ABBS 2009,41(07): Bmi-1, stem cells and cancer

Pdf file on Bmi-1, stem cells and cancer

Lili Jiang^1,2, Jun Li², and
Libing Song¹*

¹State Key Laboratory of Oncology in Southern China, Department of
Experimental Research, Cancer Center, Sun Yat-sen University, Guangzhou 510060,
China

*Correspondence address. Tel: +86-20-87343192;
Fax: +86-20-87343171; E-mail: [email protected]

Bmi-1, a polycomb gene family member, plays an important
role in cell cycle regulation, cell immortalization, and cell senescence.
Recently, numerous studies have demonstrated that Bmi-1 is involved in the regulation of
self-renewal and differentiation of stem cells. However, the molecular
mechanism underlying this biological process remains largely unclear. In the
present review, we summarized the function of Bmi-1 as a transcriptional
regulator of gene expression, with particular reference to stem cells.

Keywords     Bmi-1; stem cell;
self-renewal; cancer

Received: November 25, 2008 Accepted: April 2, 2009

Introduction

Stem cells are characterized as unspecialized precursor cells that possess
the multipotent ability to self-renew and differentiate into tissue-specialized
cells. Both tissue development and homeostasis are mediated by stem cells,
including embryonic stem (ES) cells and tissue stem cells (or adult stem cells)
[1]. ES cells that are derived from the inner cell mass of blastocyst-stage
embryos are capable of developing into the fetus. During the process, these
cells generate tissue stem cells, progenitor cells, and eventually, every cell
type that constitutes an organism. Tissue stem cells include somatic and
germline stem cells, which develop, maintain, and repair their resident tissues
in adult organisms. Self renewal is the hallmark of stem cells. Stem cells
could continuously divide into two types of daughter cells. One type of
daughter cell would take on the identity of the parent cell, and the other
could transform into a progenitor cell that would further differentiate into
specialized cell types. Both ES and tissue stem cells are capable of producing
various types of differentiated cells and undergoing continuous
self-replication. Stem cell research has enlightened the scientific community
on the effective cell-based therapies for certain diseases such as diabetes,
neurodegenerative diseases, and cancer [2]. It has been reported that the
proliferation and differentiation of stem cells might be related to the
regulation of Hox (homeobox-containing) genes, which are crucial for cell fate determination
and proliferation and for the regulation of the development of an organism
[3,4]. The transcriptional repression and activation of Hox genes could be
regulated by the polycomb group (PcG) and Trithorax-group (TrxG) genes, which are
essential for the maintenance of the physiological levels of the Hox genes during
development [5,6]. PcG family proteins, which are
well-known epigenetic gene silencers, have been demonstrated to be associated
with the self-renewal and differentiation of stem cells [5]. Moreover, Bmi-1, the first identified
PcG gene, has also been documented to be involved in the transcriptional
repression of Hox genes and affect the stem cell self-renewal, embryonic development, and
proliferation [7–10]. In the present
review, we summarized the function of Bmi-1 as a transcriptional regulator of
gene expression, with particular reference to stem cells.

Genetic Structure of Bmi-1

Polycomb group proteins act as epigenetic gene silencers with essential
roles associated with organism development through the formation of a minimum
of two multimeric complexes, i.e. the polycomb repressive complex 1 (PRC1) and
the polycomb repressive complex 2 (PRC2) [5,7,11–15]. B-cell-specific Moloney murine leukemia virus integration site 1 (Bmi-1), which is one of the
core members of the PRC1 complex, was identified as an oncogene that cooperates
with c-myc in the initiation of lymphoma [7,11]. The Bmi-1 gene localizes on
human chromosome 10p11.23 and extends over 4.9 kb, which comprises 10 exons and
9 introns. The length of the Bmi-1 cDNA is approximately 3.2 kb (A _ 959, C _ 591, G _
678, and T _ 975) and further, it encodes a 36.9-kDa nuclear protein consisting of 326
amino acids. The Bmi-1 protein contains a conserved RING finger domain in its
N-terminal end and a central helix-turn-helix-turn-helix-turn motif (H-T-H-T),
which is required for inducing telomerase activity and immortalization of human
epithelial cells [12,16,17].

