Pancreatic cancer (PC) has a high rate of mortality and a poorly understood mechanism of progression. MicroRNA (miRNA) molecules have been proved to play an important role in malignant transformation and cancer development. Thousands of miRNAs have been screened in PC and several of them, such as miR-21, 155, and 196a, show up- or down-regulation that is associated with progression of the disease. However, the roles of these molecules in the regulation of tumorigenesis are not clear. Some studies have investigated whether circulating miRNAs could be detected in serum of patients with PC and whether expression levels of specific miRNAs differed between PC patients, pancreatitis patients, and healthy individuals. The current review focuses on this topic along with a possible role for miRNAs in the early diagnosis of PC.
Get full access to this article
View all access options for this article.
References
1.
HayatMJ, HowladerN, ReichmanMEet al.Cancer statistics, trends, and multiple primary cancer analyses from the Surveillance, Epidemiology, and End Results (SEER) Program[J]Oncologist, 2007; 12:20.
2.
SergeantG, VankelecomH, GremeauxLet al.Role of cancer stem cells in pancreatic ductal adenocarcinoma[J]Nat Rev Clin Oncol, 2009; 6:580.
3.
LeeRC, FeinbaumRL, AmbrosV. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14[J]Cell, 1993; 75:843.
4.
BartelDP. MicroRNAs: Genomics, biogenesis, mechanism, and function[J]Cell, 2004; 116:281.
5.
AmbrosV. The functions of animal microRNAs[J]Nature, 2004; 431:350.
6.
PasquinelliAE, ReinhartBJ, SlackFet al.Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA[J]Nature, 2000; 408:86.
7.
LiM, Marin-MullerC, BharadwajUet al.MicroRNAs: Control and loss of control in human physiology and disease[J]World J Surg, 2009; 33:667.
8.
NelsonKM, WeissGJ. MicroRNAs and cancer: Past, present, and potential future[J]Mol Cancer Ther, 2008; 7:3655.
9.
SinghPK, BrandRE, MehlaK. MicroRNAs in pancreatic cancer metabolism. Nat Rev Gastroenterol Hepatol, 2012; 9:334.
10.
ChoWC. MicroRNAs: Potential biomarkers for cancer diagnosis, prognosis and targets for therapy. Int J Biochem Cell Biol, 2010; 42:1273.
11.
ChoWC. MicroRNAs in cancer - from research to therapy. Biochim Biophys Acta, 2010; 1805:209.
12.
LeeY, KimM, HanJet al.MicroRNA genes are transcribed by RNA polymerase II[J]EMBO J, 2004; 23:4051.
13.
CaiX, HagedornCH, CullenBR. Human microRNAs are processed from capped, polyadenylated transcripts that can also function as mRNAs[J]RNA, 2004; 10:1957.
GregoryRI, YanKP, AmuthanGet al.The Microprocessor complex mediates the genesis of microRNAs[J]Nature, 2004; 432:235.
18.
DenliAM, TopsBB, PlasterkRHet al.Processing of primary microRNAs by the Microprocessor complex[J]Nature, 2004; 432:231.
19.
YiR, QinY, MacaraIGet al.Exportin-5 mediates the nuclear export of pre-microRNAs and short hairpin RNAs[J]Genes Dev, 2003; 17:3011.
20.
LundE, GuttingerS, CaladoAet al.Nuclear export of microRNA precursors[J]Science, 2004; 303:95.
21.
BohnsackMT, CzaplinskiK, GorlichD. Exportin 5 is a RanGTP-dependent dsRNA-binding protein that mediates nuclear export of pre-miRNAs[J]RNA, 2004; 10:185.
ChendrimadaTP, GregoryRI, KumaraswamyEet al.TRBP recruits the Dicer complex to Ago2 for microRNA processing and gene silencing[J]Nature, 2005; 436:740.
HeL, HannonGJ. MicroRNAs: Small RNAs with a big role in gene regulation[J]Nat Rev Genet, 2004; 5:522.
27.
Mohammed AbbaHA. MicroRNAs as regulatory molecules in cancer a focus on models defining miRNA functions[J]Cancer Models, 2009; 6:13.
