Current View of microRNA Processing

Shuai Jiang1,* and Wei Yan2,*

1
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA. 2Department of Cancer Biology,
Beckman Research Institute of City of Hope, Duarte, CA, USA. *The authors contribute equally to this work.

ABSTR ACT: Small evolutionarily conserved noncoding RNAs, microRNAs (miRNAs), regulate gene expression either by translational repression or
by mRNA degradation in mammals. miRNAs play functional roles in diverse physiological and pathological processes. miRNA processing is accurately
regulated through multifarious factors. The canonical miRNA processing pathway consists of four sequential steps: (a) miRNA gene is transcribed into
primary miRNA (pri-miRNA) mainly by RNA polymerase II; (b) pri-miRNA is processed into precursor miRNA (pre-miRNA) through microprocessor
complex; (c) pre-miRNA is exported from the nucleus to the cytoplasm with the assistance of Exportin 5 (EXP5/XPO5) protein; and (d) pre-miRNA is
further processed into mature miRNA via Dicer. Emerging evidence has also demonstrated that some miRNAs undergo alternative processing pathways.
Dysregulation of miRNA processing is closely related to tumorigenesis. Here, we review the current advances in the knowledge of miRNA processing and
briefly discuss its impact on human cancers.

KEY WORDS: microRNAs, microRNA processing, canonical pathways, noncanonical pathways, cancer

CITATION: Jiang and Yan. Current View of microRNA Processing. Signal Transduction
Insights 2016:5 9–13 doi:10.4137/STI.S12317.
TYPE: Review
RECEIVED: January 21, 2016. RESUBMITTED: March 1, 2016. ACCEPTED FOR
PUBLICATION: March 8, 2016.
ACADEMIC EDITOR: Edgar Grinstein, Editor in Chief
PEER REVIEW: Three peer reviewers contributed to the peer review report. Reviewers’
reports totaled 862 words, excluding any confidential comments to the academic editor.
FUNDING: Authors disclose no external funding sources.
COMPETING INTERESTS: Authors disclose no potential conflicts of interest.
COPYRIGHT: © the authors, publisher and licensee Libertas Academica Limited.
This is an open-access article distributed under the terms of the Creative Commons
CC-BY-NC 3.0 License.
CORRESPONDENCE: luckysjiang@caltech.edu
Paper subject to independent expert single-blind peer review. All editorial decisions
made by independent academic editor. Upon submission manuscript was subject to
anti-plagiarism scanning. Prior to publication all authors have given signed confirmation
of agreement to article publication and compliance with all applicable ethical and legal
requirements, including the accuracy of author and contributor information, disclosure
of competing interests and funding sources, compliance with ethical requirements
relating to human and animal study participants, and compliance with any copyright
requirements of third parties. This journal is a member of the Committee on Publication
Ethics (COPE).
Provenance: the authors were invited to submit this paper.
Published by Libertas Academica. Learn more about this journal.

Introduction to the cytoplasm mediated through Ran GTPase Exportin-5

MicroRNAs (miRNAs) have been reported to be key players
in various biological processes.1 They globally regulate gene
expression at the posttranscriptional level and participate
in multiple physiological and pathological contexts, includ-
ing immune cell development, as well as tumorigenesis. 2–9
miRNAs directly bind to a complementary sequence in the
3′ untranslated region (3′UTR), leading to either target
mRNA degradation or protein translation inhibition.10–13
The fundamental roles of miRNAs draw attention of scien-
tific researchers. miRNA biogenesis pathways also attract
more interests for scientists to better understand how miR-
NAs are processed.
It is widely recognized that there are four main steps for
miRNA processing pathway.14–20 Through RNA polymerase II,
miRNA gene is first transcribed from genomic DNA (intronic,
intergenic, or polycistronic loci) into long primary transcript
(pri-miRNA). miRNAs can also be produced either from
separate transcription units or from a common transcription
unit. Second, pri-miRNA is cleaved into 70 nt long precursor
miRNA (pre-miRNA). This step is carried out by a micropro-
cessor complex consisting of Drosha and DiGeorge Critical
Region 8 (DGCR8). DGCR8 can reportedly bind to double-
stranded RNA-binding domain of pri-miRNA by specially
recognizing its “UGU” motif. Drosha can bind to the basal
“UG” motif and the stem region of hairpin structure in pri-
miRNA.21 Third, pre-miRNA is exported from the nucleus
(EXP5/XPO5) complex. Finally, pre-miRNA is processed
by Dicer-transactivating response RNA-binding protein
(TRBP) complex to generate mature miRNA. After enter-
ing into an Argonaute protein (AGO)-containing miRNA-
induced silencing complex (miRISC) duplex, pre-miRNA
unwinds its duplex and generate the mature miRNA strand
and its complementary miRNA* strand. In most cases, the
miRNA* strand can be degraded in the cytoplasm. However,
some miRNA* strands continue performing functional roles
in cells.22,23
It has been established that miRNA biogenesis can be
regulated at multiple levels. More and more new regulators,
including smads, p53, p63, p73, NF-κB, and RNA-binding
protein (RBP) Lin28, have been emerged in some miRNA
processing pathways.24–28 Dysregulated miRNA processing
has been well documented to be associated with human can-
cers. Here, we have reviewed the current understanding of
both canonical and noncanonical miRNA biogenesis pathways
in mammals and their potential clinical use in human cancers.
