Therapeutic potential of MicroRNA let-7:
tumor suppression or impeding normal
stemness
Shao-Chih Chiu,*† Hao-Yu Chung,‡§¶ Der-Yang Cho,*# Tzu-Min Chan,†
Ming-Chao Liu,*† Hiang-Ming Huang,# Tsyng-You Li,* Jian-Yong Lin,*
Pei-Chang Chou,* Ru-Huei Fu,*† Wen-Kuang Yang,║ Horng-Jyh Harn, and
Shinn-Zong Lin,*†§¶1
* Graduate Institute of Immunology, China Medical University, Taichung, Taiwan
† Center for Neuropsychiatry, China Medical University Hospital, Taichung, Taiwan
‡ Graduate Institute of Clinical Medical Science, China Medical University, Taichung,
Taiwan
§ Department of Neurosurgery, China Medical University Beigan Hospital, Yunlin,
Taiwan
¶ Department of Neurosurgery, Tainan Municipal An-Nan Hospital-China Medical
University, Tainan, Taiwan
# Department of Neurosurgery, China Medical University Hospital, Taichung, Taiwan
 Everfront Biotech Inc., New Taipei City, Taiwan
║Cell/Gene Therapy Research Laboratory, China Medical University Hospital,
Taichung, Taiwan
Department of Pathology, China Medical University Hospital, Taichung, Taiwan
Department of Medicine, China Medical University, Taichung, Taiwan
1
1
Corresponding author
Running title: Therapeutic potential of let-7
Address correspondence to Prof. Shinn-Zong Lin, MD., PhD., Graduate Institute of
Immunology, China Medical University, Taichung, Taiwan. Tel: +886-4-22052121
ext. 6034; Fax: +886-4-220806666; e-mail: shinnzong@yahoo.com.tw
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Abstract
The first microRNA, let-7 and its family, is discovered in Caenorhabditis elegans and
functionally conserved from worms to humans in the regulation of embryonic
development and stemness. Let-7 family has been shown its essential role in stem cell
differentiation and tumor suppressive activity, and so, deregulating expression of let-7
is commonly reported in many human cancers. Emerging evidence is accumulated
and suggests that reestablishment of let-7 in tumor cells is a valuable therapeutic
strategy. However, findings reach beyond tumor therapeutics and probably impinge on
stemness and differentiation of stem cells. In this review, we discuss the role of let-7
in development and differentiation of normal adult stem/progenitor cells, and offer a
viewpoint of the association between deregulated let-7 expression and tumorigenesis.
The regulation of let-7 expression, cancer-relevant let-7 targets, and the application of
let-7 are highlighted.
Key words: Let-7, Stemness, Caner therapy
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Introduction
The earliest found microRNAs, lethal-7 (let-7), has been shown its essential role in
the development of Caenorhabditis elegans and Drosophila melanogaster (73,78),
and is highly conserved in its DNA sequence and function across different species.
During embryo development, accumulation of let-7 can activate some pluripotent
factors, such as LIN28, for determination of differentiation. Current opinions revealed
that let-7 controls ‘stemness’ by repressing self-renewal and promoting differentiation
in normal development for many kinds of stem cells/progenitors.
Recently, there are plentiful studies of let-7 focused on fundamental roles in cell
proliferation, reprogramming, development, differentiation and tumorigenesis (for
reviews, see Refs (9,71,79)). Although let-7 functionally involved to regulate the
differentiation of stem cells/progenitors and to reprogram cell fates, it is still elusive
for physiological or biological activities of let-7 family. Recently, growing evidences
reveal that let-7 acts as a tumor suppressor via targeting numerous genes. Most of
studies suggest that level of let-7 expressed in various tumor stem-like cells is lower
than it in differentiated counterpart cells. To examine how to regulate and process the
expression of let-7 in tumor cells could be valuable in helping us to use let-7 as a tool
for cancer treatment. Furthermore, critical discussion about normal adult stem cells
and tumor cells should be examined for the further development of let-7-based
therapy.
