Gene Summary

Gene:BMI1; BMI1 proto-oncogene, polycomb ring finger
Aliases: PCGF4, RNF51, FLVI2/BMI1, flvi-2/bmi-1
Summary:This gene encodes a ring finger protein that is major component of the polycomb group complex 1 (PRC1). This complex functions through chromatin remodeling as an essential epigenetic repressor of multiple regulatory genes involved in embryonic development and self-renewal in somatic stem cells. This protein also plays a central role in DNA damage repair. This gene is an oncogene and aberrant expression is associated with numerous cancers and is associated with resistance to certain chemotherapies. A pseudogene of this gene is found on chromosome X. Read-through transcription also exists between this gene and the upstream COMM domain containing 3 (COMMD3) gene. [provided by RefSeq, Sep 2015]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:polycomb complex protein BMI-1
Source:NCBIAccessed: 14 March, 2017


What does this gene/protein do?
Show (31)
Pathways:What pathways are this gene/protein implicaed in?
Show (1)

Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 14 March 2017 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Proto-Oncogene Proteins
  • Apoptosis
  • Zinc Finger Protein GLI1
  • Sensitivity and Specificity
  • Ubiquitination
  • Wnt Proteins
  • Resting Phase, Cell Cycle
  • Twist-Related Protein 1
  • Zinc Fingers
  • Thiazoles
  • Superoxides
  • Young Adult
  • ras Proteins
  • BMI1
  • Tissue Array Analysis
  • Transduction
  • Ubiquitin Thiolesterase
  • Cell Proliferation
  • Neoplastic Cell Transformation
  • Treatment, BMT & Stem Cell Transplant
  • Chromosome 10
  • Transcription Factors
  • Prostate Cancer
  • Tea
  • Biomarkers, Tumor
  • Repressor Proteins
  • Cancer Gene Expression Regulation
  • Cancer Stem Cells
  • Telomerase
  • MicroRNAs
  • Stomach Cancer
  • beta Catenin
  • Polycomb Repressive Complex 1
  • Skin Cancer
  • Urothelium
  • Stem Cells
  • Reproducibility of Results
  • Bladder Cancer
  • Reactive Oxygen Species
  • Up-Regulation
  • Nuclear Proteins
Tag cloud generated 14 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: BMI1 (cancer-related)

Hsu CC, Chang WC, Hsu TI, et al.
Suberoylanilide hydroxamic acid represses glioma stem-like cells.
J Biomed Sci. 2016; 23(1):81 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Glioma stem-like cells (GSCs) are proposed to be responsible for high resistance in glioblastoma multiforme (GBM) treatment. In order to find new strategies aimed at reducing GSC stemness and improving GBM patient survival, we investigated the effects and mechanism of a histone deacetylases (HDACs) inhibitor, suberoylanilide hydroxamic acid (SAHA), since HDAC activity has been linked to cancer stem-like cell (CSC) abundance and properties.
METHODS: Human GBM cell lines were plated in serum-free suspension cultures allowed for sphere forming and CSC enrichment. Subsequently, upon SAHA treatment, the stemness markers, cell proliferation, and viability of GSCs as well as cellular apoptosis and senescence were examined in order to clarify whether inhibition of GSCs occurs.
RESULTS: We demonstrated that SAHA attenuated cell proliferation and diminished the expression stemness-related markers (CD133 and Bmi1) in GSCs. Furthermore, at high concentrations (more than 5 μM), SAHA triggered apoptosis of GSCs accompanied by increases in both activation of caspase 8- and caspase 9-mediated pathways. Interestingly, we found that a lower dose of SAHA (1 μM and 2.5 μM) inhibited GSCs via cell cycle arrest and induced premature senescence through p53 up-regulation and p38 activation.
CONCLUSION: SAHA induces apoptosis and functions as a potent modulator of senescence via the p38-p53 pathway in GSCs. Our results provide a perspective on targeting GSCs via SAHA treatment, and suggest that SAHA could be used as a potent agent to overcome drug resistance in GBM patients.

Patel N, Garikapati KR, Ramaiah MJ, et al.
miR-15a/miR-16 induces mitochondrial dependent apoptosis in breast cancer cells by suppressing oncogene BMI1.
Life Sci. 2016; 164:60-70 [PubMed] Related Publications
AIMS: miRNAs are small non-coding RNA molecules that regulate post-transcriptional gene expression. Here we have made an endeavor to search whether any miRNAs are involved in the regulation of BMI1 in breast cancer that leads to mitochondrial dependent apoptotic cell death.
MAIN METHODS: Renilla luciferase reporter assay was performed to detect the ectopically expressed miRNAs that regulate the expression of 3' UTR of BMI1. MTT assay was performed to check the cytotoxicity level. Western blotting and qRT-PCR were performed to check the expression of BMI1, pro-apoptotic, anti-apoptotic proteins and mRNA expression levels respectively. JC-1 staining, Caspase-3, Caspase-6/9 assay and mitochondrial cytosolic fractionation were performed to monitor mitochondrial dependent apoptosis. Wound healing assay was performed to investigate migration. All experiments were performed upon miR-15a and miR-16 overexpression in MCF-7, MDAMB-231 breast cancer cells.
KEY FINDINGS: In MCF-7, MDAMB-231 breast cancer cells luciferase reporter assay confirmed the significant reduction of reporter activity upon co-transfection of 3' UTR of BMI1 along with miR-15a and miR-16. miR-15a and miR-16 significantly down-regulated BMI1 protein and mRNA expression levels as well as anti-apoptotic protein BCL2 and up-regulated pro-apoptotic proteins. Ectopic expression of miR-15a, miR-16, increased mitochondrial ROS resulting in impaired mitochondrial membrane potential, followed by cytochrome-C release into the cytosol that activated Caspase-3 and Caspase-6/9 leading to intrinsic apoptosis. Additionally, it also inhibits migration.
SIGNIFICANCE: Our results suggest that overexpression of miR-15a and miR-16 mediates down-regulation of BMI1, and leads to mitochondrial mediated apoptosis.

Shahi MH, Farheen S, Mariyath MP, Castresana JS
Potential role of Shh-Gli1-BMI1 signaling pathway nexus in glioma chemoresistance.
Tumour Biol. 2016; 37(11):15107-15114 [PubMed] Related Publications
Chemoresistance is a common hurdle for the proper treatment of gliomas. The role of Shh-Gli1 signaling in glioma progression has been reported. However, its role in glioma chemoresistance has not been well studied yet. In this work, we found that Shh-Gli1 signaling regulates the expression of one stem cell marker, BMI1 (B cell-specific Moloney murine leukemia virus), in glioma. Interestingly, we also demonstrated high expression of MRP1 (multi-drug resistance protein 1) in glioma. MRP1 expression was decreased by BMI1 siRNA and Shh-Gli1 cell signaling specific inhibitor GANT61 in our experiments. GANT61 very efficiently inhibited cell colony growth in glioma cell lines, compared to temozolomide. Moreover, a synergic effect of GANT61 and temozolomide drastically decreased the LD50 of temozolomide in the cell colony experiments. Therefore, our results suggest that there is a potential nexus of Shh-Gli1-BMI1 cell signaling to regulate MRP1 and to promote chemoresistance in glioma. Henceforth, our study opens the possibility of facing new targets, Gli1 and BMI1, for the effective treatment of glioma suppression of chemoresistance with adjuvant therapy of GANT61 and temozolomide.