Role of Bmi

Bmi-1 has been demonstrated to be involved in multiple biological
processes, such as embryonic development, organ formation, tumorigenesis, stem
cells stabilization, and differentiation [8]. Bmi-1 is expressed ubiquitously
in almost all tissues and its expression is observed to be slightly higher in
the brain, spinal cord, kidney, lungs, gonads, and the placenta. However, many
studies have shown that Bmi-1 expression is frequently upregulated in various
types of human cancers, including lung cancer, ovarian cancer, acute myeloid
leukemia, nasopharyngeal carcinoma, breast cancer, and neuroblastoma, which
indicates that Bmi-1 might play important roles in cancer initiation and
progression [18–23]. The oncogenic
feature of Bmi-1 has also
been reported to be associated with the protection of cells from apoptosis. It
has been shown that the number of lymphocytes is markedly reduced in the spleen
and the thymus due to increased apoptosis in Bmi-1^-/- null mice [8]. Ectopic expression of Bmi-1 protects keratinocytes from
stress agent-induced apoptosis and the expression of Bmi-1 abrogates
MYCN-induced sensitization of SHEP1 cells, thereby protecting cells from
apoptosis [23]. In addition, numerous studies have demonstrated that expression
of Bmi-1 is statistically associated with its clinical value; this suggests
that Bmi-1 might be used as a diagnostic and prognostic marker of human cancer.
It has been reported that the expression of Bmi-1 is upregulated in
nasopharyngeal carcinoma cell lines and nasopharyngeal carcinoma tumors, and
high expression level of Bmi-1 is positively correlated with poor prognosis in
nasopharyngeal carcinoma patients [21]. Daniela et al. have reported that high expression of Bmi-1
was observed in 41 of 64 (64%) primary melanoma tissues and 117 of 165 (71%)
metastatic melanoma as compared with that in the primary melanoma, indicating
that Bmi-1 expression might be associated with clinical progress of malignant
melanoma [24]. The clinical significance of Bmi-1 has also been demonstrated in
cases of hepatocellular carcinoma, gastric carcinoma, non-small cell lung
cancer (NSCLC), oligodendroglial tumor, and breast cancer [25–29].

Association between Stem Cells and Bmi-1

Increasing evidences have indicated that Bmi-1 plays an important role in
the self-renewal and differentiation of human stem cells. Park et al. have found that Bmi-1 is highly expressed in
adult and fetal mouse and adult human hematopoietic stem cells (HSCs) using
reverse transcription-polymerase chain reaction (RT-PCR) and gene expression
analysis [10]. Furthermore, the number of HSCs has been shown to be markedly
reduced in postnatal Bmi-1^-/- mice as compared with that in the fetal
liver of Bmi-1^-/- mice. In addition, they have also demonstrated that the transplanted fetal
liver acquired from Bmi-1^-/- mice could only transiently contribute to
hematopoiesis. Moreover, the expression of genes that are associated with stem
cell self-renewal, cell survival, transcriptional factors, and cell
proliferation, including p16INKIt has been reported that the epithelial components of mammary glands
consist of stem cells and have the capacity to undergo self-renewal and multilineage
differentiation [34]. The Hedgehog pathway has been shown to be associated with
the regulation of the self-renewal and differentiation of breast stem cells;
further, factors in the hedgehog pathway were found to be highly expressed in
mammary stem/progenitor cells [35,36]. It has been
demonstrated that Bmi-1 is a downstream gene in the Hedgehog pathway, which implied that the
modulation of the Hedgehog pathway associated with the selfrenewal and
differentiation of mammary stem cells might be mediated by Bmi-1. Moreover,
Bmi-1 expression is upregulated up to six times when the Hedgehog pathway is
activated. However, its expression is significantly downregulated when the
Hedgehog pathway is blocked by small-interfering RNA (siRNA) [36].