Canonical miRNA Processing Pathways
Fine-tuning of miRNA processing is indispensable to main-
tain a physiological balance of miRNA levels in mammals.29
It is accurately controlled at both transcriptional and post-
transcriptional levels.30 Multiple factors can contribute to
miRNA processing and/or their functional roles, including

Signal Transduction Insights 2016:5 9

Jiang and Yan
the activities of miRNA processing enzymes, as well as the
stability of pri-miRNAs and pre-miRNAs.31
Pri-miRNA biogenesis. The first step of miRNA bio-
genesis is the transcription from genomic DNA largely by
RNA polymerase II, and it generates stem-loop structural pri-
miRNAs with a stable 7-methylguanosine cap and poly-(A)
tail.32–34 A common set of transcription factors, including
Myc, p53, and REST, can either enhance or block some
miRNA biogenesis during the transcription step.35–38 Other
studies have shown that platelet-derived growth factor recep-
tor and the activin/transforming growth factor-β, as well as
brain-derived neurotrophic factor, contributed to pri-miRNA
biogenesis.39–41 NF-κB can regulate pri-miR-155 transcrip-
tion as well as the transcriptional activity of let-7a-3.42,43 It is
also noted that the transcription of miR-34, miR-200, miR-
15a, and miR-16-1 can be regulated by p53.44–47 Another
study suggested that proto-oncogene Myb can bind to the pri-
miR-15a promoter in K562 cells. Reciprocally, miR-15a can
regulate the Myb gene transcripts.48 It has been shown that
Runx1 regulates miR-27a expression by directly binding to
the miR-27a promoter.49 It has been reported that transcrip-
tion factors NFI-A and C/EBP alpha can bind to the miR-
223 promoter.50 A subsequent study has shown that SMAD
proteins regulate the miR-21 biogenesis through a sequence-
specific mechanism.51
Furthermore, RNA editing can influence pri-miRNA
levels in the nucleus. Hydrolytic deamination of adenosine
(A-I) of pri-miR-142 can be edited by adenosine deaminase
acting on RNA (ADAR) and it can also be degraded by a
ribonuclease known as Tudor-SN.52
Processing from pri-miRNA to pre-miRNA. Recent
research has demonstrated that pre-miRNAs can be endowed
with the stem-loop region of pri-miRNAs and recognized by
the EXP5/XPO5 protein.53 It is well established that multiple
signal transduction molecules interact with Drosha, partici-
pating in the transition from pri-miRNA to pre-miRNA.54
Under nutrient-rich conditions, targeting rapamycin complex 1
(mTORC1) can induce Drosha degradation by affecting E3
ubiquitin Mdm2 either in a p53-dependent transcription
pathway or in a p53-independent posttranscriptional manner,
leading to overall miRNA biogenesis reduction.55,56 Drosha
expression can be enhanced in a low-glucose condition. Estro-
gen receptor alpha (ERα) also inhibits Drosha-mediated pri-
miRNA processing.57 Investigators have found that p68 and
p72 in the microprocessor complex are important for some
miRNA biogenesis.58 Furthermore, p53 can regulate Drosha-
mediated miRNA processing by binding to p68.59
Other work has shown that menin (coded by men1 gene)
engages in both miR-let-7a and miR-155 maturation from
pri-miRNA to pre-miRNA by binding to RBP ARS2.60
In addition to the above description, RBPs Lin28a/b can
block pre-let-7 processing by recruiting the uridyltrans-
ferase Zcchc11 and by interacting with the stem-loop of
pre-let-7.61,62
10 Signal Transduction Insights 2016:5
Pre-miRNA exporting into cytoplasm by Exportin-5.