The role of let-7 in normal stem/progenitor cells
Let-7 expression is missing in embryonic stem cells or adult progenitors, and then
increasing level of functional let-7 upon differentiation appears to be a common
scenario (Figure 1). These properties are also observed in tumor initiating cells; loss
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of let-7 switch normal somatic cells into tumor initiating cells. Such loss might be
caused by chromosomal abnormalities, epigenetic alterations or impaired the process
of let-7 at the post-transcriptional level (7,90). Otherwise, normal stem cells can be
transformed directly to cancer initiating cells under high self-renewing rates without
normal surveillance (Figure 1). Low amount of let-7 expression is a prominent
feature in certain stem cells.
Stem/progenitor cells have unlimited proliferating activities for self-renewal, yet
they are capable of differentiating into various cell types (pluripotency) by certain
stimuli. However, before stem cell therapies are applied, a fully understanding of the
timing that schedule pluripotent stem/progenitor cells to differentiate would be
extremely meritorious. Recent work has demonstrated that let-7 family members play
key roles in controlling the timing of differentiation or reprograming transition of
various cells via complex regulatory mechanisms or targets (5,59). Furthermore, let-7
family has also been shown to govern endogenous activities in various different adult
cells (Table I).
In Drosophila, let-7 determines the appropriate timing for cell-cycle exit,
metamorphosis, neuromusculature remodeling, juvenile-to-adult-stage transition, and
adult behavior (13,87). As found in the Drosophila model of Parkinson's disease, the
increasing level of let-7 attenuates the pathogenic leucine-rich repeat kinase 2
(LRRK2) effect by targeting mRNAs of E2F1 and DP (29). The zebrafish ortholog of
let-7 exhibits basal expression in the uninjured retina to suppress the expression of
regeneration-associated genes and to block the premature Müller glia dedifferentiation
(77). In the adult newt, let-7 controls the trans-differentiation and regeneration of lens
and pigment epithelial cells (64,95).
Numerous experiments from mammals are also investigated the activity of let-7 in
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the physiological and development function (Table I). In mice, let-7 has been shown
to regulate the neural lineage specificity in ES cells and affect the brain development
(17,56,110). Furthermore, epithelial progenitors in mammary glands were detected the
no or little level of let-7, and it suggests that progenitors retain in the status of
self-renewing and reconstitute the mammary gland by modulation of lin28/let-7 loop
(35,107). The expression of let-7 family triggers the formation of embryoid body and
differentiation of three germ layers by multiple mechanisms in human (38,98) and
mice (56,93,110) embryonic stem cells. Let-7 family has been shown to play a
essential role in the generation and development of many adult tissue cells, including
the adipogenesis in 3T3-L1 and adipocytes (50,88), the cardiac hypertrophy by
cardiomyocytes (20,108), angiogenesis of endothelial cells (15,46), liver development
(33,96), manipulation of body size and puberty (33,96) and newborn ovarian
development (1,42). In the circulating blood system, let-7 is shown not only the
developmental control in reticulocytes (49,69) and T cells (4,89) but also the
increasing sensitivity of Fas-mediated apoptosis in peripheral blood mononuclear
cells (100,104).
The regulatory mechanism of let-7 is quite essential for the maintenance of
stem/progenitor cells pluripotency as well as for reprogramming somatic cells into
induced pluripotent stem cells (Fig. 2). Lin28, sustaining the stemness state of various
stem cells, is an important regulator of let-7 and is also downregulated by let-7 during
the differentiation (18,90). Recently, lin28 and let-7 have been shown to have
opposing expression patterns for the reciprocal regulation and functions in
development and cell-fate transition. Lin28 modulates the production of endogenous
pri-let-7 and pre-let-7 transcript in ES cells. Although suppressor, lin28, induces
inhibitory oligo-uridylation in embryonic stem cells, mono-uridylation occurs in
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somatic cells without lin28 expression to promote let-7 biogenesis (30). Lin28 could
block the function of either Drosha or Dicer in the process of let-7 and act as a
posttranscriptional repressor for the let-7 biogenesis (31,86,101). The recent study is
shown that another key gene, HMGA2, for the self-renewal and the maintenance of
stemness in adult stem cells is highly expressed in hematopoietic, adipotic and neural
progenitors. During differentiation, the increasing level of let-7 directly targets on