28.
WuL, FanJ, BelascoJG. MicroRNAs direct rapid deadenylation of mRNA[J]Proc Natl Acad Sci U S A, 2006; 103:4034.
29.
DongJ, ZhaoYP, ZhouLet al.Bcl-2 upregulation induced by miR-21 via a direct interaction is associated with apoptosis and chemoresistance in MIA PaCa-2 pancreatic cancer cells[J]Arch Med Res, 2011; 42:8.
30.
AllawiHT, DahlbergJE, OlsonSet al.Quantitation of microRNAs using a modified Invader assay[J]RNA, 2004; 10:1153.
31.
WangJ, YiX, TangHet al.Direct quantification of microRNA at low picomolar level in sera of glioma patients using a competitive hybridization followed by amplified voltammetric detection. Anal Chem, 2012; 84:6400.
32.
XiaQS, IshigakiY, SunLet al.[Effect of anti-cancer drugs on the expression of BIC/miR-155 in human pancreatic cancer PANC-1 cells]Zhonghua Yi Xue Za Zhi, 2010; 90:123Chinese.
33.
SunY, GregoryKJ, ChenNGet al.Rapid and direct microRNA quantification by an enzymatic luminescence assay. Anal Biochem, 2012; 429:11.
34.
BakerMB, BaoG, SearlesCD. In vitro quantification of specific microRNA using molecular beacons. Nucleic Acids Res, 2012; 40:e13.
35.
ZhangJ, LiZ, WangHet al.Ultrasensitive quantification of mature microRNAs by real-time PCR based on ligation of a ribonucleotide-modified DNA probe. Chem Commun (Camb), 2011; 47:9465.
36.
SunM, EstrovZ, JiYet al.Curcumin (diferuloylmethane) alters the expression profiles of microRNAs in human pancreatic cancer cells[J]Mol Cancer Ther, 2008; 7:464.
37.
SchmittgenTD, LivakKJ. Analyzing real-time PCR data by the comparative C(T) method[J]Nat Protoc, 2008; 3:1101.
JiangJ, LeeEJ, GusevYet al.Real-time expression profiling of microRNA precursors in human cancer cell lines[J]Nucleic Acids Res, 2005; 33:5394.
40.
OhuchidaK, MizumotoK, LinCet al.MicroRNA-10a is overexpressed in human pancreatic cancer and involved in its invasiveness partially via suppression of the HOXA1 Gene[J]Ann Surg Oncol, 2012; 19:2394.
RoldoC, MissiagliaE, HaganJPet al.MicroRNA expression abnormalities in pancreatic endocrine and acinar tumors are associated with distinctive pathologic features and clinical behavior[J]J Clin Oncol, 2006; 24:4677.
43.
VoliniaS, CalinGA, LiuCGet al.A microRNA expression signature of human solid tumors defines cancer gene targets[J]Proc Natl Acad Sci U S A, 2006; 103:2257.
44.
SzafranskaAE, DavisonTS, JohnJet al.MicroRNA expression alterations are linked to tumorigenesis and non-neoplastic processes in pancreatic ductal adenocarcinoma[J]Oncogene, 2007; 26:4442.
45.
PanarelliNC, ChenYT, ZhouXKet al.MicroRNA expression aids the preoperative diagnosis of pancreatic ductal adenocarcinoma[J]Pancreas, 2012; 41:685.
46.
BloomstonM, FrankelWL, PetroccaFet al.MicroRNA expression patterns to differentiate pancreatic adenocarcinoma from normal pancreas and chronic pancreatitis[J]JAMA, 2007; 297:1901.
47.
DillhoffM, LiuJ, FrankelWet al.MicroRNA-21 is overexpressed in pancreatic cancer and a potential predictor of survival[J]J Gastrointest Surg, 2008; 12:2171.
48.
YuJ, OhuchidaK, MizumotoKet al.MicroRNA, hsa-miR-200c, is an independent prognostic factor in pancreatic cancer and its upregulation inhibits pancreatic cancer invasion but increases cell proliferation[J]Mol Cancer, 2010; 9:169.