It has become increasingly clear that EXP5/XPO5 belongs
to importin-β family, acting as a major exporter of nuclear
RNAs.63 EXP5/XPO5 is the rate-determining step in the
miRNA processing with a low expression in mammals.64
An additional report has described that HASTY (HST)
is the homolog of XPO5 in plants.65 It is also worth not-
ing that HST defect can block a general accumulation of
miRNAs.66,67
Mature miRNA generation. Pre-miRNA processing is
further assisted by Dicer, producing a ~22-nucleotide miRNA
duplex, with one duplex strand called miRNA* degraded and
the other strand binding to the 3′UTR of target mRNA,
leading to either mRNA cleavage or translational inhibition
(Fig. 1). Interestingly, some miRNA* can still play functional
roles in cells.22,23
The pre-miRNA maturation can also be regulated by
Dcl1 in the nucleus of plants.68 TRBP, a major component
of Dicer complex, can be regulated by mitogen-activated
kinase/extracellular-signal-regulated kinases (MAPK/ERK)
signaling pathway, and it can affect some growth-promoting
miRNA processing.69 The single-stranded RNA-binding
KH-type splicing regulatory protein has been reported as an
interacting protein with Dicer, and it can bind to the stem-
loop of pre-miRNAs.70 It has been illustrated that the Akt
kinase-induced activation on the let-7a-1 processing can be
counteracted by the splicing factor hnRNPA1 through bind-
ing to the stem-loop region of pre-let-7a.71
Other factors altering miRNA processing. It has been
appreciated that the reciprocal and double-negative regulatory
feedback loop also exists in some miRNAs biogenesis.72–74 For
example, let-7 can bind to the 3′UTR of myc mRNA by inter-
acting with RBP HuR.75 On the other hand, myc can regulate
let-7 processing by promoting Lin28, and it can also directly
regulate let-7 expression at the transcriptional level.76,77
Noncanonical miRNA Biogenesis Pathway
Noncanonical miRNA biogenesis pathway is emerging as
a highlight in some miRNA biogenesis either by Drosha-
independent or by Dicer-independent pathways. Mirtrons,
characterized in Drosophila, are a real addition to the canoni-
cal miRNA pathway in the nucleus.78,79 However, the hairpin
pre-miRNA still needs the aid from EXP5/XPO5 protein
to be exported into cytoplasm and subsequently cleaved by
Dicer.80 Furthermore, transfer RNAs (tRNAs) and small
nucleolar RNAs (snoRNAs) have alternative miRNA biogen-
esis pathways independent of Drosha.81 Pre-miR-320 is tran-
scribed directly from genome DNA that bypasses Drosha.82
Similarly, Dicer-independent pathways can produce func-
tional miRNAs.83 The biogenesis of blood-specific miR-451
is in a Dicer-independent manner, but it still requires the
assistance from Drosha.84 In Dicer-deficient cells, mature
miR-451 can be generated, while the processing of other
miRNAs is impaired.85 It is worth noting that miRNAs can
 microRNA processing

Figure 1. Current view of miRNA processing. miRNA gene is mainly transcribed by RNA polymerase II (RNA pol II) in the nucleus. After transcription,
­pri-miRNA is generated with a 7-methyguanosine cap and 3′ poly A tail. Pri-miRNA is cropped into 70–100 nt pre-miRNA by Drosha–DGCR8 complex.
Pre-miRNA is exported into the cytoplasm with the assistance of the complex consisting of Ran-GTP and Exportin-5. Pre-miRNA is cleaved by Dicer
with its partners AGO and TRBP proteins to form a 20–25 nt miRNA: miRNA* duplex. Subsequent maturation generates the mature miRISC complex with
one strand, whereas the other strand (miRNA*) is usually degraded. Mature miRNA facilitates the target mRNA cleavage and/or translational repression.
Specifically, there are some non-classical pathways. First, a non-classical pathway generating pri-miRNA is conducted from a branched miRtron.
Second, miRNA is cleaved by AGO protein to form a mature miRNA in a Dicer-independent manner, for instance, pre-miR-451. Third, miRNA can directly
bind to RBPs to prevent from binding their RNA targets via a RISC-independent pathway.

bind to RBPs to hinder RBPs from binding to their RNA
targets via a RISC-independent pathway.86 Interestingly,
recent studies have also implied that long noncoding RNAs
can regulate miRNA biogenesis and that the circular RNAs
can potentially soak up miRNAs, providing another level of
modulating miRNAs.87–89
miRNA Biogenesis and Cancer
Dysregulation of miRNA biogenesis has been frequently
observed in multiple human cancers.90,91 A global down-
regulation of mature miRNAs via miRNA profiling has also
been found in some human cancers.92–95 Processing of some
miRNAs, including miR-26b and miR-125b, is impaired in
the transition from pri-miRNA to pre-miRNA in human thy-
roid anaplastic carcinoma.96 miRNA-processing factor defect
reportedly occurs in lung cancer and ovarian cancer.97,98 Alter-
ations of the key factors in miRNA processing can significantly
affect cancer initiation and progression as well as tumor metas-
tasis either by genomic mutations or by aberrant expression.