HMGA2 to reduce the expression, following the inhibition of cell proliferation
(11,18). Recently, proteins related to the function of cell cycle, cell proliferation and
apoptosis are shown to be interrupted by let-7. Insulin-like growth factor 2
mRNA-binding proteins (IMP1), an oncofetal gene expressed during the early fetal
life, regulates the proliferation in stem cells and is targeted by let-7 for the blockade
of Myc and K-Ras expression (55,60). Genome-wide studies by the microarray
analysis in cancer cells revealed that let-7 inhibits multiple cell-cycle-associated genes,
including CDC25A, cyclin D1, D3 and A, and cdk4, 6 (51). Interestingly, the
expression of let-7a can suppress the doxorubicin- and paclitaxel-induced apoptosis
by targeting caspase-3 in cancer cell lines, A431 and HepG2 (94). In summary, let-7
family inhibits many key genes associated with cell cycle regulators such as CDC25A
and CDK6, early expressed embryonic genes including LIN28, HMGA2, Mlin-41 and
IMP-1 and growth and proliferation related genes including RAS and c-MYC. The
effects of let-7 in ES cells can be shown its inhibitory effect on the expression of lin28,
c-Myc, Sall4 and downstream genes of pluripotency factors, in particular Sox2, Oct4,
and Nanog. Moreover, wild-type ES cells transfected with let-7 are not able to induce
ES cells into differentiation due to the antagonizing effects of other miRNAs, such as
ES cell-specific cell cycle-regulating miRNAs (ESCC) in ES cells (16,56).
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Deregulation of let-7 in human cancers
Expression profiling of miRNA revealed that levels of miRNAs are differential
expressed in many human cancers, suggesting that miRNA profiling has diagnostic
and/or prognostic potential. Let-7 family has been known to regulate the proliferation,
apoptosis and differentiation in tumor cells and, thus, suggested as a potent target for
cancer therapies. Controversial expressing levels of let-7 in different cancer cells have
been shown and indeed required further examinations. Let-7 contains 9 family
members (let-7a, let-7b, let-7c, let-7d, let-7e, let-7f, let-7g, let-7i and miR-98) in
human and is highly conserved across animal species in sequence. The transcriptional
and post-transcriptional regulation of let-7 is still unclear, and let-7 targeting on
multiple genes reveals that the specificity of let-7 is necessary to be addressed.
Deregulation of let-7 could involve in etiological process by targeting apoptotic or
cell cycle related genes in a tissue or stage dependent manner. Tumor-associated let-7
family members can be acquired from the PhenomiR database
(http://mips.helmholtz-muenchen.de/phenomir/). The PhenomiR database affords
information about differential expression of let-7 family in human cancers.
Here, we summarized clinical results of expression of let-7 family members obtained
from published papers studied in human cancers (Table 2) and suggest the further
investigation of deregulation of let-7 family in various human cancers. Let-7 is
generally believed as a tumor suppressor. Loss of let-7 family also has prognostic
value while it indicates poor survival in many human cancers (19,81,103). However,
upregulation of certain let-7 family has been examined in several human cancers. The
upregulation of let-7a, b, c, e, d and f was associated with high grade of leukemia and
prostate cancer (19,28,54). Conflicting results of deregulation of let-7 in various
cancers. suggest that let-7 may have different functions in different diseases or in
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different cell contexts.
In human malignant cholangiocytes, increasing levels of let-7a contribute to the
survival effects of IL-6 activity and the constitutively increased phosphorylation of
Stat-3 through the mechanism involving in the neurofibromatosis (58). The highly
expressed let-7 has been shown to increase the chemo-resistance of hepatocellular
cancer stem cells through a novel regulatory mechanism of let-7/miR-181s (57). In
hepatocellular carcinoma HepG2 and squamous carcinomas A431 cells, let-7a targets
on caspas-3 for increasing the activity of chemo-resistance to apoptosis (94). Let-7b,
expressed in diffuse large B cell lymphomas, epigenetically downregulates the tumor
suppressor gene, PRDM1/Blimp-1 (68). In leukemia cells, let-7 isoforms, -a, -b, -c,
and- d, are expressed in the higher levels than in normal peripheral blood
mononuclear cells (100). Let-7 family is selectively secreted into the extracellular
environment via exosomes in a metastatic gastric cancer cell line and, thus, may its
oncogenic characteristics including tumorigenesis and metastasis (70). The further
investigation on the role of let-7 and its regulation in tumorigenesis is necessary and
urgent for the miRNA-based cancer therapy.
