MicroRNA 483-3p suppresses the expression of DPC4/Smad4 in pancreatic cancer
Jun Haoa, Shuyu Zhangb, Yingqi Zhoua, Xiangui Hua,⇑, Chenghao Shaoa,⇑
aDepartment of Pancreatic Surgery, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
bSchool of Radiation Medicine and Public Health, Medical College of Soochow University, Suzhou 215123, China
a r t i c l e i n f o
Received 3 September 2010
Revised 22 November 2010
Accepted 22 November 2010
Available online 27 November 2010
Edited by Tamas Dalmay
a b s t r a c t
Both deregulation of tumor-suppressor genes and misexpression of microRNAs (miRNAs) have been
implicated in the development of pancreatic cancer, but their relationship during this process
remains less clear. Here, we report that the expression of miR-483-3p is strongly enhanced in pan-
creatic cancer tissues compared to side normal tissues using a miRNA-array differential analysis.
Furthermore, DPC4/Smad4 is identified as a target of miR-483-3p and their expression levels are
inversely correlated in human clinical specimens. Ectopic expression of miR-483-3p significantly
represses DPC4/Smad4 protein levels in pancreatic cancer cell lines, and simultaneously promotes
cell proliferation and colony formation in vitro. Our findings identify miR-483-3p as a potent regu-
lator of DPC4/Smad4, which may provide a novel therapeutic strategy for the treatment of DPC4/
Smad4-driven pancreatic cancer.
? ? 2010 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
Pancreatic cancer is an aggressive malignancy with one of the
worst mortality rates. It is the sixth leading cause of death from
malignant disease in China and the fourth leading cause of can-
cer-related death in the United States [1–3]. In recent years, there
have been important advances in the understanding of the molec-
ular biology of pancreatic cancer, and genetic analyses have shown
that the genetic basis of this dismal disease is extremely complex
and heterogeneous . It has been suggested that pancreatic can-
cer is associated with the successive accumulation of gene muta-
tions such as oncogene KRAS2 and tumor-suppressor genes
INK4A, TP53 and DPC4/Smad4 [5,6]. Despite extensive research
efforts, the prognosis for pancreatic cancer is the worst among all
cancers due to minimal improvements in its prevention and
treatment, and the 5-year relative survival rate over the past dec-
ades has remained at only 5% for all stages of this disease [1,3].
Therefore, the quest for new associated factors and novel therapeu-
tic targets for pancreatic cancer remains an imperative clinical
Recently, microRNAs (miRNA) have emerged as a critical class
of negative regulators of gene expression. miRNAs are endogenous
small 21–23 nucleotide non-coding RNAs that possess remarkable
evolutionary conservation [7,8]. These small molecules elicit their
regulatory effects by base-pairing to partially complementary
mRNAs and function by at least two mechanisms: degradation of
target mRNA transcripts and inhibition of mRNA translation
[9,10]. Emerging evidence indicates that miRNAs play critical roles
in the regulation of various biological and pathologic processes,
involving cell proliferation, differentiation, apoptosis, and stress
resistance [11–13]. More importantly, it has been suggested that
the development and progression of cancer are associated with
aberrant upregulation or downregulation of specific miRNAs and
their targets in various types of cancer. And certain cancer histo-
types can be classified based on miRNA expression profiles [14–
16]. In pancreatic cancer, a multitude of misexpressed miRNAs
have been reported, such as ‘onco(genic)-miRs’, miR-21 and miR-
155, and ‘tumor suppressor miRs’, miR-29b and the miR-34 and
let-7 families [17,18]. Moreover, it was recently found that miR-
96 functions as a tumor-suppressor gene in pancreatic cancer by
repressing KRAS expression . However, it is less clear whether
there are any other miRNAs targeting these key regulatory genes in
In this study, using a miRNA array-based differential analysis,
we found that miR-483-3p expression levels of pancreatic cancer
tissues were significantly higher than those of the respective side
normal tissues. By computational prediction and luciferase repor-
ter assays, we identified DPC4/Smad4, a central mediator of TGF-
b signal transduction , as a target of miR-483-3p. We also
found that their expression levels were inversely proportional in
pancreatic cancer tissues. Furthermore, we showed that overex-
pression of miR-483-3p in pancreatic cancer cells promoted cell
proliferation and colony formation. Taken together, our results
0014-5793/$36.00 ? 2010 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
⇑Corresponding authors. Fax: +86 21 81873355 (X. Hu), +86 21 81873356
E-mail addresses: firstname.lastname@example.org (X. Hu),
email@example.com (C. Shao).
FEBS Letters 585 (2011) 207–213
journal homepage: www.FEBSLetters.org
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J. Hao et al./FEBS Letters 585 (2011) 207–213