The expression levels of miRNA processing enzymes
such as Dicer, Drosha, and EXP5/XPO5 protein have been
found to be positively correlated with invasive carcinomas.99,100
In bladder urothelial carcinoma cells, Dicer and/or Drosha
knockdown by siRNAs can decrease tumor cell proliferation
and promote tumor cell apoptosis at the posttranscriptional
levels.99–101 Furthermore, inactivated EXP5/XPO5 protein
can promote pre-miRNAs retention in the nucleus. EXP5/
XPO5 restoration shows tumor suppressive effects.102 It has
been reported that Dicer expression is strongly correlated with
human cancers. In ovarian cancer, lung cancer, and breast
cancer, enhanced Dicer expression is associated with clinical
prognosis. But it has opposite effects in colorectal cancer and
prostate cancer.103–106 TRBP knockdown can destabilize Dicer
and impair the miRNA processing in cancer cells.107 How-
ever, the mechanisms of miRNA biogenesis are complex and
still remain to be further characterized. Identifying other fac-
tors such as RBPs or other noncoding RNAs in the miRNA
processing will provide potential strategies for cancer therapy.
Conclusions and Perspectives
Over the past two decades, it has become increasingly clear
that investigating the mechanisms of miRNA processing

Signal Transduction Insights 2016:5 11

Jiang and Yan
would be critical to decipher complicated regulatory networks
mediated by miRNAs in mammals. However, we are still
lacking deeper understanding of miRNA machinery and its
physiological roles in various biological aspects. Here, we have
provided an overview of where and how miRNAs are pro-
cessed, including the canonical and noncanonical pathways,
and how it is linked to human cancers.
We believe that future studies will focus on several major
points: (a) to identify more factors that are involved in miRNA
processing; (b) to elucidate how other noncoding RNAs such
as piRNAs interact with miRNA biogenesis pathways; (c) to
characterize the physiological functions of key factors such
as Exportin-5 in human diseases; (d) to discover more non-
classical pathways in miRNA processing; (e) to research on
miRNA processing pathways in other species; and (f) to iden-
tify the differences of miRNA processing pathways between
a common set of miRNAs and extracellular miRNAs such as
exosomal miRNAs.
Herein, we bring together much of the current work
regarding miRNA processing. It has so far only touched the
surface of this fertile field of research. Thus, knowledge of
miRNA processing in the physiological and pathological roles
should be advanced in the near future. Further research will
undoubtedly result in new discoveries regarding cancer therapy.
Acknowledgment
We apologize to colleagues whose original papers could not be
cited due to space limitations.
Author Contributions
All the authors conceived, organized, drafted, reviewed, and
approved the manuscript.
REFERENCES
1. Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell.
2004;116:281–297.
2. Boldin MP, Baltimore D. MicroRNAs, new effectors and regulators of NF-
kappaB. Immunol Rev. 2012;246:205–220.
3. Casalini P, Iorio MV. MicroRNAs and future therapeutic applications in cancer.
J BUON. 2009;14(suppl 1):S17–S22.
4. Catalucci D, Gallo P, Condorelli G. MicroRNAs in cardiovascular biology and
heart disease. Circ Cardiovasc Genet. 2009;2:402–408.
5. Coolen M, Bally-Cuif L. MicroRNAs in brain development and physiology.
Curr Opin Neurobiol. 2009;19:461–470.
6. O’Connell RM, Rao DS, Chaudhuri AA, Baltimore D. Physiological and path-
ological roles for microRNAs in the immune system. Nat Rev Immunol. 2010;10:
111–122.
7. So AY, Zhao JL, Baltimore D. The Yin and Yang of microRNAs: leukemia and
immunity. Immunol Rev. 2013;253:129–145.
8. Sonkoly E, Pivarcsi A. microRNAs in inflammation. Int Rev Immunol. 2009;28:
535–561.
9. Taganov KD, Boldin MP, Baltimore D. MicroRNAs and immunity: tiny players
in a big field. Immunity. 2007;26:133–137.
10. Eulalio A, Huntzinger E, Izaurralde E. Getting to the root of miRNA-mediated
gene silencing. Cell. 2008;132:9–14.
11. Ibrahim SA, Hassan H, Gotte M. MicroRNA-dependent targeting of the extra-
cellular matrix as a mechanism of regulating cell behavior. Biochim Biophys Acta.