As accordant with the physiological function of let-7 family, miRNA-based cancer
gene therapy offers the theoretical theme of targeting multiple genes and interfering
with networks controlled by let-7. Reconstitution of tumor-suppressive activity of
let-7 has produced favorable antitumor outcomes in experimental models. Pending
subjects need to be discussed and resolved prior to the consideration of let-7-based
cancer gene therapy. It contains several issues including the need for the specificity of
mRNA targeted by let-7 in various cancers, the incomplete knowledge of regulatory
mechanism and biogenesis of let-7 that affect the therapeutic efficiency, the
possibility for nonspecific immune activation and the lack of a defined, optimal
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system of delivery. The limitation to tumor-suppressor let-7 therapy is the paucity of
let-7-targeted genes known to induce or preserve malignant phenotypes; moreover,
more than one genetic alterations are necessary for carcinogenesis. Many
differentiated tumors with average or high expression of let-7 are reported. Also, as it
is true for many gene therapeutics, the eradication of treated tumors is rare even in
experimental systems because of the technical difficulty of transducing sufficiently
large proportions of cells in the tumors.
Complexity and uncertainty of let-7 biology and its regulatory mechanism
Although restoration of normal let-7 expression provides the possibility for the
future cancer therapy, limited knowledge concerning its transcriptional,
post-transcriptional and processing control during biogenesis of let-7 and
tumorigenesis make it difficult to directly apply let-7 as a therapeutic strategy. It is
necessary to confirm that the downregulation of let-7 in tumors is a primarily
pathogenic factor during tumorigenesis. Supporting the hypothesis for cancer stem
cells, many studies convey the opinion that the epigenetic downregulation of let-7 in
cancer stem/progenitor cells is common and leads the upregulation of oncofetal genes
(HMGA2, lin28, Ras, Myc, etc.) and, thereby, to progress of stemness activity and
tumorigenesis. Nevertheless, many data have been shown the tumor-suppressive role
of let-7, the high expression of let-7 in tumors is still observed and would be
beneficial to survival signals (57,68,100).
Generation and maturauration of miRNAs is govern by various regulatory and
transporting machinery at different stages of primary-, precursor- and maturemiRNAs. Finally, the miRNA-associated protein-RNA-induced silencing complex
(miRISC) interacts with miRNAs and performs endogenous functions (12,14).
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Therefore, genetic and epigenetic defects likely affect both coding and noncoding
RNA transcription, contributing independently or in concert to the altered expression
of miRNAs. In ES cells, the core transcription factors, Oct4/Sox2/Nanog/Tcf3,
promote the transcription of both primary pri-Let-7g and Lin28. Appropriated
expression of pri-Let-7g can be detected, but, however, mature form of let-7g is
missing after the blockade of lin28 (110). In this post-transcriptional regulation, two
major factors, Drosha and Dicer, are shown to be mediated by lin28 resulting in the
inhibition of let-7 maturation (30,53). It is suggested that the inhibition of maturation
process of pri-Let-7 transcripts plays an important role in the maintenance of
pluripotent state. It is also shown that a feedback loop between lin28 and let-7 for
regulating pre-let-7 maturation during neural stem-cell commitment (74,80). Thus, the
negative lin28/let-7 circuit loop has a major influence over ES cell fate. Although,
there are many anti-tumor effects by use of let-7 for treatment with cancer cells in
various experimental models, let-7 is still involved in a complex and unclear
regulatory network of miRNA to govern the supplement of stem/progenitor cells for
the self-renewal or differentiation. Further studies are required.
Current approach and delivery system for the let-7-based gene therapy and their
limitation
Most recently, many researchers used numbers of strategies to deliver let-7 into
different cancer cells in experimental models for the purpose of gene therapy.
However, clinically applicable tools for the gene delivery are limited and focused on
retroviral-based or adenoviral-based vectors. New delivery methods are required to
develop for improving the safety and efficacy of let-7 gene-based therapy. The first
case of let-7 functioning as a tumor suppressor in vivo has been shown to suppress
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non-small cell lung tumorigenesis (47). Although the sustained expression of let-7 is
sufficient to inhibit tumorigenesis, authors infer that let-7g could be present and active
in escaping tumors (47). It is suggested that let-7 resistant tumors might eventually
relapse. It is important to understand the effect of long-term expressed let-7 on tumors
or other normal cells or the use of let-7 miRNAs as a therapeutic agent. A general
drawback for current gene therapy strategies is lack of specific marker to target tumor
cells while systematically administrating the viral vector carrying the gene of interest.
