor of poor outcome in patients with ovarian carcinoma. BMC Cancer10,133–141 (2010).Crossref, Medline, CAS, Google Scholar12 Song W, Tao K, Li H et al.: Bmi-1 is related to proliferation, survival and poor prognosis in pancreatic cancer. Cancer Sci.101(7),1754–1760 (2010).Crossref, Medline, CAS, Google ScholarEvaluation of: Ochiai H, Takenobu H, Nakagawa A et al.: Bmi1 is a MYCN target gene that regulates tumorigenesis through repression of KIF1Bβ and TSLC1 in neuroblastoma. Oncogene 29(18), 2681–2690 (2010).BMI-1 is one component of the polycomb repressive complex 1, which contributes to the epigenetic gene silencing of important tumor suppressors, such as p16INK4a. Overexpression of BMI-1 is associated with many types of cancer. Furthermore, expression of BMI-1 is reduced in cells undergoing senescence [1], which is an intrinsic tumor suppressive mechanism [2]. It has been reported that BMI-1 is a direct transcriptional target of c-Myc, and that a fine-tuned expression of c-Myc can inhibit senescence by upregulating BMI-1 in human fibroblasts [3,4]. BMI-1 has also been demonstrated to be a direct transcriptional target of E2F1 [5] and SALL4 [6]. In a recent article, Ochiai et al. show that similar to c-Myc, MYCN is also a positive regulator of BMI-1 in neuroblastoma cells [7]. Mutating the MYCN binding site of the BMI-1 promoter significantly reduces the ability of endogenous MYCN to activate BMI-1 transcription, as evidenced by the promoter–reporter assays suggesting the importance of MYCN in BMI-1 expression in neuroblastoma. The expression of BMI-1 and MYCN also correlated well in various neuroblastoma cell lines, and exogenous expression of BMI-1 led to enhanced proliferation and colony formation in soft agar. Along these lines, depletion of BMI-1 contributed to differentiation in neuroblastoma cells. The authors further demonstrated that the two tumor suppressor genes, KIF1Bβ and TSLC1, are direct targets of BMI-1, and proposed that suppressing KIF1Bβ and TSLC1 may be important for MYCN-mediated progression of neuroblastoma.This article raises several interesting questions that remain to be answered. Since there are several cancer-relevant targets of MYCN and c-Myc that are known, to what extent does BMI-1 contribute to MYCN- or c-Myc-mediated oncogenesis? More importantly, does the reduction of KIF1Bβ and TSLC1 by BMI-1 contribute to BMI-1- and MYCN-mediated progression of neuroblastoma? Nonetheless, a direct link between MYCN and BMI-1 in neuroblastomas presented in this article is an interesting finding in the field of brain cancer.References1 Itahana K, Zou Y, Itahana Y et al.: Control of the replicative life span of human fibroblasts by p16 and the polycomb protein Bmi-1. Mol. Cell Biol.23(1),389–401 (2003).Crossref, Medline, CAS, Google Scholar2 Dimri GP: What has senescence got to do with cancer? Cancer Cell7(6),505–512 (2005).Crossref, Medline, CAS, Google Scholar3 Guo WJ, Datta S, Band V et al.: Mel-18, a polycomb group protein, regulates cell proliferation and senescence via transcriptional repression of Bmi-1 and c-Myc oncoproteins. Mol. Biol. Cell18(2),536–546 (2007).Crossref, Medline, CAS, Google Scholar4 Guney I, Wu S, Sedivy JM: Reduced c-Myc signaling triggers telomere-independent senescence by regulating Bmi-1 and p16(INK4a). Proc. Natl Acad. Sci. USA103(10),3645–3650 (2006).Crossref, Medline, CAS, Google Scholar5 Nowak K, Kerl K, Fehr D et al.: Bmi-1 is a target gene of E2F-1 and is strongly expressed in primary neuroblastomas. Nucleic Acids Res.34(6),1745–1754 (2006).Crossref, Medline, CAS, Google Scholar6 Yang J, Chai L, Liu F et al.: Bmi-1 is a target gene for SALL4 in hematopoietic and leukemic cells. Proc. Natl Acad. Sci. USA104(25),10494–10499 (2007).Crossref, Medline, CAS, Google Scholar7 Ochiai H, Takenobu H, Nakagawa A et al.: Bmi-1 is a MYCN target gene that regulates tumorigenesis through repression of KIF1Bβ and TSLC1 in neuroblastoma. Oncogene29(18),2681–2690 (2010).Crossref, Medline, CAS, Google ScholarEvaluation of: Zhu W, Huang L, Xu X, Qian H, Xu W: Anti-proliferation effect of BMI-1 in U937 cells with siRNA. Int. J. Mol. Med. 25(6), 889–895 (2010).Many oncoproteins are still difficult to target using drugs and antibodies. RNAi therapy is one of the emerging and very promising methods for decreasing the expression of a chosen protein, such as an oncoprotein that supports the growth and survival of cancer cells [1,2]. The major challenge with RNAi therapy has been the delivery of siRNA to specific tissues and organs that express the target gene. Recently, delivery using lentiviruses, adenoviruses and nanoparticles has been successfully attempted in a mammalian system to treat cancer [2]. In addition, Phase I clinical trials using the systemic administration of siRNA nanoparticles to patients with solid cancers has been successfully conducted [3].The second challenge is to find the best candidate gene(s) for each cancer type for RNAi-based therapy. Since BMI-1 is overexpressed in many types