Zhang Z, Bu X, Chen H, et al.
Bmi-1 promotes the invasion and migration of colon cancer stem cells through the downregulation of E-cadherin.
Int J Mol Med. 2016; 38(4):1199-207 [PubMed] Free Access to Full Article Related Publications
Metastasis and recurrence are the challenges of cancer therapy. Recently, mounting evidence has suggested that cancer stem cells (CSCs) and epithelial-mesenchymal transition (EMT) are critical factors in tumor metastasis and recurrence. The oncogene, Bmi-1, promotes the development of hematologic malignancies and many solid tumors. The aim of the present study was to elucidate the mechanisms through which Bmi-1 promotes the invasion and migration of colon CSCs (CCSCs) using the HCT116 colon cancer cell line. Sphere formation medium and magnetic‑activated cell sorting were used to enrich and screen the CCSCs. CD133 and CD44 were regarded as markers of CCSCs and they were found to be co-expressed in the HCT116 colon cancer cell line. Colony formation assay, cell proliferation assay and viability assay using the Cell Counting Kit-8, and transplantation assay using nude mice injected with CCSCs were used to examine the CCSCs. The CD133+CD44+ HCT116 cells exhibited greater cloning efficiency, an enhanced proliferative ability, increased cell viability and stronger tumorigenicity; these cells were used as the CCSCs for subsequent experiments. In addition, the invasive and migratory abilities of the CD133+CD44+ HCT116 cells were markedly decreased when Bmi-1 was silenced by small interfering RNA (siRNA). The results of RT-qPCR and western blot analysis suggested that Bmi-1 had a negative effect on E-cadherin expression. On the whole, our findings suggest that Bmi-1 promotes the invasion and migration of CCSCs through the downregulation of E-cadherin, possibly by inducing EMT. Our findings thus indicate that Bmi-1 may be a novel therapeutic target for the treatment of colon cancer.

Kaufhold S, Garbán H, Bonavida B
Yin Yang 1 is associated with cancer stem cell transcription factors (SOX2, OCT4, BMI1) and clinical implication.
J Exp Clin Cancer Res. 2016; 35:84 [PubMed] Free Access to Full Article Related Publications
The transcription factor Yin Yang 1 (YY1) is frequently overexpressed in cancerous tissues compared to normal tissues and has regulatory roles in cell proliferation, cell viability, epithelial-mesenchymal transition, metastasis and drug/immune resistance. YY1 shares many properties with cancer stem cells (CSCs) that drive tumorigenesis, metastasis and drug resistance and are regulated by overexpression of certain transcription factors, including SOX2, OCT4 (POU5F1), BMI1 and NANOG. Based on these similarities, it was expected that YY1 expression would be associated with SOX2, OCT4, BMI1, and NANOG's expressions and activities. Data mining from the proteomic tissue-based datasets from the Human Protein Atlas were used for protein expression patterns of YY1 and the four CSC markers in 17 types of cancer, including both solid and hematological malignancies. A close association was revealed between the frequency of expressions of YY1 and SOX2 as well as SOX2 and OCT4 in all cancers analyzed. Two types of dynamics were identified based on the nature of their association, namely, inverse or direct, between YY1 and SOX2. These two dynamics define distinctive patterns of BMI1 and OCT4 expressions. The relationship between YY1 and SOX2 expressions as well as the expressions of BMI1 and OCT4 resulted in the classification of four groups of cancers with distinct molecular signatures: (1) Prostate, lung, cervical, endometrial, ovarian and glioma cancers (YY1(lo)SOX2(hi)BMI1(hi)OCT4(hi)) (2) Skin, testis and breast cancers (YY1(hi)SOX2(lo)BMI1(hi)OCT4(hi)) (3) Liver, stomach, renal, pancreatic and urothelial cancers (YY1(lo)SOX2(lo)BMI1(hi)OCT4(hi)) and (4) Colorectal cancer, lymphoma and melanoma (YY1(hi)SOX2(hi)BMI1(lo)OCT4(hi)). A regulatory loop is proposed consisting of the cross-talk between the NF-kB/PI3K/AKT pathways and the downstream inter-regulation of target gene products YY1, OCT4, SOX2 and BMI1.

Li RZ, Wang LM
Decreased microRNA-452 expression and its prognostic significance in human osteosarcoma.
World J Surg Oncol. 2016; 14:150 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: MicroRNA-452 (miR-452) was previously reported to be dysregulated in several types of human cancers and involved in tumor progression. The aim of this study was to investigate the clinical significance and prognostic value of miR-452 expression in human osteosarcoma.
METHODS: The expression of miR-452 was detected in 95 pairs of osteosarcoma specimens and adjacent noncancerous bone tissues using quantitative RT-PCR (qRT-PCR) assay. Then, the association of miR-452 levels with clinicopathological features and prognosis was analyzed. The roles of miR-452 in regulating osteosarcoma cell proliferation, apoptosis, and invasion were evaluated in vitro.
RESULTS: miR-452 expression was significantly downregulated in osteosarcoma tissues than those in corresponding noncancerous bone tissues (P < 0.001). Decreased miR-452 expression was linked to larger tumor size, high tumor grade, advanced clinical stage, distant metastasis, and shorter overall survival. Multivariate Cox regression analysis confirmed that low level of miR-452 expression predicted poor prognosis independently. miR-452 overexpression in MG-63 cells suppressed cell proliferation, promoted cell apoptosis, inhibited cell invasion, and led to decreased BMI1 protein levels.
CONCLUSIONS: These findings suggest that miR-452 downregulation may be involved in osteosarcoma formation and progression and that miR-452 would serve as a novel prognostic biomarker for patients with this disease.