Cancer Stem Cells

Tumor tissues are composed of heterogeneous groups of cells. Some cells
are identified as cancer stem cells that are capable of causing constant
expansion of existing tumors or form new tumors in the body [37]. Hewitt et al. have found that only 1–4% of the transplanted cells in the spleen can retain the ability of
cloning after transplanting murine leukemia cells into mice with similar
genetic backgrounds as donors. This observation indicated that only part of the
cells from tumors could form tumors again [38]. Subsequently, Trott further
demonstrated that only the cells that were isolated from a particular subgroup
have high cloning ability; moreover, he proposed that ,1%
of tumor cells possess the quality of cancer stem cells that retain their ability
to undergo self-renewal and differentiation into specialized cells [39]. In
1997, human LSCs were identified by Bonnet et al. [40]. It was shown that even though
different types of leukemia cells could be isolated from leukemia patients,
only those whose surfaces expressed markers, such as CD34⁺CD38^–Thy-1^–, possess the ability to undergo
self-renewal and form tumor in vitro [40]. In addition, AI-Hajj et al. identified and isolated cancer stem cells of CD44⁺CD24^–/low lineage from breast cancers tissues [41]. Furthermore, they demonstrated
that these cells could be considered to be breast tumor-initiating cells since
as few as 100 cells with CD44⁺CD24^–/low characteristic were observed to be able to form tumors in mice, whereas
tens of thousands of cells without these phenotypes failed to form tumors [41].
Moreover, the expression of Bmi-1 has been found to be upregulated up to 5-fold in CD44⁺CD24^–/lowlin^– cells as compared with that in the cells isolated from the same tumor,
which are the cells that are negative for cancer stem cell marker [36]. All
these findings strongly suggest the existence of cancer stem cells.