It is critical for minimizing unexpected side effects. The alternative way for most
clinical trials has relied on gene delivery directly into accessible tumors.
In addition to viral vector-based gene therapy, synthetic miRNA has also been used
to in the gain-of-function assays. These miRNA mimics are small, chemically
modified RNA molecules that mimic endogenous mature miRNA molecules, and are
commercially available (3). By use of the formulated synthetic miRNA, the
therapeutic potential of synthetic miR-34a against human multiple myeloma cells in
vitro and in vivo has been successfully shown the therapeutic activity in preclinical
models. MiR-34a-based treatment strategies provide a proof-of-concept that
formulated synthetic miRNA has support a framework for development of
miR-34a-based treatment strategies in patients (22). Since miRNA mimics have no
vector-based toxicity, if their delivery agents do not cause side effects over long-term
use, it can be a promising therapeutic approach for tumors.
Alternative ways to bypass disadvantages of let-7-based therapy
Although it is understandable that let-7 plays a critical role in regulating the
self-renewal and pluripotency of ES cells, much less is known about the molecular
mechanisms for regulating let-7 expression to keep the pluripotency in
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stem/progenitor cells. It is necessary to perform the systematic examination and study
of both functional trans-molecules, and cis-regulatory elements involved in the
regulation of let-7 expression between the transition of stem/progenitor and
differentiated cells. A recent study involving large scale identification of let-7
promoters in both human and mouse cells is an excellent starting point for
characterizing individual miRNA promoters (16,18). Studies in cluster promoters of
miRNAs has been demonstrated the binding of Sox2, Oct4, and Nanog in the let-7
promoter region. It suggests that the different hierarchical regulation of let-7 via
biogenesis, integrated circuits with let-7 and other factors forms a regulatory feedback
loop. As noted above, c-Myc has been shown to transcriptionally repress the
expression of let-7 in human liver cells (104). Unexpectedly, although mature let-7
family members are depleted in undifferentiated cells, the primary let-7 transcripts
and the hairpin precursors can be detected in these cells in vitro, as well as during
early developmental stages of mice in vivo (32,101). The accumulation of mature let-7
miRNA thus appears to be regulated, at least in part, post-transcriptionally. Recently,
LIN28 and LIN28B, two homologs of the C. elegans heterochronic gene lin28, were
shown to inhibit the processing of let-7 family members (101). Additionally, mouse
lin41 has been shown to suppress let-7 activity, at least in part, by antagonizing
Argonaute 2 (80). Taken together, studies on the expression of let-7 have shown a role
in inhibiting the induction of pluripotency in progenitor cells. It will be important to
study whether depletion of MYC or LIN28 can substitute for the antisense
knockdown of let-7. Evidence in limitation of let-7 is that forced expression of let-7
(by co-transfection of mature let-7 or use of transgenic let-7 precursors not subject to
LIN28 regulation) can interfere with reprogramming of fibroblasts into iPS cells.
13
Lin28, with multi-functions, provide an alternative approach to block let-7
associated tumorigenesis
There is a tight link between inflammation and cancer in epidemiological and
clinical aspects. Inappropriate resolution of inflammatory responses often leads to
various chronic diseases including cancer (92). In the tumor transformation of breast
cell, the transient activation of Src triggers an inflammatory response mediated by
NF-B that directly activates lin28 transcription and rapidly reduces let-7 levels
(36,102). NF-B is important in regulating normal innate and adaptive immune
responses seen in states of inflammation. However, evidence revealing particular
mechanisms by which NF-κB influences cancer initiation, promotion, and progression
is fascinating and still vague (25,66). It suggests that the activity of let-7 is obstructed
by activation of lin28 through the epigenetic signaling molecules, such as NF-B.