2014;1840:2609–2620.
12. McDaneld TG. MicroRNA: mechanism of gene regulation and application to
livestock. J Anim Sci. 2009;87:E21–E28.
12 Signal Transduction Insights 2016:5
13. Park JH, Shin C. MicroRNA-directed cleavage of targets: mechanism and
experimental approaches. BMB Rep. 2014;47:417–423.
14. Bahubeshi A, Tischkowitz M, Foulkes WD. miRNA processing and human
cancer: DICER1 cuts the mustard. Sci Transl Med. 2011;3:111s146.
15. Conrad R, Barrier M, Ford LP. Role of miRNA and miRNA processing factors
in development and disease. Birth Defects Res C Embryo Today. 2006;78:107–117.
16. Davis-Dusenbery BN, Hata A. Smad-mediated miRNA processing: a critical
role for a conserved RNA sequence. RNA Biol. 2011;8:71–76.
17. Hata A, Davis BN. Regulation of pri-miRNA processing through Smads. Adv
Exp Med Biol. 2010;700:15–27.
18. Lehrbach NJ, Miska EA. Regulation of pre-miRNA processing. Adv Exp Med
Biol. 2010;700:67–75.
19. Pekarik V. Design of shRNAs for RNAi-A lesson from pre-miRNA processing:
possible clinical applications. Brain Res Bull. 2005;68:115–120.
20. Pontes O, Pikaard CS. siRNA and miRNA processing: new functions for Cajal
bodies. Curr Opin Genet Dev. 2008;18:197–203.
21. Auyeung VC, Ulitsky I, McGeary SE, Bartel DP. Beyond secondary structure:
primary-sequence determinants license pri-miRNA hairpins for processing. Cell.
2013;152:844–858.
22. Shan SW, Fang L, Shatseva T, et al. Mature miR-17-5p and passenger miR-
17-3p induce hepatocellular carcinoma by targeting PTEN, GalNT7 and vimen-
tin in different signal pathways. J Cell Sci. 2013;126:1517–1530.
23. Yang X, Du WW, Li H, et al. Both mature miR-17-5p and passenger strand
miR-17-3p target TIMP3 and induce prostate tumor growth and invasion.
Nucleic Acids Res. 2013;41:9688–9704.
24. Davis BN, Hilyard AC, Nguyen PH, Lagna G, Hata A. Smad proteins bind
a conserved RNA sequence to promote microRNA maturation by Drosha.
Mol Cell. 2010;39:373–384.
25. Zhou R, Hu G, Gong AY, Chen XM. Binding of NF-kappaB p65 subunit to the
promoter elements is involved in LPS-induced transactivation of miRNA genes
in human biliary epithelial cells. Nucleic Acids Res. 2010;38:3222–3232.
26. Mayr F, Heinemann U. Mechanisms of Lin28-mediated miRNA and mRNA
regulation—a structural and functional perspective. Int J Mol Sci. 2013;14:
16532–16553.
27. Jiang S, Baltimore D. RNA-binding protein Lin28 in cancer and immunity.
Cancer Lett. 2016;375:108–113.
28. Viswanathan SR, Daley GQ , Gregory RI. Selective blockade of microRNA pro-
cessing by Lin28. Science. 2008;320:97–100.
29. Shukla GC, Singh J, Barik S. MicroRNAs: processing, maturation, target recog-
nition and regulatory functions. Mol Cell Pharmacol. 2011;3:83–92.
30. Shalgi R, Brosh R, Oren M, Pilpel Y, Rotter V. Coupling transcriptional and
post-transcriptional miRNA regulation in the control of cell fate. Aging. 2009;
1:762–770.
31. Krol J, Loedige I, Filipowicz W. The widespread regulation of microRNA bio-
genesis, function and decay. Nat Rev Genet. 2010;11:597–610.
32. Cai X, Hagedorn CH, Cullen BR. Human microRNAs are processed from
capped, polyadenylated transcripts that can also function as mRNAs. RNA.
2004;10:1957–1966.
33. Lee Y, Jeon K, Lee JT, Kim S, Kim VN. MicroRNA maturation: stepwise pro-
cessing and subcellular localization. EMBO J. 2002;21:4663–4670.
34. Lee Y, Kim M, Han J, et al. MicroRNA genes are transcribed by RNA poly-
merase II. EMBO J. 2004;23:4051–4060.
35. Davis BN, Hata A. Regulation of MicroRNA biogenesis: a miRiad of mecha-
nisms. Cell Commun Signal. 2009;7:18.