Biological Functions of BmiStem Cells

A number of studies have demonstrated that Bmi-1 plays an important role
in the self-renewal and differentiation of human hematopoietic and LSCs [9,10,20,42,43]. Lessard et al. have reported that even though acute
myeloid leukemia (AML) could develop in mice that were transplanted with bone
marrow cells derived from either Bmi-1^+/+ or Bmi-1^-/- recipient mouse, the stem cell number in the peripheral leukemia cells
from Bmi-1 wild-type mice was
significantly higher than that in Bmi-1-knockout mice [30]. Furthermore, the number of leukemia cells derived
from Bmi-1^-/- mouse reduced by 15+4 times when compared with that in the control cells from Bmi-1 wild-type mouse
following 10 days of culture in vitro [30]. They further observed that the number of leukemia cells derived from
Bmi-1^-/- mouse in the S-phase reduced significantly and most of the cells were
accumulated in the G1 phase; moreover, the number of apoptotic cells increased
and their colonyforming abilities decreased. All these results strongly implied
that Bmi-1 has a critical and dose-dependent role in regulating the
proliferation of cancer cells and the development of leukemia. Medulloblastoma
is a type of brain tumor that originates from progenitor cells from the
external granular layer of the external cerebellum. It has been shown that
knockdown BmiThe Hedgehog signaling pathway has been demonstrated to be associated with
the regulation of mammary stem cell self-renewal and multilineage
differentiation, which are mediated by Gli transcription factors [36].
Interestingly, both Gli1- and Gli2-overexpressing mammospheres are also
observed to display higher Bmi-1 expression levels. While downregulation of
Bmi-1 could significantly reduce the effects of Hedgehog signaling activation
on both primary and secondary mammosphere formation, which suggested that that
the effects of Hedgehog signaling pathway on mammary stem cells or progenitor
cells were mediated by the polycomb gene Bmi-1 [36]. Recently, Yang et al. reported that the
ectopic expression of SALL4, which was elevated in human leukemia cell lines
and primary acute myelocytic leukemia, could enhance the multipotency and
selfrenewal ability of HSCs. A further study demonstrated that Bmi-1 expression
could be upregulated by SALL4 through the methylation of histones H3K4 and H3KRecently, a number of studies have documented that the activation of
nuclear factor kappa B (NF-kB), which is a transcription regulator, is
associated with the regulation of stem cells. Aberrantly active forms of NF-kB have been observed
in different types of cancer, including breast cancer, colon cancer, non-small
cell lung cancer, squamous head and neck cancer, and gastric cancer [62–66]. It has been reported that the NF-kB pathway is activated
in LSC population but not in normal hematopoietic stem cells [67]. Inhibition
of NF-kB with the proteasome inhibitor MG-132, which is a well-known inhibitor of
NF-kB, could induce leukemia-specific apoptosis [68]. NF-kB pathway inhibitors
preferentially inhibit breast cancer stem-like cells [69]. Tumor necrosis
factor (TNF-a) could promote the proliferation of adult NSCs via the IKK/NF-kB signaling pathway
[70]. Li et al. found that abnormal activation of NF-kB at an early stage of
mesenchymal stem cell not only inhibits the differentiation of mesenchymal stem
cells but also enhances the proliferation and invasion abilities of
fibroblast-like synoviocytes (FLSs) [71]. However, the biological significance
of NF-kB pathway on stem cells remains largely unknown. In 2001, Cheng et al. reported that the
Notch-1 signal transduction pathway, which is an important regulatory mechanism
of stem cells, is associated with the induction of NF-kB expression [72]. They
found that the DNA binding and transcriptional activities of NF-kB were dramatically
decreased in HPCs that were derived from Notch-AS-Tg (Notch-1 antisense
transgenic) mice; further, it was found that the decrease in NF-kB activity in HPC was
due to transactional repression of NF-kB subunits by Notch-1 factor. It has been
reported that Bmi-1 is upregulated by NF-kB in Epstein–Barr Virus-negative Hodgkin lymphoma (HL) cells [73]. In brief, Bmi-1
plays important roles in the regulation of stem cells via the activation of
multiple pathways (Fig. 1). However, the precise mechanism of Bmi-1 on the regulation of chromatin
remodeling still remains largely unclear. Cao et al. demonstrated that Bmi-1 and other
components of the PcG complexes bind to the promoter of HoxC13 and lead to the HRecently, an 11-gene signature was described as a conserved Bmi-1-driven
pathway, which defines stem cell-ness of highly invasive tumors of multiple
tissue origin and correlates with therapy failure [21]. Furthermore, the expression
level of Bmi-1 has been shown to be negatively correlated with the therapy of
NSCLC patients. Disease-free survival for stage I and II patients who had
received adjuvant therapy was better in the case of Bmi-1 negative patients
when compared with their Bmi-1 positive counterparts [27]. Moreover, Guo et al. indicated that
ablation of Bmi-1 expression in tumors by various therapeutic approaches might
help in cancer treatment [76]. All these studies suggested that the PcG protein
Bmi-1 could also be a valid target for cancer therapy.

Conclusions

Bmi-1, a member of the PcG family, has been reported to be associated with
the initiation and progression of various types of tumor-initiating cells,
which might originate from cancer stem cells. Further, numerous studies have
demonstrated that Bmi-1 plays vital roles on the self-renewal and
differentiation of stem cells through multiple pathways in vitro and vivo. Hence, it is of
great clinical value to further understand the molecular mechanism underlying
the regulation of Bmi-1 on stem cells, which not only provide a better
understanding of the roles of Bmi

Funding

This work was supported by grants from the Foundation of Ministry of
Science and Technology of China (No.30670803 and 30770836) and the Foundation
of Ministry of Science and Technology of Guangdong Province,

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