Although let-7 targets on lin28 expression to blockade the oncogenetic activity, lin28
is also shown a feedback loop to downregulate expression of let-7 by interfering with
pri- and pre-let-7 processing. Directly elevating let-7 in the treatment of cancer
therapy is possibly inefficient for the reason that lin28 is continuously expressed
under the inflammatory microenvironment of tumor site. Since the expression of lin28
is reciprocal to the maturation of mature let-7, lin28 is abundant in early
developmental stages and declines upon differentiation
While using of let-7 as a target for the cancer therapy, there is still a possibility to
impair the replenishment of normal stem/progenitor cell owing to no specific
tumor-targeting strategy. Suppression of lin28 may provide an appropriate strategy for
the further cancer gene therapy. Although lin28 is found to be highly expressed for
maintaining the pluripotency in ES cells by the blockade of let-7 expression, lin28 is
shown to differentially promote and inhibit the specific differentiation during
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neurogliogenesis (90,97). It suggests that lin28 does not function exclusively through
blocking let-7 family. Moreover, in neural stem/progenitor cells, the mechanism for
keeping the stemness is associated with the regulation of Musashi1 (Msi1) in concert
with lin28 (43). This study reveals that Msi1 acts as a novel factor can influence
stem-cell maintenance by controlling synergistically with lin28 for the blockade of
let-7 expression.
With all efforts and advances continued to develop miRNA-mediated therapies,
obstacles still remain. One should be emphasized for maintaining the specificity of
target. MiRNA targeting is known to be sequence-specific rather than gene-specific,
and let-7 family has been shown its multiple targeted genes. It should be noted that
silencing genes by miRNAs require partial complementary binding between miRNAs
and protein-coding transcripts. Therefore, it is important to evaluate effects of specific
miRNA-mediated therapy on a proteome-wide scale to prevent unexpected gene
alteration in non-tumor cells.
Conclusion and prospect
In summary, let-7 controls multiple targets to regulate stemness and differentiation
as required for proper development and tumor suppression. The identity of these
targets, and their physiological relevance, has primarily emerged. For the coming
cancer therapeutic, patents for the let-7 based therapy in Australia (2007/333109 A1),
USA (20090163430), and China (CN102038959) were filed.
We are now starting to learn how to regulate the expression of let-7 and to find out
the tumor-specific genes targeted by let-7 for the future let-7 based therapy. Such
investigation will be valuable in helping us to understand the regulation of cell fates,
in particular stem/progenitor cell fates. Therefore, it will be necessary to define the
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transcriptional regulatory networks and cell signaling pathways that distinguish
normal stem/progenitor cells from transformed cells. Although studies show a
promising therapeutic approach for treating various kinds of cancer by let-7, it should
be noted that these studies looked at the impairment of tumor initiation, not remission
of pre-existing tumors, the latter being much associated with the clinically relevant
situation. Other targets such as HMGA2 or lin28 might provide the profound
regulation of stemness and differentiation to substitute for let-7 based cancer therapy.
In the present-day, many open questions about let-7 function in normal stemness,
development and differentiation of stem/progenitor cells are still unsolved. The
mechanisms of let-7 resistance might be emerged during the extended treatment of
exogenous let-7. Mostly, additional pluripotent factors or inhibitors for substituting
let-7 family are continuously addressed in cancer therapies.
ACKNOWLEDGEMENTS: This study was supported by grants from National Science
Council (NSC 98-2314-B-039-008-MY2, NSC 102-2314-B-039-022, and NSC
102-2314-B-039-021-MY3) and China Medical University and Hospital
(CMU99-N2-01-[1&2], DMR-101-116 and DMR-102-053) awarded to Dr. Shao-Chih
Chiu.
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Table 1. Let-7 expressed in somatic and stem/progenitor cells.