36. Feng Z, Zhang C, Wu R, Hu W. Tumor suppressor p53 meets microRNAs.
J Mol Cell Biol. 2011;3:44–50.
37. Packer AN, Xing Y, Harper SQ , Jones L, Davidson BL. The bifunctional
microRNA miR-9/miR-9* regulates REST and CoREST and is downregulated
in Huntington’s disease. J Neurosci. 2008;28:14341–14346.
38. Wang X, Zhao X, Gao P, Wu M. c-Myc modulates microRNA processing via
the transcriptional regulation of Drosha. Sci Rep. 2013;3:1942.
39. Butz H, Racz K, Hunyady L, Patocs A. Crosstalk between TGF-beta signaling
and the microRNA machinery. Trends Pharmacol Sci. 2012;33:382–393.
40. Costa PM, Cardoso AL, Pereira de Almeida LF, Bruce JN, Canoll P, Pedroso
de Lima MC. PDGF-B-mediated downregulation of miR-21: new insights into
PDGF signaling in glioblastoma. Hum Mol Genet. 2012;21:5118–5130.
41. Huang YW, Ruiz CR, Eyler EC, Lin K, Meffert MK. Dual regulation of
miRNA biogenesis generates target specificity in neurotrophin-induced protein
synthesis. Cell. 2012;148:933–946.
42. Kluiver J, van den Berg A, de Jong D, et al. Regulation of pri-microRNA BIC
transcription and processing in Burkitt lymphoma. Oncogene. 2007;26:3769–3776.
43. Wang DJ, Legesse-Miller A, Johnson EL, Coller HA. Regulation of the let-
7a-3 promoter by NF-kappaB. PLoS One. 2012;7:e31240.
44. Raver-Shapira N, Marciano E, Meiri E, et al. Transcriptional activation of
miR-34a contributes to p53-mediated apoptosis. Mol Cell. 2007;26:731–743.
45. Schubert J, Brabletz T. p53 Spreads out further: suppression of EMT and
stemness by activating miR-200c expression. Cell Res. 2011;21:705–707.

46. Taira N, Yamaguchi T, Kimura J, et al. Induction of amphiregulin by p53 pro-
motes apoptosis via control of microRNA biogenesis in response to DNA dam-
age. Proc Natl Acad Sci U S A. 2014;111:717–722.
47. Veronese A, Pepe F, Chiacchia J, et al. Allele-specific loss and transcription of
the miR-15a/16-1 cluster in chronic lymphocytic leukemia. Leukemia. 2015;29:
86–95.
48. Zhao H, Kalota A, Jin S, Gewirtz AM. The c-myb proto-oncogene and
microRNA-15a comprise an active autoregulatory feedback loop in human
hematopoietic cells. Blood. 2009;113:505–516.
49. Tang W, Yu F, Yao H, et al. miR-27a regulates endothelial differentiation of
breast cancer stem like cells. Oncogene. 2014;33:2629–2638.
50. Fazi F, Rosa A, Fatica A, et al. A minicircuitry comprised of microRNA-223 and
transcription factors NFI-A and C/EBPalpha regulates human granulopoiesis.
Cell. 2005;123:819–831.
51. Davis BN, Hilyard AC, Lagna G, Hata A. SMAD proteins control DROSHA-
mediated microRNA maturation. Nature. 2008;454:56–61.
52. Yang W, Chendrimada TP, Wang Q , et al. Modulation of microRNA process-
ing and expression through RNA editing by ADAR deaminases. Nat Struct Mol
Biol. 2006;13:13–21.
53. Guttler T, Gorlich D. Ran-dependent nuclear export mediators: a structural per-
spective. EMBO J. 2011;30:3457–3474.
54. Lee Y, Han J, Yeom KH, Jin H, Kim VN. Drosha in primary microRNA pro-
cessing. Cold Spring Harb Symp Quant Biol. 2006;71:51–57.
55. Jewell JL, Flores F, Guan KL. Micro(RNA) managing by mTORC1. Mol Cell.
2015;57:575–576.
56. Ye P, Liu Y, Chen C, et al. An mTORC1-Mdm2-Drosha axis for miRNA bio-
genesis in response to glucose- and amino acid-deprivation. Mol Cell. 2015;57:
708–720.
57. Newman MA, Hammond SM. Emerging paradigms of regulated microRNA
processing. Genes Dev. 2010;24:1086–1092.
58. Blahna MT, Hata A. Smad-mediated regulation of microRNA biosynthesis.
FEBS Lett. 2012;586:1906–1912.
59. Elston R, Inman GJ. Crosstalk between p53 and TGF-beta signalling. J Signal
Transduct. 2012;2012:294097.