49.
ZhangY, LiM, WangHet al.Profiling of 95 microRNAs in pancreatic cancer cell lines and surgical specimens by real-time PCR analysis[J]World J Surg, 2009; 33:698.
50.
KongX, DuY, WangGet al.Detection of Differentially Expressed microRNAs in Serum of Pancreatic Ductal Adenocarcinoma Patients: miR-196a Could Be a Potential Marker for Poor Prognosis[J]Dig Dis Sci, 2011; 56:602.
51.
WangJ, ChenJ, ChangPet al.MicroRNAs in plasma of pancreatic ductal adenocarcinoma patients as novel blood-based biomarkers of disease[J]Cancer Prev Res (Phila), 2009; 2:807.
52.
XiaL, ZhangD, DuRet al.miR-15b and miR-16 modulate multidrug resistance by targeting BCL2 in human gastric cancer cells[J]Int J Cancer, 2008; 123:372.
53.
BhaumikD, ScottGK, SchokrpurSet al.Expression of microRNA-146 suppresses NF-kappaB activity with reduction of metastatic potential in breast cancer cells[J]Oncogene, 2008; 27:5643.
54.
HurstDR, EdmondsMD, ScottGKet al.Breast cancer metastasis suppressor 1 up-regulates miR-146, which suppresses breast cancer metastasis[J]Cancer Res, 2009; 69:1279.
55.
HabbeN, KoorstraJB, MendellJTet al.MicroRNA miR-155 is a biomarker of early pancreatic neoplasia[J]Cancer Biol Ther, 2009; 8:340.
56.
WangB, HsuSH, MajumderSet al.TGFbeta-mediated upregulation of hepatic miR-181b promotes hepatocarcinogenesis by targeting TIMP3[J]Oncogene, 2010; 29:1787.
57.
NamEJ, YoonH, KimSWet al.MicroRNA expression profiles in serous ovarian carcinoma[J]Clin Cancer Res, 2008; 14:2690.
58.
AdamL, ZhongM, ChoiWet al.miR-200 expression regulates epithelial-to-mesenchymal transition in bladder cancer cells and reverses resistance to epidermal growth factor receptor therapy[J]Clin Cancer Res, 2009; 15:5060.
59.
CiafreSA, GalardiS, MangiolaAet al.Extensive modulation of a set of microRNAs in primary glioblastoma[J]Biochem Biophys Res Commun, 2005; 334:1351.
60.
HeH, JazdzewskiK, LiWet al.The role of microRNA genes in papillary thyroid carcinoma[J]Proc Natl Acad Sci U S A, 2005; 102:19075.
61.
CalinGA, FerracinM, CimminoAet al.A MicroRNA signature associated with prognosis and progression in chronic lymphocytic leukemia[J]N Engl J Med, 2005; 353:1793.
62.
YanaiharaN, CaplenN, BowmanEet al.Unique microRNA molecular profiles in lung cancer diagnosis and prognosis[J]Cancer Cell, 2006; 9:189.
63.
ChangTC, WentzelEA, KentOAet al.Transactivation of miR-34a by p53 broadly influences gene expression and promotes apoptosis[J]Mol Cell, 2007; 26:745.
64.
JiQ, HaoX, ZhangMet al.MicroRNA miR-34 inhibits human pancreatic cancer tumor-initiating cells[J]PLoS One, 2009; 4:e6816.
65.
YuS, LuZ, LiuCet al.miRNA-96 suppresses KRAS and functions as a tumor suppressor gene in pancreatic cancer[J]Cancer Res, 2010; 70:6015.
66.
OlieRA, HafnerC, KuttelRet al.Bcl-2 and bcl-xL antisense oligonucleotides induce apoptosis in melanoma cells of different clinical stages[J]J Invest Dermatol, 2002; 118:505.
67.
CroceCM. Causes and consequences of microRNA dysregulation in cancer[J]Nat Rev Genet, 2009; 10:704.
68.
