Bmi-1 Signaling Research Articles

Role of HIF-1α-Activated IL-22/IL-22R1/Bmi1 Signaling Modulates the Self-Renewal of Cardiac Stem Cells in Acute Myocardial Ischemia

Impaired tissue regeneration negatively impacts on left ventricular (LV) function and remodeling after acute myocardial infarction (AMI). Little is known about the intrinsic regulatory machinery of ischemia-induced endogenous cardiac stem cells (eCSCs) self-renewing divisions after AMI. The interleukin 22 (IL-22)/IL-22 receptor 1 (IL-22R1) pathway has emerged as an important regulator of several cellular processes, including the self-renewal and proliferation of stem cells. However, whether the hypoxic environment could trigger the self-renewal of eCSCs via IL-22/IL-22R1 activation remains unknown. In this study, the upregulation of IL-22R1 occurred due to activation of hypoxia-inducible factor-1α (HIF-1α) under hypoxic and ischemic conditions. Systemic IL-22 administration not only attenuated cardiac remodeling, inflammatory responses, but also promoted eCSC-mediated cardiac repair after AMI. Unbiased RNA microarray analysis showed that the downstream mediator Bmi1 regulated the activation of CSCs. Therefore, the HIF-1α-induced IL-22/IL-22R1/Bmi1 cascade can modulate the proliferation and activation of eCSCs in vitro and in vivo. Collectively, investigating the HIF-1α-activated IL-22/IL-22R1/Bmi1 signaling pathway might offer a new therapeutic strategy for AMI via eCSC-induced cardiac repair.Graphical

PP2A inhibitor SET promotes mTORC1 and Bmi1 signaling through Akt activation and maintains the colony-formation ability of cancer cells

Protein phosphatase 2A (PP2A) is an essential tumor suppressor, with its activity often hindered in cancer cells by endogenous PP2A inhibitory proteins like SE translocation (SET). SET/PP2A axis plays a pivotal role in the colony-formation ability of cancer cells and the stabilization of c-Myc and E2F1 proteins implicated in this process. However, in osteosarcoma cell line HOS, SET knock-down (KD) suppresses the colony-formation ability without affecting c-Myc and E2F1. This study aimed to unravel the molecular mechanism through which SET enhances the colony-formation ability of HOS cells and determine if it is generalized to other cancer cells. Transcriptome analysis unveiled that SET KD suppressed mTORC1 signaling. SET KD inhibited Akt phosphorylation, an upstream kinase for mTORC1. PP2A inhibitor blocked SET KD-mediated decrease in phosphorylation of Akt and a mTORC1 substrate p70S6K. A constitutively active Akt restored decreased colony-formation ability by SET KD, indicating the SET/PP2A/Akt/mTORC1 axis. Additionally, enrichment analysis highlighted that Bmi-1, a polycomb group protein, is affected by SET KD. SET KD decreased Bmi-1 protein by Akt inhibition but not by mTORC1 inhibition, and exogenous Bmi-1 expression rescued the reduced colony formation by SET KD. Four out of eight cancer cell lines exhibited decreased Bmi-1 by SET KD. Further analysis of these cell lines revealed that Myc activity plays a role in SET KD-mediated Bmi-1 degradation. These findings provide new insights into the molecular mechanism of SET-regulated colony-formation ability, which involved Akt-mediated activation of mTORC1/p70S6K and Bmi-1 signaling.

Human embryonic stem cell-derived mesenchymal stem cell secretome reverts silica-induced airway epithelial cell injury by regulating Bmi1 signaling.

Silicosis is an irreversible chronic pulmonary disease caused by long-term inhalation and deposition of silica particles, which is currently incurable. The exhaustion of airway epithelial stem cells plays a pathogenetic role in silicosis. In present study, we investigated therapeutic effects and potential mechanism of human embryonic stem cell (hESC)-derived MSC-likes immune and matrix regulatory cells (IMRCs) (hESC-MSC-IMRCs), a type of manufacturable MSCs for clinical application in silicosis mice. Our results showed that the transplantation of hESC-MSC-IMRCs led the alleviation of silica-induced silicosis in mice, accompanied by inhibiting epithelia-mesenchymal transition (EMT), activating B-cell-specific Moloney murine leukemia virus integration site 1 (Bmi1) signaling and airway epithelial cell regeneration. In consistence, the secretome of hESC-MSC-IMRC exhibited abilities to restore the potency and plasticity of primary human bronchial epithelial cells (HBECs) proliferation and differentiation following the SiO2 -induced HBECs injury. Mechanistically, the secretome resolved the SiO2 -induced HBECs injury through the activation of BMI1 signaling and restoration of airway basal cell proliferation and differentiation. Moreover, the activation of BMI1 significantly enhanced the capacity of HBEC proliferation and differentiation to multiple airway epithelial cell types in organoids. Cytokine array revealed that DKK1, VEGF, uPAR, IL-8, Serpin E1, MCP-1 and Tsp-1 were the main factors in the hESC-MSC-IMRC secretome. These results demonstrated a potential therapeutic effect of hESC-MSC-IMRCs and their secretome for silicosis, in part through a mechanism by activating Bmi1 signaling to revert the exhaustion of airway epithelial stem cells, subsequentially enhance the potency and plasticity of lung epithelial stem cells.