Yi C, Li BB, Zhou CX
Bmi-1 expression predicts prognosis in salivary adenoid cystic carcinoma and correlates with epithelial-mesenchymal transition-related factors.
Ann Diagn Pathol. 2016; 22:38-44 [PubMed] Related Publications
Salivary adenoid cystic carcinoma (AdCC) is known for its high propensity to invade and metastasize. Bmi-1 acts as an oncogene by controlling cell cycle and self-renewal of adult stem cells, and its overexpression correlates with metastasis and poor prognosis in several cancers. Epithelial-mesenchymal transition (EMT) plays a central role in cancer metastasis. A key step in EMT is the down-regulation of E-cadherin that can be repressed by the transcriptional factors, such as Snail and Slug. In the present study, we investigated Bmi-1, Snail, Slug, and E-cadherin expression by immunohistochemistry in 102 patients with AdCC and analyzed statistically whether their expression correlated with clinicopathologic factors and prognosis. Reverse transcription-polymerase chain reaction was also performed in 22 tumor tissues and the adjacent noncancerous tissues to confirm Bmi-1 status in AdCCs. Our data demonstrated significant associations between the tumor metastasis and the expression of Bmi-1, Snail, Slug, and E-cadherin. Furthermore, a high level of Bmi-1 was not only correlated with the overexpression of Snail and Slug but also indicated an unfavorable metastasis-free survival and served as a high-risk marker for AdCC. In addition, Bmi-1 messenger RNA level was found much higher in AdCC tissues than in the adjacent noncancerous salivary gland tissues. Our results suggest that Bmi-1 may play a crucial role in AdCC progression by interaction with EMT-related markers and predict poor survival.

Bo C, Li N, Li X, et al.
Long noncoding RNA uc.338 promotes cell proliferation through association with BMI1 in hepatocellular carcinoma.
Hum Cell. 2016; 29(4):141-7 [PubMed] Related Publications
Hepatocellular carcinoma (HCC) is one of the most common human cancers all over the world. Increasing evidences have demonstrated that long noncoding RNAs (lncRNAs) play important roles in malignant transformation, tumor growth and metastasis in HCC. Among lncRNAs, ultraconserved RNAs (ucRNAs) containing an ultraconserved region have been report to contribute to human cancers. lncRNA ultraconserved element 338 (uc.338) was first found to be upregulated in HCC and promote cell growth. However, the exact mechanism by which uc.338 modulates cell growth remains unclear. In the present study, we demonstrated that uc.338 promotes HCC cell proliferation and induces cell cycle progression. RNA-immunoprecipitation and RNA pull-down assays showed that uc.338 associated with BMI1. We found that uc.338 promotes HCC cell proliferation and induces cell cycle progression through association with BMI1. uc.338 also modulated the transcription of CDKN1A. The oncogenic activity of uc.338 is partially due to its repression of p21. uc.338 may be a potential target for HCC therapy.

Yang XX, Sang MX, Zhu SC, et al.
Radiosensitization of esophageal carcinoma cells by the silencing of BMI-1.
Oncol Rep. 2016; 35(6):3669-78 [PubMed] Related Publications
Radiotherapy (RT) has been widely used to treat cancer patients, particularly esophageal cancer patients. B-cell-specific Moloney murine leukemia virus integration site-1 (BMI-1) plays an important role in promoting the growth of cancer cells after exposure to irradiation. The present study aimed to characterize the effects of BMI-1 on the proliferation and invasion of cancer cells, as well as the mechanism involved in the regulation of the growth of esophageal cancer ECA109 and TE13 cells. The expression levels of the BMI-1 gene and protein in esophageal cancer ECA109 and TE13 cells were determined by quantitative PCR and western blotting after transfection. Co-immunoprecipitation (Co-IP) assay was employed to detect the interaction of BMI-1 with r-H2AX and H2AK119ub. We used flow cytometry to analyze the cell cycle distribution and apoptosis of transfected cells after irradiation or not, and examined cellular growth and invasion in vitro by MTS and Transwell assays. The results revealed that shRNA targeting the BMI-1 gene and protein downregulated BMI-1 expression after transfection for 24 h. The proliferation and invasion of tumor cells in the BMI-1‑shRNA group were suppressed after RT. In addition, the interaction of BMI-1, H2AK119ub and r-H2AX was increased after exposure to IR, followed by an increased apoptosis rate and decreased percentage of cells arrested at the G2/M phase after irradiation and silencing of BMI-1 by shRNA. Knockdown of BMI-1 expression decreased the phosphorylation of H2AX, upregulated p16, and induced the radiosensitivity of esophageal cancer ECA109 and TE13 cells in vitro and significantly inhibited the growth and invasion of tumor cells. The mechanisms were found to be abrogation of cell cycle arrest at the G2/M stage and promotion of apoptosis.

Chen SJ, Chen YT, Zeng LJ, et al.
Bmi1 combines with oncogenic KRAS to induce malignant transformation of human pancreatic duct cells in vitro.
Tumour Biol. 2016; 37(8):11299-309 [PubMed] Related Publications
It is critical to understand the pathogenesis of preinvasive stages of pancreatic duct adenocarcinoma (PDAC) for developing novel potential diagnostic and therapeutic targets. The polycomb group family member B-lymphoma Moloney murine leukemia virus insertion region-1 (Bmi1) is overexpressed and involved in cancer progression in PDAC; however, its role in the multistep malignant transformation of human pancreatic duct cells has not been directly demonstrated. In this study, we stably expressed Bmi1 in a model of telomerase-immortalized human pancreatic duct-derived cells (HPNE) and showed that Bmi1 promoted HPNE cell proliferation, migration, and invasion but not malignant transformation. We then used mutant KRASG12D as a second oncogene to transform HPNE cells and showed that it further enhanced Bmi1-induced malignant potential. More importantly, coexpression of KRASG12D and Bmi1 caused anchorage-independent growth transformation in vitro but still failed to produce tumors in nude mice. Finally, we found that mutant KRASG12D induced HPNE-Bmi1 cells to undergo partial epithelial-mesenchymal transition (EMT) likely via upregulation of snail. Knockdown of KRASG12D significantly reduced the expression of snail and vimentin at both the messenger RNA (mRNA) and protein level and further impaired the anchorage-independent growth capability of invasive cells. In summary, our findings demonstrate that coexpression of Bmi1 and KRASG12D could lead to transformation of HPNE cells in vitro and suggest potential new targets for diagnosis and treatment of PDAC.