of cancer, BMI-1 could be a potential target for RNAi therapy against cancer. Several studies have been recently reported, which evaluated the effect of knockdown of BMI-1 in various cancer types, such as breast cancer [4,5], neuroblastoma [4,6,7], ovarian cancer [4], lung cancer [8], nasopharyngeal cancer [9], cervical cancer [10], pancreatic cancer [11] and leukemia cells [12]. In these studies, depletion of BMI-1 caused cell cycle arrest, senescence or apoptosis, depending on the cell context. In a recent study, Zhu et al. tested multiple siRNAs to efficiently knockdown BMI-1 in U937 leukemia cells. The authors demonstrated that BMI-1 depletion causes a reduction of proliferation and apoptosis, proposing that BMI-1 could be an attractive target for treating leukemia cells overexpressing BMI-1 [13].Although the underlying mechanism of the reduction of proliferation and apoptosis mediated by depletion of BMI-1 remains to be elucidated in each cancer type, BMI-1 is known to repress the Ink4a–Arf locus, which encodes ARF and p16. Therefore, BMI-1 is able to target ARF–Mdm2–p53 and p16–pRb, the two major tumor suppressor pathways. BMI-1 is also able to inhibit apoptosis mediated by the ARF–Mdm2–p53 pathway [14]; however, U937 and many other cancer cells are p53 negative, hence BMI-1 may have additional apoptosis-relevant targets other than the ARF to inhibit apoptosis in cancer cells. Such targets could be proapoptotic genes such as BMI-1[15]. BMI-1 may also suppress apoptosis by upregulating Akt [5].Financial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.References1 Bumcrot D, Manoharan M, Koteliansky V et al.: RNAi therapeutics: a potential new class of pharmaceutical drugs. Nat. Chem. Biol.2(12),711–719 (2006).Crossref, Medline, CAS, Google Scholar2 Castanotto D, Rossi JJ: The promises and pitfalls of RNA-interference-based therapeutics. Nature457(7228),426–433 (2009).Crossref, Medline, CAS, Google Scholar3 Davis ME, Zuckerman JE, Choi CH et al.: Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles. Nature464(7291),1067–1070 (2010).Crossref, Medline, CAS, Google Scholar4 Liu L, Andrews LG, Tollefsbol TO: Loss of the human polycomb group protein BMI1 promotes cancer-specific cell death. Oncogene25(31),4370–4375 (2006).Crossref, Medline, CAS, Google Scholar5 Guo WJ, Zeng MS, Yadav A et al.: Mel-18 acts as a tumor suppressor by repressing Bmi-1 expression and down-regulating Akt activity in breast cancer cells. Cancer Res.67(11),5083–5089 (2007).Crossref, Medline, CAS, Google Scholar6 Cui H, Hu B, Li T et al.: Bmi-1 is essential for the tumorigenicity of neuroblastoma cells. Am. J. Pathol.170(4),1370–1378 (2007).Crossref, Medline, CAS, Google Scholar7 Ochiai H, Takenobu H, Nakagawa A et al.: Bmi1 is a MYCN target gene that regulates tumorigenesis through repression of KIF1Bβ and TSLC1 in neuroblastoma. Oncogene29(18),2681–2690 (2010).Crossref, Medline, CAS, Google Scholar8 Yu Q, Su B, Liu D et al.: Antisense RNA-mediated suppression of Bmi-1 gene expression inhibits the proliferation of lung cancer cell line A549. Oligonucleotides17(3),327–335 (2007).Crossref, Medline, CAS, Google Scholar9 Qin L, Zhang X, Zhang L et al.: Downregulation of BMI-1 enhances 5-fluorouracil-induced apoptosis in nasopharyngeal carcinoma cells. Biochem. Biophys. Res. Commun.371(3),531–535 (2008).Crossref, Medline, CAS, Google Scholar10 Jiang Y, Su B, Meng X et al.: Effect of siRNA-mediated silencing of Bmi-1 gene expression on HeLa cells. Cancer Sci.101(2),379–386 (2010).Crossref, Medline, CAS, Google Scholar11 Song W, Tao K, Li H et al.: Bmi-1 is related to proliferation, survival and poor prognosis in pancreatic cancer. Cancer Sci.101(7),1754–1760 (2010).Crossref, Medline, CAS, Google Scholar12 Rizo A, Olthof S, Han L et al.: Repression of BMI1 in normal and leukemic human CD34(+) cells impairs self-renewal and induces apoptosis. Blood114(8),1498–1505 (2009).Crossref, Medline, CAS, Google Scholar13 Zhu W, Huang L, Xu X, Qian H, Xu W: Anti-proliferation effect of BMI-1 in U937 cells with siRNA. Int. J. Mol. Med.25(6),889–895. (2010).Crossref, Medline, CAS, Google Scholar14 Jacobs JJ, Scheijen B, Voncken JW et al.: Bmi-1 collaborates with c-Myc in tumorigenesis by inhibiting c-Myc-induced apoptosis via INK4a/ARF. Genes Dev.13(20),2678–2690 (1999).Crossref, Medline, CAS, Google Scholar15 Jagani Z, Wiederschain D, Loo A et al.: The Polycomb group protein Bmi-1 is essential for the growth of multiple myeloma cells. Cancer Res.70(13),5528–5538 (2010).Crossref, Medline, CAS, Google ScholarFiguresReferencesRelatedDetailsCited ByKnockdown BMI1 expression inhibits proliferation and invasion in human bladder cancer T24 cells3 July 2013 | Molecular and Cellular Biochemistry, Vol. 382, No. 1-2 Vol. 2, No. 5 Follow us on social media for the latest updates Metrics Downloaded 480 times History Published online 9 November 2010 Published in print October 2010 Information© Future Medicine LtdPDF download
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