EPCT-05. Phase Ib study of unesbulin (PTC596) in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG) and high-grade glioma (HGG): A report from the COllaborative Network for NEuro-Oncology Clinical Trials (CONNECT)

BACKGROUND: The B-cell-specific Moloney murine leukemia virus integration site-1 (BMI-1) protein, implicated in self-renewal and DNA-damage signaling, is highly expressed in DIPG and HGG. Preclinically, BMI-1 modulation by unesbulin (PTC596 [which mediates hyperphosphorylation and subsequent degradation of BMI-1]) leads to DIPG/HGG cell proliferation blockade, mitotic abnormalities, and tumor cell sensitization to radiation-induced DNA damage. METHODS: This phase Ib study sought to determine the maximally tolerated dose/ recommended phase 2 dose (RP2D) of unesbulin administered concurrently with radiotherapy and adjuvantly in children with newly diagnosed DIPG or HGG. Patients were enrolled according to a Rolling-6 design and received oral unesbulin twice weekly during radiotherapy and as maintenance therapy. RESULTS: Twenty-seven patients enrolled (median age: 8.5 years [range: 2-18]), including 18 patients with DIPG and nine patients with HGG. Unesbulin was administered in capsule formulation in the first nine patients, then tablet formulation for subsequent patients. Within the capsule formulation group, three dose-limiting toxicities (DLTs) were observed in two patients on dose level 2 (grade 4 neutropenia). Within the tablet formulation group, four DLTs were experienced by three patients on dose level 2 (grade 3 ALT elevation, grade 3 dehydration/vomiting, grade 3 decreased ejection fraction, grade 4 neutropenia). Dose level 1 was declared the RP2D, and six additional patients enrolled in the expansion cohort at this dose without DLTs. Most common drug-related grade 3/4 toxicities were neutropenia (48%), leucopenia (35%), and elevated ALT (26%). Similar pharmacokinetic profiles were observed for capsule and tablet formulations, consistent with adult data. Survival outcomes and genomics results will be shared at time of presentation. CONCLUSIONS: The RP2D of unesbulin in children newly diagnosed with DIPG or HGG is 200mg/m2 twice weekly, concurrent with and following radiotherapy. The recently opened surgical cohort will assess intratumoral pharmacokinetics and inhibition of tumor BMI-1 signaling, with results forthcoming.

Bmi1 signaling maintains the plasticity of airway epithelial progenitors in response to persistent silica exposures

Silicosis is caused by the continuous inhalation of environmental silica dust. The repetitive exposure of silica induces airway epithelial cell injury, leads proliferative exhaustion of epithelial stem cells, ultimately results in the lung remodeling and the development of silicosis. The B-cell-specific Moloney murine leukemia virus integration site 1 (Bmi1) is a pivotal transcription factor in stem cell self-renewal and proliferation of many tissues including the lung, but its role in the airway basal cell proliferation and differentiation during the pathogenesis of silicosis in lung has yet been investigated. In this study, the function of Bmi1 in airway basal cell proliferation and differentiation in response to silica challenge was investigated in lungs of silicosis mice and primary human bronchial epithelia cells (HBECs) exposed to silica dioxide (SiO2). Results showed a decreased expression of Bmi1 protein, epithelial basal cell markers Krt14 and Krt5, club cell marker Clara cell secretory protein, and ciliated cell marker acetyl-α-tubulin in silicosis lungs, compared to healthy mice. In consistence, a persistent exposure of SiO2 reduced the capacity of cell proliferation and differentiation in HBECs, as ascertained by the reduction of differentiated epithelial cell markers and BMI1 expression, while an increased P21-positive senescent cell fraction. Moreover, an overexpression of BMI1 in HBECs reduced the SiO2-senescent cells, enhanced the potency of cell proliferation and differentiation, and increased capacity of airway epithelial regeneration in response to the persistent exposure of SiO2. These data suggest that Bmi1 is a key transcription factor engaging in maintaining the self-renewal, proliferation and differentiation of epithelial stem cells in lung during the development of silicosis disease.