Taran K, Wysocka A, Sitkiewicz A, et al.
Evaluation of potential prognostic value of Bmi-1 gene product and selected markers of proliferation (Ki-67) and apoptosis (p53) in the neuroblastoma group of tumors.
Postepy Hig Med Dosw (Online). 2016; 70:110-6 [PubMed] Related Publications
INTRODUCTION: Cancer in children is a very important issue in pediatrics. The least satisfactory treatment outcome occurs among patients with clinically advanced neuroblastomas. Despite much research, the biology of this tumor still remains unclear, and new prognostic factors are sought. The Bmi-1 gene product is a currently highly investigated protein which belongs to the Polycomb group (PcG) and has been identified as a regulator of primary neural crest cells. It is believed that Bmi‑1 and N-myc act together and are both involved in the pathogenesis of neuroblastoma. The aim of the study was to assess the potential prognostic value of Bmi-1 protein and its relations with mechanisms of proliferation and apoptosis in the neuroblastoma group of tumors.
MATERIAL/METHODS: 29 formalin-fixed and paraffin-embedded neuroblastoma tissue sections were examined using mouse monoclonal antibodies anti-Bmi-1, anti-p53 and anti-Ki-67 according to the manufacturer's instructions.
RESULTS: There were found statistically significant correlations between Bmi-1 expression and tumor histology and age of patients.
CONCLUSIONS: Bmi-1 seems to be a promising marker in the neuroblastoma group of tumors whose expression correlates with widely accepted prognostic parameters. The pattern of BMI-1 expression may indicate that the examined protein is also involved in maturation processes in tumor tissue.

Bolomsky A, Schlangen K, Schreiner W, et al.
Targeting of BMI-1 with PTC-209 shows potent anti-myeloma activity and impairs the tumour microenvironment.
J Hematol Oncol. 2016; 9:17 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The polycomb complex protein BMI-1 (BMI-1) is a putative oncogene reported to be overexpressed in multiple myeloma (MM). Silencing of BMI-1 was shown to impair the growth and survival of MM cells. However, therapeutic agents specifically targeting BMI-1 were not available so far. Here, we investigated PTC-209, a novel small molecule inhibitor of BMI-1, for its activity in MM.
METHODS: BMI-1 expression was analysed in human MM cell lines and primary MM cells by using publically available gene expression profiling (GEP) data. The anti-MM activity of PTC-209 was investigated by viability testing, cell cycle analysis, annexin V and 7-AAD staining, quantification of cleaved poly(ADP-ribose) polymerase (PARP), JC-1 as well as colony formation assays. Deregulation of central myeloma growth and survival genes was studied by quantitative PCR and flow cytometry, respectively. In addition, the impact of PTC-209 on in vitro osteoclast, osteoblast and tube formation was analysed.
RESULTS: We confirmed overexpression of BMI-1 in MM patients by using publically available GEP datasets. Of note, BMI-1 expression was further increased at relapse which translated into significantly shorter overall survival in relapsed/refractory patients treated with bortezomib or dexamethasone. Treatment with PTC-209 significantly decreased viable cell numbers in human MM cell lines, induced a G1 cell cycle arrest, promoted apoptosis and demonstrated synergistic activity with pomalidomide and carfilzomib. The anti-MM activity of PTC-209 was accompanied by a significant decrease of cyclin D1 (CCND1) and v-myc avian myelocytomatosis viral oncogene homolog (MYC) expression as well as upregulation of cyclin-dependent kinase inhibitor 1A (CDKN1A) and cyclin-dependent kinase inhibitor 1B (CDKN1B). We also observed upregulation of NOXA (up to 3.6 ± 1.2-fold induction, P = 0.009) and subsequent downregulation of myeloid cell leukemia 1 (MCL-1) protein levels, which likely mediates the apoptotic effects of PTC-209. Importantly, the anti-MM activity was upheld in the presence of stromal support or myeloma growth factors insulin-like growth factor 1 (IGF-1) and interleukin 6 (IL-6). In the MM microenvironment, PTC-209 impaired tube formation, impaired osteoclast development and decreased osteoblast formation in a dose-dependent manner (P < 0.01 at 1 μM, respectively). The latter might be attributed to an induction of DKK1 and was reversed by concurrent anti-DKK1 antibody treatment.
CONCLUSIONS: We confirmed overexpression of BMI-1 in MM highlighting its role as an attractive drug target and reveal therapeutic targeting of BMI-1 by PTC-209 as a promising novel therapeutic intervention for MM.

Sang Y, Tang J, Li S, et al.
LncRNA PANDAR regulates the G1/S transition of breast cancer cells by suppressing p16(INK4A) expression.
Sci Rep. 2016; 6:22366 [PubMed] Free Access to Full Article Related Publications
It has been reported that lncRNA PANDAR (promoter of CDKN1A antisense DNA damage-activated RNA) is induced as a result of DNA damage, and it regulates the reparation of DNA damage. In this study, we investigated the role of lncRNA PANDAR in the progression of breast cancer and found that PANDAR was up-regulated in breast cancer tissues and cell lines. The knockdown of PANDAR suppresses G1/S transition of breast cancer cells. We demonstrated mechanistically that the regulation of G1/S transition by PANDAR was partly due to the transcriptional modulation of p16(INK4A). Moreover, we showed that PANDAR impacted p16(INK4A) expression by regulating the recruitment Bmi1 to p16(INK4A) promoter. To our knowledge, this is the first study which showed the functional roles and mechanisms of PANDAR in regulating the progression of breast cancer. The PANDAR/Bmi1/p16(INK4A) axis could serve as novel targets for breast cancer therapy.

Wu WR, Sun H, Zhang R, et al.
Methylation-associated silencing of miR-200b facilitates human hepatocellular carcinoma progression by directly targeting BMI1.
Oncotarget. 2016; 7(14):18684-93 [PubMed] Free Access to Full Article Related Publications
This study aims to investigate the biological function of microRNA-200b and BMI1, predicted target of microRNA-200b in human hepatocellular carcinoma (HCC). MicroRNA-200b and BMI1 expression in HCC tissues were evaluated by qPCR. A luciferase reporter assay was used to validate BMI1 as a direct target of microRNA-200b. The effect of microRNA-200b on HCC progression was studied in vitro and in vivo. Methylation specific PCR (MSP) and bisulfite sequencing PCR (BSP) were used to detect the methylation status of the microRNA-200b promoter. Significant downregulation of microRNA-200b was observed in 83.3% of HCC tissues. By contrast, BMI1 was significantly overexpressed in 66.7% of HCC tissues. The results of the luciferase assay confirmed BMI1 as a direct target gene of microRNA-200b. Forced expression of microRNA-200b in HCC cells dramatically repressed proliferation, colony formation, cell cycle progression, and invasion. Moreover, microRNA-200b synergized with 5-fluorouracil to induce apoptosis in vitro and suppressed tumorigenicity in vivo. In addition, MSP analysis and BSP revealed that CpG sites in the promoter region of microRNA-200b were extensively methylated in HCC, with concomitant downregulation of microRNA-200b expression. Furthermore, microRNA-200b was activated in HCC cells after treatment with 5-azacytidine, whereas BMI1 expression was clearly downregulated. Our results indicate that microRNA-200b is partially silenced by DNA hypermethylation and that it can repress tumor progression by directly targeting BMI1 in HCC.