60. Gurung B, Katona BW, Hua X. Menin-mediated regulation of miRNA biogen-
esis uncovers the IRS2 pathway as a target for regulating pancreatic beta cells.
Oncoscience. 2014;1:562–566.
61. Piskounova E, Polytarchou C, Thornton JE, et al. Lin28A and Lin28B inhibit
let-7 microRNA biogenesis by distinct mechanisms. Cell. 2011;147:1066–1079.
62. Thornton JE, Chang HM, Piskounova E, Gregory RI. Lin28-mediated con-
trol of let-7 microRNA expression by alternative TUTases Zcchc11 (TUT4) and
Zcchc6 (TUT7). RNA. 2012;18:1875–1885.
63. Leisegang MS, Martin R, Ramirez AS, Bohnsack MT. Exportin t and exportin 5:
tRNA and miRNA biogenesis—and beyond. Biol Chem. 2012;393:599–604.
64. Yi R, Doehle BP, Qin Y, Macara IG, Cullen BR. Overexpression of exportin 5
enhances RNA interference mediated by short hairpin RNAs and microRNAs.
RNA. 2005;11:220–226.
65. Bollman KM, Aukerman MJ, Park MY, Hunter C, Berardini TZ, Poethig RS.
HASTY, the Arabidopsis ortholog of exportin 5/MSN5, regulates phase change
and morphogenesis. Development. 2003;130:1493–1504.
66. Kim VN. MicroRNA biogenesis: coordinated cropping and dicing. Nat Rev Mol
Cell Biol. 2005;6:376–385.
67. Park MY, Wu G, Gonzalez-Sulser A, Vaucheret H, Poethig RS. Nuclear
processing and export of microRNAs in Arabidopsis. Proc Natl Acad Sci U S A.
2005;102:3691–3696.
68. Lee WC, Lu SH, Lu MH, Yang CJ, Wu SH, Chen HM. Asymmetric bulges
and mismatches determine 20-nt microRNA formation in plants. RNA Biol.
2015;12:1054–1066.
69. Paroo Z, Ye X, Chen S, Liu Q. Phosphorylation of the human microRNA-
generating complex mediates MAPK/Erk signaling. Cell. 2009;139:112–122.
70. Slezak-Prochazka I, Durmus S, Kroesen BJ, van den Berg A. MicroRNAs, mac-
rocontrol: regulation of miRNA processing. RNA. 2010;16:1087–1095.
71. Michlewski G, Caceres JF. Antagonistic role of hnRNP A1 and KSRP in the
regulation of let-7a biogenesis. Nat Struct Mol Biol. 2010;17:1011–1018.
72. Cai S, Zhou P, Liu Z. Functional characteristics of a double negative feedback
loop mediated by microRNAs. Cogn Neurodyn. 2013;7:417–429.
73. Agami R. microRNAs, RNA binding proteins and cancer. Eur J Clin Invest.
2010;40:370–374.
74. Jiang P, Coller H. Functional interactions between microRNAs and RNA bind-
ing proteins. Microrna. 2012;1:70–79.
75. Wang J, Guo Y, Chu H, Guan Y, Bi J, Wang B. Multiple functions of the RNA-
binding protein HuR in cancer progression, treatment responses and prognosis.
Int J Mol Sci. 2013;14:10015–10041.
microRNA processing
76. Suzuki HI, Katsura A, Miyazono K. A role of uridylation pathway for blockade
of let-7 microRNA biogenesis by Lin28B. Cancer Sci. 2015;106:1174–1181.
77. Wang T, Wang G, Hao D, et al. Aberrant regulation of the LIN28A/LIN28B
and let-7 loop in human malignant tumors and its effects on the hallmarks of
cancer. Mol Cancer. 2015;14:125.
78. Ladewig E, Okamura K, Flynt AS, Westholm JO, Lai EC. Discovery of hundreds
of mirtrons in mouse and human small RNA data. Genome Res. 2012;22:1634–1645.
79. Okamura K, Hagen JW, Duan H, Tyler DM, Lai EC. The mirtron pathway
generates microRNA-class regulatory RNAs in Drosophila. Cell. 2007;130:
89–100.
80. Kohler A, Hurt E. Exporting RNA from the nucleus to the cytoplasm. Nat Rev
Mol Cell Biol. 2007;8:761–773.
81. Yang JS, Lai EC. Alternative miRNA biogenesis pathways and the interpreta-
tion of core miRNA pathway mutants. Mol Cell. 2011;43:892–903.