Bmi-1 determines the stemness of renal stem or progenitor cells

Renal stem or progenitor cells (RSCs), labeled with CD24 and CD133, play an important role during the repair of renal injury. Bmi-1 is a critical factor in regulating stemness of adult stem cells or progenitor cells. To investigate whether Bmi-1 determines the stemness of RSCs by inhibiting p16 and p53, and/or maintaining redox balance, RSCs were isolated, cultured and analyzed for stemness characterizations. In RSCs from Bmi-1-deficient (Bmi-1−/−) mice and wild type (WT) littermates, self-renewal, stemness, and expressions of molecules for regulating redox balance and cell cycle progression were compared. Self-renewal of RSCs from Bmi-1 and p16 double-knockout (Bmi-1−/−p16−/−), Bmi-1 and p53 double-knockout (Bmi-1−/−p53−/−) and N-acetylcysteine (NAC)-treated Bmi-1−/− mice were further analyzed for amelioration. Human renal proximal tubular epithelial cells (HK2) were also used for signaling analysis. Our results showed that third-passage RSCs from WT mice had good stemness; Bmi-1 deficiency led to the decreased stemness, and the increased apoptosis for RSCs; NAC treatment or p16/p53 deletion ameliorated the decreased self-renewal of RSCs in Bmi-1 deficiency mice by maintaining redox balance or inhibiting cell cycle arrest respectively; Oxidative stress (OS) could negatively feedback regulate the mRNA expressions of Bmi-1, p16 and p53. In conclusion, Bmi-1 determined the stemness of RSCs through maintaining redox balance and preventing cell cycle arrest. Thus, Bmi-1 signaling molecules would be novel therapeutic targets for maintaining RSCs and hampering the progression of kidney diseases to prevent renal failure.

Downregulation of hsa_circ_0007534 restricts the proliferation and invasion of cervical cancer through regulating miR-498/BMI-1 signaling

AimsHsa_circ_0007534 has been reported to be a novel cancer-related circRNA affecting multiple cancers. However, little is known about the role of hsa_circ_0007534 in cervical cancer specifically. In the current study, we aimed to explore the expression and function of hsa_circ_0007534 in cervical cancer. Main methodsThe expression of circRNA, miRNA and mRNA was measured using real-time quantitative polymerase chain reactions. Protein expression was assessed by Western blot. Knockdown of has_circ_0007534 was achieved by siRNA-mediated gene silencing. Cell proliferation was determined using a cell counting kit-8 and colony formation assays. Cell invasion was assessed using a Transwell invasion assay. RNA interactions were measured using an RNA pull-down and dual-luciferase reporter assays. Key findingsThe expression of hsa_circ_0007534 was upregulated in cervical cancer tissues and cell lines. Depletion of hsa_circ_0007534 decreased both the proliferation and invasion of cervical cancer cells. MicroRNA-498 (miR-498) was identified as a target of the miRNA encoded by hsa_circ_0007534. Levels of miR-498 were decreased in cervical cancer tissues, a finding that was inversely correlated with hsa_circ_0007534 expression. miR-498 overexpression repressed the proliferation and invasion of cervical cancer cells. B-cell-specific Moloney murine leukemia virus integration site 1 (BMI-1) was verified as a target gene of miR-498. BMI-1 overexpression reversed the effects of hsa_circ_0007534 depletion or miR-498 overexpression on cervical cancer cell proliferation and invasion. SignificanceOur study demonstrates that downregulation of hsa_circ_0007534 represses the proliferation and invasion of cervical cancer through regulating the miR-498/BMI-1 axis, suggesting the hsa_circ_0007534/miR-498/BMI-1 axis as a potential therapeutic target to treat cervical cancer.

Molecular Mechanisms Associated with ROR1-Mediated Drug Resistance: Crosstalk with Hippo-YAP/TAZ and BMI-1 Pathways.

Signaling via the Wnt-related receptor tyrosine kinase-like orphan receptor 1 (ROR1) triggers tumorigenic features associated with cancer stem cells (CSCs) and epithelial–mesenchymal transition (EMT), while aberrant expression of ROR1 is strongly linked to advanced disease progression and chemoresistance. Several recent studies have shown that Wnt5a binding to ROR1 promotes oncogenic signaling by activating multiple pathways such as RhoA/Rac1 GTPases and PI3K/AKT, which in turn could induce transcriptional coactivator YAP/TAZ or polycomb complex protein BMI-1 signaling, respectively, to sustain stemness, metastasis and ultimately drug-resistance. These data point towards a new feedback loop during cancer development, linking Wnt5a-ROR1 signaling activation to YAP/TAZ or BMI-1 upregulation that could play an important role in disease progression and treatment resistance. This review focuses on the crosstalk between Wnt5a-ROR1 and YAP/TAZ or the BMI-1 signaling network, together with the current advancements in targeted strategies for ROR1-positive cancers.