Ma M, Zhao L, Sun G, et al.
Mda-7/IL-24 enhances sensitivity of B cell lymphoma to chemotherapy drugs.
Oncol Rep. 2016; 35(5):3122-30 [PubMed] Related Publications
Interleukin-24 (IL-24) is a cytokine encoded by a tumor suppressor gene of the IL-10 family, also known as the melanoma differentiation associated gene-7 (Mda-7) and first discovered in human melanoma cells. Mda-7/IL-24 has been shown to inhibit the proliferation of various human tumor cell lines, but its effect on the sensitivity of B cell lymphoma to chemotherapy agents is not yet clear. The present study investigated the effects of Mda-7/IL-24 overexpression on the sensitivity of human B cell lymphoma cells to chemotherapy, as well as its mechanism of action. The sensitivity of stable Mda-7/IL-24 overexpressing Raji and Daudi cells to cis-diamminedichloroplatinum (CDDP), epirubicin and vinblastine (VCR) were assessed by the MTS method, and the IC50 value calculated. Cell apoptosis and the intracellular accumulation of Rhodamine-123 were assayed by flow cytometry. The expression of multidrug resistance gene 1 (MDR1), B-cell-specific Moloney murine leukemia virus insertion site 1 (BMI1), topoisomerase II (Topo II) and multidrug resistance-related protein 1 (MRP1) mRNA and protein were analyzed by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blotting, respectively. In addition, western blot analysis was also used to investigate the effect of Mda-7/IL-24 on activity of GTP-RhoA-ERK signaling pathway in Raji and Daudi cells. Growth inhibition and apoptosis rates of Mda-7/IL-24 overexpressing Raji and Daudi cells were higher than those of non-transfected cells and cells transfected with vector alone when treated with CDDP, epirubicin and VCR. The IC50 values of CDDP, epirubicin and VCR were lower for Mda-7/IL-24-overexpressing Raji and Daudi cells than for non-transfected cells and cells transfected with empty vector. Intracellular accumulation of Rhodamine-123 and the expression of Topo II were higher, while the levels of MDR1, BMI and MRP1 mRNA and protein were lower, in Mda-7/IL-24 overexpressing Raji and Daudi cells. Furthermore, the activities of GTP-RhoA-ERK signaling pathway in Raji and Daudi cells were suppressed. These results indicated that Mda-7/IL-24 enhanced the sensitivity of B lymphoma cells to chemotherapy agents by altering the expression of multidrug-resistance genes via downregulating GTP-RhoA-ERK signaling pathway, suggesting that treatment of B cell lymphomas with Mda-7/IL-24 could avoid MDR.

Zhang Y, Zhou SY, Yan HZ, et al.
miR-203 inhibits proliferation and self-renewal of leukemia stem cells by targeting survivin and Bmi-1.
Sci Rep. 2016; 6:19995 [PubMed] Free Access to Full Article Related Publications
Drug resistance is one of the leading causes of failed cancer therapy in the treatment of acute myeloid leukemia. Although the mechanisms of resistance are poorly understood, they may be related to the presence of leukemia stem cells (LSCs). Down-regulation of the miR-203 reportedly contributes to oncogenesis and chemo-resistance in multiple cancers. We found that miR-203 expression was down-regulated in CD34 + AML cells as compared with CD34- cells isolated from patients as well as in LSC-enriched (CD34 + CD38-) cell lines KG-1a or MOLM13. Additionally, re-expression of miR-203 led to decreased cell proliferation, self-renewal, and sphere formation in LSCs. Moreover, miR-203 was found to directly target the 3'un-translated regions of survivin and Bmi-1 mRNAs affecting proliferation and self-renewal in LSCs. In this study, we identified a novel miR-203/survivin/Bmi-1 axis involved in the regulation of biological properties of LSCs. This axis may represent a new therapeutic target for acute myeloid leukemia and a potential prognosis/diagnostic marker for LSCs therapy.

Bak Y, Kwon T, Bak IS, et al.
IL-32θ inhibits stemness and epithelial-mesenchymal transition of cancer stem cells via the STAT3 pathway in colon cancer.
Oncotarget. 2016; 7(6):7307-17 [PubMed] Free Access to Full Article Related Publications
Interleukin (IL)-32 is a well-known cytokine associated with inflammation, virus infections and cancer. IL-32θ is a newly identified isoform of IL-32, whose function has yet to be elucidated. In this study, we investigated IL-32θ function in colon cancer stem cells. Using samples from colon cancer patients, we found that the expression of IL-32θ mRNAs was significantly suppressed in tumor regions. We investigated the effects of IL-32θ on colon cancer. Ectopic expression of IL-32θ attenuated invasion, migration in vitro and in vivo tumorigenicity of colon cancer cells. IL-32θ inhibited epithelial-mesenchymal transition (EMT), resulting in the suppression of their migratory and invasive capabilities of HT29 colon cancer cells. In addition, IL-32θ altered various properties of CSCs, including sphere formation and expression of stemness related genes. IL-32θ directly bound to STAT3 and inhibited its nuclear translocation, leading to inhibited transcription of downstream factors, including Bmi1 and ZEB1. We showed that IL-32θ inhibited the STAT3-ZEB1 pathway and consequently inhibited key factors of stemness and EMT. Taken together, our findings reveal that IL-32θ can be a tumor suppressor, indicating that IL-32θ could possibly be used in therapies for colon cancer.

Yang F, Lv LZ, Cai QC, Jiang Y
Potential roles of EZH2, Bmi-1 and miR-203 in cell proliferation and invasion in hepatocellular carcinoma cell line Hep3B.
World J Gastroenterol. 2015; 21(47):13268-76 [PubMed] Free Access to Full Article Related Publications
AIM: To investigate the potential roles of enhancer of zeste homolog2 (EZH2), Bmi-1 and miR-203 in cell proliferation and invasion in hepatocellular carcinoma (HCC) cell line Hep3B.
METHODS: A total of 73 patients who underwent surgical resection at Fuzong Clinical Medical College of Fujian Medical University were enrolled in this study. Hep3B cells were cultivated in RPMI 1640 medium supplemented with 10% fetal bovine serum at 37 °C. Vectors that containing cDNA of the EZH2 gene or miR-203 targeted shRNA plasmid were constructed, and then transfected into Hep3B cells. The mRNA expression of miR-203, EZH2, and Bmi-1 was analyzed using quantitative real-time polymerase chain reaction analysis, and the protein levels of EZH2 and Bmi-1 were detected by Western blot analysis. Effect of EZH2 or miR-203 on cell proliferation was observed by methyl thiazolyl tetrazolium assay, and cell apoptosis was assessed using flow cytometry. Besides, effect of EZH2 or miR-203 on tumor cell invasion was detected using Transwell assay.
RESULTS: The mRNA levels of EZH2 and Bmi-1 in HCC tissues and in Hep3B cells were significantly higher compared with those in normal samples (P < 0.01), while miR-203 level was significantly lower in HCC tissues (P < 0.01). Hep3B cells transfected with EZH2-shRNA or miR-203-shRNA showed lower expression levels of EZH2 and Bmi-1 (P < 0.05). Compared with controls, Hep3B cells transfected with EZH2-shRNA had relative slow cell proliferation, indicating that low expression of EZH2 and Bmi-1 and overexpression of miR-203 could inhibit Hep3B cell proliferation (P < 0.05). The average apoptosis rate of Hep3B cells transfected with EZH2-shRNA vector was about 18.631%, while that of Hep3B cells transfected with shRNA vector was about 5.33%, suggesting that EZH2 was down-regulated by transfecting with EZH2-shRNA, and the down-regulated EZH2 contributed to the cell apoptosis. Low expression of EZH2 and Bmi-1 and overexpression of miR-203 could reduce Hep3B cell invasion (P < 0.05).
CONCLUSION: Our study suggests that EZH2 and Bmi-1 are up-regulated while miR-203 is down-regulated in Hep3B cells. MiR-203 may contribute to the metastasis and enhance apoptosis of HCC cells by regulating EZH2 and Bmi-1. Our study may provide a theoretical basis for metastasis of HCC and targeted therapy of HCC.