82. Xie M, Li M, Vilborg A, et al. Mammalian 5′-capped microRNA precursors that
generate a single microRNA. Cell. 2013;155:1568–1580.
83. Yang JS, Lai EC. Dicer-independent, Ago2-mediated microRNA biogenesis in
vertebrates. Cell Cycle. 2010;9:4455–4460.
84. Cifuentes D, Xue H, Taylor DW, et al. A novel miRNA processing pathway
independent of dicer requires Argonaute2 catalytic activity. Science. 2010;328:
1694–1698.
85. Yang JS, Maurin T, Robine N, et al. Conserved vertebrate mir-451 provides a
platform for dicer-independent, Ago2-mediated microRNA biogenesis. Proc
Natl Acad Sci U S A. 2010;107:15163–15168.
86. Eiring AM, Harb JG, Neviani P, et al. miR-328 functions as an RNA decoy to
modulate hnRNP E2 regulation of mRNA translation in leukemic blasts. Cell.
2010;140:652–665.
87. Liz J, Portela A, Soler M, et al. Regulation of pri-miRNA processing by a
long noncoding RNA transcribed from an ultraconserved region. Mol Cell.
2014;55:138–147.
88. Wang K, Sun T, Li N, et al. MDRL lncRNA regulates the processing of miR-484
primary transcript by targeting miR-361. PLoS Genet. 2014;10:e1004467.
89. Chen I, Chen CY, Chuang TJ. Biogenesis, identification, and function of exonic
circular RNAs. Wiley Interdiscip Rev RNA. 2015;6:563–579.
90. Croce CM. Causes and consequences of microRNA dysregulation in cancer.
Nat Rev Genet. 2009;10:704–714.
91. Ohtsuka M, Ling H, Doki Y, Mori M, Calin GA. MicroRNA processing and
human cancer. J Clin Med. 2015;4:1651–1667.
92. Macfarlane LA, Murphy PR. MicroRNA: biogenesis, function and role in
cancer. Curr Genomics. 2010;11:537–561.
93. Jansson MD, Lund AH. MicroRNA and cancer. Mol Oncol. 2012;6:590–610.
94. Liu X, Chen Z, Yu J, Xia J, Zhou X. MicroRNA profiling and head and neck
cancer. Comp Funct Genomics. 2009;2009:837514.
95. Wu X, Ajani JA, Gu J, et al. MicroRNA expression signatures during malignant
progression from Barrett’s esophagus to esophageal adenocarcinoma. Cancer
Prev Res. 2013;6:196–205.
96. Fuziwara CS, Kimura ET. MicroRNA deregulation in anaplastic thyroid cancer
biology. Int J Endocrinol. 2014;2014:743450.
97. Lin PY, Yu SL, Yang PC. MicroRNA in lung cancer. Br J Cancer. 2010;103:
1144–1148.
98. Melo SA, Esteller M. A precursor microRNA in a cancer cell nucleus: get me out
of here! Cell Cycle. 2011;10:922–925.
99. Surova O, Akbar NS, Zhivotovsky B. Knock-down of core proteins regulating
microRNA biogenesis has no effect on sensitivity of lung cancer cells to ionizing
radiation. PLoS One. 2012;7:e33134.
100. Huang JT, Wang J, Srivastava V, Sen S, Liu SM. MicroRNA machinery genes
as novel biomarkers for cancer. Front Oncol. 2014;4:113.
101. Muqbil I, Bao B, Abou-Samra AB, Mohammad RM, Azmi AS. Nuclear
export mediated regulation of microRNAs: potential target for drug interven-
tion. Curr Drug Targets. 2013;14:1094–1100.
102. Melo SA, Moutinho C, Ropero S, et al. A genetic defect in exportin-5 traps pre-
cursor microRNAs in the nucleus of cancer cells. Cancer Cell. 2010;18:303–315.
103. Bian X, Shen Y, Zhang G, et al. Expression of dicer and its related miRNAs in
the progression of prostate cancer. PLoS One. 2015;10:e0120159.
104. Huang J, Hu W, Sood AK. Prognostic biomarkers in ovarian cancer. Cancer Bio-
mark. 2010;8:231–251.
105. Schoof CR, Botelho EL, Izzotti A, Vasques Ldos R. MicroRNAs in cancer
treatment and prognosis. Am J Cancer Res. 2012;2:414–433.
106. Caffrey E, Ingoldsby H, Wall D, et al. Prognostic significance of deregulated
dicer expression in breast cancer. PLoS One. 2013;8:e83724.
107. Lin S, Gregory RI. MicroRNA biogenesis pathways in cancer. Nat Rev Cancer.
2015;15:321–333.
Signal Transduction Insights 2016:5 13