MicroRNA 141 represses nasopharyngeal carcinoma growth through inhibiting BMI1

Distant metastasis is the primary cause of mortality in patients with nasopharyngeal carcinoma (NPC). Unveiling the mechanism of metastasis will aid in shedding light on the clinical therapeutic strategies in NPC treatment. The present study revealed that the expression of microRNA 141 (miR-141) was downregulated in NPC tumor cells, particularly in metastatic ones. Ectopic expression of miR-141 blocked the proliferative and invasive ability of the tumor cells in vitro, and inhibited NPC tumor growth in vivo. Mechanistic studies identified that BMI1 served as the direct target of miR-141, and overexpression of BMI1 reversed the tumor repressor effect of miR-141. Prognostic analysis revealed that this miR-141/BMI1 signaling axis correlated with the clinical stage of patients with NPC. The study of miR-141 provided novel insight into the mechanism of NPC progression, which was correlated with the stage and metastatic state of patients. This miR-141/BMI1 axis may serve as a novel pharmacological target in NPC treatment.

MiR-218 inhibits acute promyelocytic leukemia cell growth by targeting BMI-1.

Acute promyelocytic leukemia (APL) is a subtype of acute myelocytic leukemia. Previous studies have reported a number of functions and therapeutic roles of microRNAs (miRs) in APL, and have suggested that miR-218 acts as a tumor suppressor in a number of types of human cancer; however, its role in APL remains unclear. In the present study, the expression of miR-218 and its effects on the viability and proliferation of HL-60 cells was investigated. Reverse transcription-quantitative polymerase chain reaction analysis demonstrated that miR-218 was frequently downregulated in APL marrow tissues compared with normal marrow tissues. Overexpression of miR-218 significantly inhibited cell proliferation, arrested the cell cycle in the G0/G1 phase and induced apoptosis. In addition, B-cell-specific Moloney murine leukemia virus integration site 1 (BMI-1) mRNA expression was negatively associated with miR-218 expression; BMI-1 mRNA and protein expression were downregulated following transfection with miR-218 mimic. These results indicate that miR-218 functions as tumor suppressor in APL, and the miR-218/BMI-1 signaling axis may be a potential novel diagnostic marker and therapeutic target for the treatment of APL.

Protein S Negatively Regulates Neural Stem Cell Self-Renewal through Bmi-1 Signaling.

Revealing the molecular mechanisms underlying neural stem cell self-renewal is a major goal toward understanding adult brain homeostasis. The self-renewing potential of neural stem and progenitor cells (NSPCs) must be tightly regulated to maintain brain homeostasis. We recently reported the expression of Protein S (PROS1) in adult hippocampal NSPCs, and revealed its role in regulation of NSPC quiescence and neuronal differentiation. Here, we investigate the effect of PROS1 on NSPC self-renewal and show that genetic ablation of Pros1 in neural progenitors increased NSPC self-renewal by 50%. Mechanistically, we identified the upregulation of the polycomb complex protein Bmi-1 and repression of its downstream effectors p16Ink4a and p19Arf to promote NSPC self-renewal in Pros1-ablated cells. Rescuing Pros1 expression restores normal levels of Bmi-1 signaling, and reverts the proliferation and enhanced self-renewal phenotypes observed in Pros1-deleted cells. Our study identifies PROS1 as a novel negative regulator of NSPC self-renewal. We conclude PROS1 is instructive for NSPC differentiation by negatively regulating Bmi-1 signaling in adult and embryonic neural stem cells.

NRF2 enhances self-renewal activity of breast cancer stem cells through activation of NOTCH1 and BMI-1 signaling

NRF2 enhances self-renewal activity of breast cancer stem cells through activation of NOTCH1 and BMI-1 signaling

Role of the polycomb group gene BMI1 in normal and leukemic hematopoietic stem and progenitor cells

The polycomb group gene BMI1 fulfills essential roles in both normal and leukemic stem cells. The underlying molecular mechanisms are beginning to become unraveled and an overview of the current knowledge on BMI1 signaling in normal and leukemic stem cells will be presented here. In addition to a role in bypassing senescence and the orchestration of the symmetry of hematopoietic stem cell divisions, it has recently become clear that BMI1 also functions in the protection against oxidative stress. In the absence of BMI1, reactive oxygen species accumulate, associating with activation of DNA damage response pathways and increased apoptosis. BMI1-mediated control over reactive oxygen species levels might occur independently of the INK4a/ARF pathway, but rather involves impaired mitochondrial functions. In human hematopoietic malignancies, BMI1 is frequently overexpressed, which associates with poor prognosis. Down modulation of BMI1 impairs self-renewal and long-term expansion of leukemic stem cells. Understanding molecular mechanisms by which BMI1 affects stem cell fate will increase our insights into the biology of hematopoietic stem cells and will also aid in understanding the process of leukemic transformation and ultimately in the identification of drugable targets that might facilitate the eradication of leukemic stem cells.