Sibin MK, Lavanya CH, Bhat DI, et al.
CD133 and BMI1 expressions and its prognostic role in primary glioblastoma.
J Genet. 2015; 94(4):689-96 [PubMed] Related Publications
Glioblastoma is the most common malignant brain tumour, generated by bulk of malignant cancer stem cells, which express various stem cell factors like CD133, BMI1 and nestin. There are several studies which show the importance of CD133 in cancer, but the function and interaction with other major oncogenes and tumour suppressor genes is still not understood. This study aimed to analyse the expression of CD133 mRNA and its correlations with BMI1 protein expression and TP53 mutations in newly diagnosed glioblastoma patients and its role in prognosis. Overexpression of CD133 mRNA and BMI1 protein was found in 47.6 and 76.2% patients respectively and TP53 mutations was seen in 57.1% of patients in our study.There was no correlation among TP53 mutations and expressions of CD133 and BMI1. We found that high level of BMI1 expression was favourable for the patient survival (P=0.0075) and high CD133 mRNA expression was unfavourable for the patient survival (P=0.0226).CD133 mRNA and BMI1 protein expression could independently predict the glioblastoma patient survival in multivariate analysis. In conclusion, the overexpression of these stem cell markers is a common event in glioblastoma progression and could be used as potential prognostic markers.

Ferretti R, Bhutkar A, McNamara MC, Lees JA
BMI1 induces an invasive signature in melanoma that promotes metastasis and chemoresistance.
Genes Dev. 2016; 30(1):18-33 [PubMed] Free Access to Full Article Related Publications
Melanoma can switch between proliferative and invasive states, which have identifying gene expression signatures that correlate with good and poor prognosis, respectively. However, the mechanisms controlling these signatures are poorly understood. In this study, we identify BMI1 as a key determinant of melanoma metastasis by which its overexpression enhanced and its deletion impaired dissemination. Remarkably, in this tumor type, BMI1 had no effect on proliferation or primary tumor growth but enhanced every step of the metastatic cascade. Consistent with the broad spectrum of effects, BMI1 activated widespread gene expression changes, which are characteristic of melanoma progression and also chemoresistance. Accordingly, we showed that up-regulation or down-regulation of BMI1 induced resistance or sensitivity to BRAF inhibitor treatment and that induction of noncanonical Wnt by BMI1 is required for this resistance. Finally, we showed that our BMI1-induced gene signature encompasses all of the hallmarks of the previously described melanoma invasive signature. Moreover, our signature is predictive of poor prognosis in human melanoma and is able to identify primary tumors that are likely to become metastatic. These data yield key insights into melanoma biology and establish BMI1 as a compelling drug target whose inhibition would suppress both metastasis and chemoresistance of melanoma.

Lin X, Ojo D, Wei F, et al.
A Novel Aspect of Tumorigenesis-BMI1 Functions in Regulating DNA Damage Response.
Biomolecules. 2015; 5(4):3396-415 [PubMed] Free Access to Full Article Related Publications
BMI1 plays critical roles in maintaining the self-renewal of hematopoietic, neural, intestinal stem cells, and cancer stem cells (CSCs) for a variety of cancer types. BMI1 promotes cell proliferative life span and epithelial to mesenchymal transition (EMT). Upregulation of BMI1 occurs in multiple cancer types and is associated with poor prognosis. Mechanistically, BMI1 is a subunit of the Polycomb repressive complex 1 (PRC1), and binds the catalytic RING2/RING1b subunit to form a functional E3 ubiquitin ligase. Through mono-ubiquitination of histone H2A at lysine 119 (H2A-K119Ub), BMI1 represses multiple gene loci; among these, the INK4A/ARF locus has been most thoroughly investigated. The locus encodes the p16INK4A and p14/p19ARF tumor suppressors that function in the pRb and p53 pathways, respectively. Its repression contributes to BMI1-derived tumorigenesis. BMI1 also possesses other oncogenic functions, specifically its regulative role in DNA damage response (DDR). In this process, BMI1 ubiquitinates histone H2A and γH2AX, thereby facilitating the repair of double-stranded DNA breaks (DSBs) through stimulating homologous recombination and non-homologous end joining. Additionally, BMI1 compromises DSB-induced checkpoint activation independent of its-associated E3 ubiquitin ligase activity. We review the emerging role of BMI1 in DDR regulation and discuss its impact on BMI1-derived tumorigenesis.

Mayr C, Wagner A, Loeffelberger M, et al.
The BMI1 inhibitor PTC-209 is a potential compound to halt cellular growth in biliary tract cancer cells.
Oncotarget. 2016; 7(1):745-58 [PubMed] Free Access to Full Article Related Publications
BMI1 is a core component of the polycomb repressive complex 1 (PRC1) and is up-regulated in biliary tract cancer (BTC), contributing to aggressive clinical features. In this study we investigated the cytotoxic effects of PTC-209, a recently developed inhibitor of BMI1, in BTC cells. PTC-209 reduced overall viability in BTC cell lines in a dose-dependent fashion (0.04 - 20 µM). Treatment with PTC-209 led to slightly enhanced caspase activity and stop of cell proliferation. Cell cycle analysis revealed that PTC-209 caused cell cycle arrest at the G1/S checkpoint. A comprehensive investigation of expression changes of cell cycle-related genes showed that PTC-209 caused significant down-regulation of cell cycle-promoting genes as well as of genes that contribute to DNA synthesis initiation and DNA repair, respectively. This was accompanied by significantly elevated mRNA levels of cell cycle inhibitors. In addition, PTC-209 reduced sphere formation and, in a cell line-dependent manner, aldehyde dehydrogease-1 positive cells. We conclude that PTC-209 might be a promising drug for future in vitro and in vivo studies in BTC.