ParkJK, LeeEJ, EsauCet al.Antisense inhibition of microRNA-21 or -221 arrests cell cycle, induces apoptosis, and sensitizes the effects of gemcitabine in pancreatic adenocarcinoma[J]Pancreas, 2009; 38:e190.
69.
MoriyamaT, OhuchidaK, MizumotoKet al.MicroRNA-21 modulates biological functions of pancreatic cancer cells including their proliferation, invasion, and chemoresistance[J]Mol Cancer Ther, 2009; 8:1067.
70.
BurkU, SchubertJ, WellnerUet al.A reciprocal repression between ZEB1 and members of the miR-200 family promotes EMT and invasion in cancer cells[J]EMBO Rep, 2008; 9:582.
71.
WangF, XueX, WeiJet al.hsa-miR-520h downregulates ABCG2 in pancreatic cancer cells to inhibit migration, invasion, and side populations[J]Br J Cancer, 2010; 103:567.
72.
YanH, WuJ, LiuWet al.MicroRNA-20a overexpression inhibited proliferation and metastasis of pancreatic carcinoma cells[J]Hum Gene Ther, 2010; 21:1723.
73.
LiY, VandenboomTN, WangZet al.miR-146a suppresses invasion of pancreatic cancer cells[J]Cancer Res, 2010; 70:1486.
74.
LinF, WangX, JieZet al.Inhibitory effects of miR-146b-5p on cell migration and invasion of pancreatic cancer by targeting MMP16[J]J Huazhong Univ Sci Technolog Med Sci, 2011; 31:509.
75.
LaurilaEM, SandstromS, RantanenLMet al.Both inhibition and enhanced expression of miR-31 lead to reduced migration and invasion of pancreatic cancer cells[J]Genes Chromosomes Cancer, 2012; 51:557.
76.
GiovannettiE, FunelN, PetersGJet al.MicroRNA-21 in pancreatic cancer: Correlation with clinical outcome and pharmacologic aspects underlying its role in the modulation of gemcitabine activity[J]Cancer Res, 2010; 70:4528.
77.
HwangJH, VoortmanJ, GiovannettiEet al.Identification of microRNA-21 as a biomarker for chemoresistance and clinical outcome following adjuvant therapy in resectable pancreatic cancer[J]PLoS One, 2010; 5:e10630.
78.
HeL, HeX, LimLPet al.A microRNA component of the p53 tumour suppressor network[J]Nature, 2007; 447:1130.
79.
ZenzT, MohrJ, ElderingEet al.miR-34a as part of the resistance network in chronic lymphocytic leukemia[J]Blood, 2009; 113:3801.
80.
AliS, AhmadA, BanerjeeSet al.Gemcitabine sensitivity can be induced in pancreatic cancer cells through modulation of miR-200 and miR-21 expression by curcumin or its analogue CDF[J]Cancer Res, 2010; 70:3606.
81.
SoubaniO, AliAS, LognaFet al.Re-expression of miR-200 by novel approaches regulates the expression of PTEN and MT1-MMP in pancreatic cancer. Carcinogenesis, 2012; 33:1563.
82.
HollyEA, ChalihaI, BracciPMet al.Signs and symptoms of pancreatic cancer: A population-based case-control study in the San Francisco Bay area[J]Clin Gastroenterol Hepatol, 2004; 2:510.
83.
XuQ, ZhangTP, ZhaoYP. Advances in early diagnosis and therapy of pancreatic cancer[J]Hepatobiliary Pancreat Dis Int, 2011; 10:128.
84.
SahaniDV, ShahZK, CatalanoOAet al.Radiology of pancreatic adenocarcinoma: Current status of imaging[J]J Gastroenterol Hepatol, 2008; 23:23.
85.
VolmarKE, VollmerRT, JowellPSet al.Pancreatic FNA in 1000 cases: A comparison of imaging modalities[J]Gastrointest Endosc, 2005; 61:854.
86.
LawrieCH, GalS, DunlopHMet al.Detection of elevated levels of tumour-associated microRNAs in serum of patients with diffuse large B-cell lymphoma[J]Br J Haematol, 2008; 141:672.