microRN
Cells
A let-7
Biological activities
Targets of let-7
References
families
3T3-L1 cells,
let-7a, b,
To be up-regulated during
d, e, g, i
adipogenesis
let-7,
To suppress the cardiac
Swine
HMGA2
(50,88)
Cyclin D2
(20,108)
E2F1, DP
(29,72)
adipocytes
Cardiomyocytes
miR-98
Dopaminergic
hypertrophy
To attenuate pathogenic
Let-7
neurons
LRRK2 effects
To promote ES cells
Embryonic stem
lin28, c-Myc,
let-7, b, c
differentiation, EB
cells
(17,56,110)
N-Myc, lin-41
formation
Endothelial
thrombospondin
Let-7f
To promote angiogenesis
cells
(15,46)
-1, argonaute 1
To be highly expressed in
Let-7a, b,
adult liver development;
c
to attenuates oxidant
Bach1, TGF
Liver cells
(33,96)
beta-R1
injury
To be up-regulated in
Lung cells
Let-7a, c
allergic asthma and
repress cell proliferation
17
IL-6, RAS
(39,99)
To differentiate
Mammary
progenitors, decrease
lin28/let-7
epithelial
let-7
colony numbers, and
(35,107)
regulatory loop
progenitors
reduce self-renewing
cells
To induce osteoblastic
and osteocytic
Mesenchymal
Let-7a, c,
stem cells
e, f, g, i
differentiation; to
HNF4A
(24,44)
suppress the expression
of HNF4A
ascl1a, hspd1,
To inhibit Müller glia
Müller glia
Let-7a, f
oct4, pax6b and
(77)
dedifferentiation
c-myc
To inhibit the
proliferation of neural
c-Myc, SOX-2,
stem cell, promote
cyclin D1, cell
(16,45,84,1
neuronal differentiation
adhesion
09)
and act as a
molecules
Neural
stem/progenitor
let-7a, b
cells
spatio-temporal code
To be highly expressed in
newborn ovary and
Ovary cells
Let-7d, i
promote ovarian
development and early
folliculogenesis
18
N/A
(1,42)
Peripheral blood Let-7a, b,
To increase the sensitivity
mononuclear
c, d, g, i,
of Fas-mediated
cells
miR-98
apoptosis
Fas
(100,104)
HbF
(49,69)
To be up-regulated during
erythroid cells/
Let-7a, c,
the fetal-to-adult
Reticulocytes
d, e, g, i
developmental transition
in reticulocytes.
To reduce muscle cell
Association with
renewal and impair cell
CDK6, CDC25A
Skeletal muscle
Let-7b, e
(23)
cells
cycle function.
and CDC34
To inhibit the memory
Let-7a, b,
fate determination of T
c, d, g
cells, to modulate
T cells
IL-10
(4,89)
Igf2, IMP
(40,91)
production of cytokines
Testis-derived
To be upregulated and
male germ-line
Let-7a, d
promote ageing
stem cells
N/A, not applicable
19
Table 2. Deregulation of let-7 in human cancers.
Cancer types
let-7 family members
Expression level
Reference
let-7a, c, d, f, g
Downregulated
(26,37,85,103)
let-7a, b, e, i, f
Upregulated
(14,37)
let-7a, I, f
Downregulated
(52,103)
let-7a, b, c, e, f, g
Downregulated
(2,41,61,103)
let-7a, b, d, e, f, g, i, and mirR-98
Upregulated
(61,62)
Gastric cancer
let-7a, b, c
Downregulated
(63)
Hepatocellular
let-7a, b, c, d, e, f, g
Downregulated
(8,81,103,111)
carcinoma
let-7a, b, c, d, e, f, g, i, and mirR-98
Upregulated
(34)
Acute myeloid
let-7a, b, c, e, g
Downregulated
(10,28,54,103)
leukemia
let-7a, b, c, e, d, f, g, and mirR-98
Upregulated
(28,54)
Lung cancer
let-7a, b, c, f, g, i, and mirR-98
Downregulated
(27,67,103,105)
Ovarian cancer
let-7a, b, c, d, f, and mirR-98 mir98
Downregulated
(21,65,103,106)
let-7a
Downregulated
(81,83)
let-7d, f
Upregulated
(48)
let-7a, b, c, d, f, g
Downregulated
(19,75,82,103)
let-7b, d, i
Upregulated
(6,19,76,82)
Breast cancer
Brain tumors
Colorectal cancer
Pancreatic cancer
Prostate cancer
20
Figure 1
21
Figure 2
22
Figure Legends
Figure 1. differential level of let-7 expression in normal progenitors and cancer initiating cells.
During differentiation process, progenitors become more restricted to specific cell lineages.
Broken arrows indicate proposed sources of cancer stem cells: loss of let-7 could transformed
normal proliferating or differentiated progenitors into dedifferentiated cancer stem cells.
Figure 2. Regulation of let-7 activities on self-renewal and stemness maintenance.
23
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