Sławek S, Szmyt K, Fularz M, et al.
Pluripotency transcription factors in lung cancer-a review.
Tumour Biol. 2016; 37(4):4241-9 [PubMed] Related Publications
Lung cancer is the leading cause of cancer-related mortality worldwide. Diagnosis of lung cancer in an early stage is still a challenge due to the asymptomatic course of early stages of the disease and the lack of a standard screening program for the population. Nowadays, learning about the mechanisms that lead to cancerogenesis in the lung is crucial for the development of new diagnostic and therapeutic strategies. Recently, many studies have proved that cancer stem cells (CSCs) are responsible for the initiation, progression, metastasis, recurrence, and even resistance of chemo- and radiotherapeutic treatment in patients with lung cancer. The expression of pluripotency transcription factors is responsible for stemness properties. In this review, we summarize the current knowledge on the role of CSCs and pluripotency transcription factors in lung carcinogenesis.

Xu X, Liu Y, Su J, et al.
Downregulation of Bmi-1 is associated with suppressed tumorigenesis and induced apoptosis in CD44⁺ nasopharyngeal carcinoma cancer stem-like cells.
Oncol Rep. 2016; 35(2):923-31 [PubMed] Related Publications
Bmi-1 (B-cell-specific Moloney murine leukemia virus insertion site 1) is a member of the Polycomb group gene (PcG) family, which is involved in the proliferation, migration and tumorigenesis of several types of cancer stem cells (CSCs). However, its precise role and mechanism in CD44+ nasopharyngeal carcinoma (NPC) cancer stem-like cells (CSC-LCs) remain poorly understood. In our previous study, we successfully silenced Bmi-1 by short hairpin RNA (shRNA) in CD44+ NPC CSC-LCs and obtained stable Bmi-1 knockdown (KD) cell lines. In the present study, we tested the cell proliferation by CCK-8 assay and apoptosis by flow cytometry. Scratch wound healing assay, together with Transwell migration and invasion assays were used to measure the migration and invasion capacity. We further evaluated the tumorigenicity of CD44+ NPC CSC-LCs transfected with Bmi-1 shRNA in vivo. Based on our results, knockdown of Bmi-1 by shRNA resulted in the inhibition of tumor proliferation, migration and invasion in vitro, followed by cell apoptosis. In addition, our results preliminarily demonstrated that inhibition of Bmi-1 expression by shRNA increased tumor apoptosis through the p16INK4a-p14ARF-p53 pathway. Bmi-1 silencing in CD44+ NPC CSC-LCs also resulted in the failure to develop tumors in vivo. These results provide important insights into the role of Bmi-1 in the occurrence and development of NPC. Based on our findings, regulation of Bmi-1 in CD44+ NPC CSC-LCs may provide a potential molecular target for the therapy of NPC, and targeted silencing of Bmi-1 by shRNA may have clinical future implications in NPC therapy.

Ge G, Zhou C, Ren Y, et al.
Enhanced SLC34A2 in breast cancer stem cell-like cells induces chemotherapeutic resistance to doxorubicin via SLC34A2-Bmi1-ABCC5 signaling.
Tumour Biol. 2016; 37(4):5049-62 [PubMed] Related Publications
Even though early detection methods and treatment options are greatly improved, chemoresistance is still a tremendous challenge for breast cancer therapy. Breast cancer stem cells (BCSCs) represent a subpopulation that is central to chemoresistance. We aim to investigate the relationship between SLC34A2 and chemoresistance in BCSCs and identify the underlying mechanisms by which SLC34A2 regulates chemoresistance in BCSCs. Fluorescence Activated Cell Sorting (FACS) analysis showed the presence of a variable fraction of CD44(+)CD24(-) cells in 25 out of 25 breast cancer samples. We cultured primary breast cancer sample cells and breast cancer cell line cells to induce sphere formation in serum-free medium. Following sorting of CD44(+)CD24(-) cells from spheres, we showed that CD44(+)CD24(-) cells displayed stem cell-like features and were resistant to chemotherapy drug doxorubicin. Significantly, enhanced SLC34A2 expression correlated with chemoresponse and survival of breast cancer patients. We subsequently indicated that increased SLC34A2 expression in BCSCs directly contributed to their chemoresistance by a series of in vitro and in vivo experiments. Furthermore, we demonstrated that SLC34A2 induced chemoresistance in BCSCs via SLC34A2-Bmi1-ABCC5 signaling. Finally, we showed that ABCC5 was a direct transcriptional target of Bmi1 by chromatin immunoprecipitation (ChIP). In conclusion, our work indicated that decreased SLC34A2 expression sensitized BCSCs to doxorubicin via SLC34A2-Bmi1-ABCC5 signaling and shed new light on understanding the mechanism of chemoresistance in BCSCs. This study not only bridges the missing link between stem cell-related transcription factor (Bmi1) and ABC transporter (ABCC5) but also contributes to development of potential therapeutics against breast cancer.

Martínez-Fernández M, Dueñas M, Feber A, et al.
A Polycomb-mir200 loop regulates clinical outcome in bladder cancer.
Oncotarget. 2015; 6(39):42258-75 [PubMed] Free Access to Full Article Related Publications
Bladder cancer (BC) is a highly prevalent disease, ranking fifth in the most common cancers worldwide. Various miRNAs have recently emerged as potential prognostic biomarkers in cancer. The miR-200 family, which repressed the epithelial-to-mesenchymal transition (EMT), is repressed in multiple advanced cancers. However, its expression and function in BC is still poorly understood. Here we show that miR-200 family displays increased expression, probably due to the activation of specific oncogenic signaling pathways, and reduced promoter methylation, in BC compared to normal bladder samples. Furthermore, we show that the expression of these miRNAs is decreased in high grade and stage tumors, and the down-regulation is associated with patient's poor clinical outcome. Our data indicate that the miR-200 family plays distinct roles in Non-Muscle (NMIBC) and Muscle-Invasive BC (MIBC). In MIBC, miR-200 expression post transcriptionally regulates EMT-promoting transcription factors ZEB1 and ZEB2, whereas suppresses BMI1 expression in NMIBC. Interestingly, we show that increased EZH2 and/or BMI1 expression repress the expression of miR-200 family members. Collectively, these findings support a model of BC progression through a coordinated action between the Polycomb Repression Complex (PRC) members repressing the miR-200 expression, which ultimately favors invasive BC development. Since pharmacological inhibition of EZH2 in BC cell lines lead to increased miR-200 expression, our findings may support new therapeutic strategies for BC clinical management.

Hatta M, Naganuma K, Kato K, Yamazaki J
3-Deazaneplanocin A suppresses aggressive phenotype-related gene expression in an oral squamous cell carcinoma cell line.
Biochem Biophys Res Commun. 2015 Dec 4-11; 468(1-2):269-73 [PubMed] Related Publications
In tumor tissues, alterations of gene expression caused by aberrant epigenetic modifications confer phenotypic diversity on malignant cells. Although 3-deazaneplanocin A (DZNep) has been shown to reactivate tumor suppressor genes in several cancer cells, it remains unclear whether DZNep attenuates the malignant phenotypes of oral squamous cell carcinoma (OSCC) cells. In this study, we investigated the effect of DZNep on the expression of genes related to aggressive phenotypes, such as epithelial-mesenchymal transition, in OSCC cells. We found that DZNep reduced the cellular levels of polycomb group proteins (EZH2, SUZ12, BMI1, and RING1A) and the associated trimethylation of Lys27 on histone H3 and monoubiquitination of Lys119 on histone H2A in the poorly differentiated OSCC cell line SAS. Immunocytochemical staining demonstrated that DZNep induced the reorganization of filamentous actin and the membrane localization of E-cadherin associated with cell-cell adhesions. We also found an inhibitory effect of DZNep on cell proliferation using a WST assay. Finally, quantitative RT-PCR analysis demonstrated that genes involved in the aggressive phenotypes (TWIST2, EGFR, ACTA2, TGFB1, WNT5B, and APLIN) were down-regulated, whereas epithelial phenotype genes (CDH1, CLDN4, IVL, and TGM1) were up-regulated in SAS cells treated with DZNep. Collectively, our findings suggest that DZNep reverses the aggressive characteristics of OSCC cells through the dynamic regulation of epithelial plasticity via the reprogramming of gene expression patterns.

Qazi MA, Vora P, Venugopal C, et al.
A novel stem cell culture model of recurrent glioblastoma.
J Neurooncol. 2016; 126(1):57-67 [PubMed] Related Publications
Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults with average disease relapse at 9 months and median survival rarely extending beyond 15 months. Brain tumor stem cells (BTSCs) have been implicated in not only initiating GBM but also conferring resistance to therapy. However, it is not clear whether the BTSC population that initiates tumor growth is also responsible for GBM recurrence. In this study, we have developed a novel in vitro treatment model to profile the evolution of primary treatment-naïve GBM BTSCs through chemoradiotherapy. We report that our in vitro model enriched for a CD15+/CD133- BTSC population, mirroring the phenotype of BTSCs in recurrent GBM. We also show that in vitro treatment increased stem cell gene expression as well as self-renewal capacity of primary GBMs. In addition, the chemoradiotherapy-refractory gene signature obtained from gene expression profiling identified a hyper-aggressive subtype of glioma. The delivery of in vitro chemoradiotherapy to primary GBM BTSCs models several aspects of recurrent GBM biology, and could be used as a discovery and drug-screening platform to uncover new biological drivers and therapeutic targets in GBM.

Luo HB, Li B, Yuan WG, Xu CR
Knockdown of Bmi1 inhibits bladder cancer cell growth both in vitro and in vivo by blocking cell cycle at G1 phase and inducing apoptosis.
J Huazhong Univ Sci Technolog Med Sci. 2015; 35(5):730-5 [PubMed] Related Publications
Bmi1 is a member of the polycomb group family of proteins, and it drives the carcinogenesis of various cancers and governs the self-renewal of multiple types of stem cells. However, its role in the initiation and progression of bladder cancer is not clearly known. The present study aimed to investigate the function of Bmi1 in the development of bladder cancer. Bmi1 expression was detected in human bladder cancer tissues and their adjacent normal tissues (n=10) by immunohistochemistry, qRT-PCR and Western blotting, respectively. Bmi1 small interference RNA (siRNA) was synthesized and transfected into human bladder carcinoma cells (EJ) by lipofectamine 2000. The Bmil expression at mRNA and protein levels was measured in EJ cells transfected with Bmil siRNA (0, 80, 160 nmol/L) by qRT-PCR and Western blotting, respectively. Cell viability and Ki67 expression (a marker of cell proliferation) were determined in Bmi1 siRNA-transfected cells by CCK-8 assay and qRT-PCR, respectively. Cell cycle of transfected cells was flow-cytometrically determined. Immunofluorescence and Western blotting were used to detect the expression levels of cell cycle-associated proteins cyclin D1 and cyclin E in the cells. Pro-apoptotic proteins Bax and caspase 3 and anti-apoptotic protein Bcl-2 were detected by Western blotting as well. Additionally, xenograft tumor models were established by inoculation of EJ cells (infected with Bmil shRNA/pLKO.1 lentivirus or not) into nude mice. The tumor volumes were measured every other day for 14 days. The results showed that the Bmil expression was significantly increased in bladder tumor tissues when compared with that in normal tissues (P<0.05). Perturbation of Bmi1 expression by using siRNA could significantly inhibit the proliferation of EJ cells (P<0.05). Bmi1 siRNA-transfected EJ cells were accumulated in G1 phase and the expression levels of cyclin D1 and cyclin E were down-regulated. Bax and caspase-3 expression levels were significantly increased and Bcl-2 levels decreased after Bmi1 knockdown. Tumor volume was conspicuously reduced in mice injected with EJ cells with Bmi1 knockdown. Our findings indicate that Bmi1 is a potential driver oncogene of bladder cancer and it may become a potential treatment target for human bladder cancer.

Rassouli FB, Matin MM, Saeinasab M
Cancer stem cells in human digestive tract malignancies.
Tumour Biol. 2016; 37(1):7-21 [PubMed] Related Publications
Digestive tract malignancies, including oral, pharyngeal, esophageal, gastric, and colorectal cancers, are among the top 10 most common cancers worldwide. In spite of using various treatment modalities, cancer patients still suffer from recurrence and metastasis of malignant cells. Cancer stem cells (CSCs) are undifferentiated and highly proliferative malignant cells with unique properties mediated by overexpression of stemness markers, metastasis-related proteins, drug transporters, and DNA repair machinery. Due to their salient characteristics, it has been suggested that CSCs are responsible for tumor initiation, progression, invasion, recurrence, and therapy resistance. Exploring different aspects of CSC biology has fueled a great enthusiasm in designing novel therapeutic strategies to help patients. For instance, identification of markers associated with digestive tract CSCs, such as CD44, CD133, CD24, EpCAM, LGR5, ALDH1, and BMI1, has made it possible to develop more accurate diagnosis approaches. In addition, specifically targeting CSCs by their markers imposes fewer side effects and improves therapeutic outcomes. Here, we focus on the current status of CSC biology in digestive tract cancers, with emphasis on CSC markers, and review achieved progress in eradication of digestive tract CSC cells.

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