IorioMV, FerracinM, LiuCGet al.MicroRNA gene expression deregulation in human breast cancer[J]Cancer Res, 2005; 65:7065.
89.
CalinGA, LiuCG, SevignaniCet al.MicroRNA profiling reveals distinct signatures in B cell chronic lymphocytic leukemias[J]Proc Natl Acad Sci U S A, 2004; 101:11755.
90.
MichaelMZ, O’ ConnorSM, van HolstPNet al.Reduced accumulation of specific microRNAs in colorectal neoplasia[J]Mol Cancer Res, 2003; 1:882.
91.
SzafranskaAE, DoleshalM, EdmundsHSet al.Analysis of microRNAs in pancreatic fine-needle aspirates can classify benign and malignant tissues[J]Clin Chem, 2008; 54:1716.
92.
BauerAS, KellerA, CostelloEet al.Diagnosis of pancreatic ductal adenocarcinoma and chronic pancreatitis by measurement of microRNA abundance in blood and tissue. PLoS One, 2012; 7:e34151.
93.
AnsariD, ChenBC, DongLet al.Pancreatic cancer: translational research aspects and clinical implications. World J Gastroenterol, 2012; 18:1417.
94.
PiepoliA, TavanoF, CopettiMet al.Mirna expression profiles identify drivers in colorectal and pancreatic cancers. PLoS One, 2012; 7:e33663.
95.
JiaoLR, FramptonAE, JacobJet al.MicroRNAs targeting oncogenes are down-regulated in pancreatic malignant transformation from benign tumors. PLoS One, 2012; 7:e32068.
96.
CordelierP, TorrisaniJ. MicroRNAs in Pancreatic Cancer: Potential Interests as Biomarkers and Therapeutic Tools. ChoWC. MicroRNAs in Cancer Translational Research. New York: Springer, 2011; 287.
97.
FramptonAE, KrellJ, JacobJet al.microRNAs as markers of survival and chemoresistance in pancreatic ductal adenocarcinoma. Expert Rev Anticancer Ther, 2011; 11:1837.
98.
AlbulescuR, NeaguM, AlbulescuLet al.Tissular and soluble miRNAs for diagnostic and therapy improvement in digestive tract cancers. Expert Rev Mol Diagn, 2011; 11:101.
99.
GreitherT, GrocholaLF, UdelnowAet al.Elevated expression of microRNAs 155, 203, 210 and 222 in pancreatic tumors is associated with poorer survival[J]Int J Cancer, 2010; 126:73.
100.
HanounN, DelpuY, SuriawinataAet al.The silencing of microRNA 148a production by DNA hypermethylation is an early event in pancreatic carcinogenesis[J]Clin Chem, 2010; 56:1107.
101.
GogginsM. Identifying molecular markers for the early detection of pancreatic neoplasia[J]Semin Oncol, 2007; 34:303.
102.
GoldDV, ModrakDE, YingZet al.New MUC1 serum immunoassay differentiates pancreatic cancer from pancreatitis[J]J Clin Oncol, 2006; 24:252.
103.
LiuJ, GaoJ, DuYet al.Combination of plasma microRNAs with serum CA19-9 for early detection of pancreatic cancer[J]Int J Cancer, 2012; 131:683.
104.
LiuR, ChenX, DuYet al.Serum microRNA expression profile as a biomarker in the diagnosis and prognosis of pancreatic cancer[J]Clin Chem, 2012; 58:610.
105.
HoAS, HuangX, CaoHet al.Circulating miR-210 as a Novel Hypoxia Marker in Pancreatic Cancer[J]Transl Oncol, 2010; 3:109.
106.
FireA, XuS, MontgomeryMKet al.Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans[J]Nature, 1998; 391:806.
107.
ElbashirSM, HarborthJ, LendeckelWet al.Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells[J]Nature, 2001; 411:494.
108.
BorelF, KonstantinovaP, JansenPL. Diagnostic and therapeutic potential of miRNA signatures in patients with hepatocellular carcinoma[J]J Hepatol, 2012; 56:1371.
109.
MorrisseyDV, LockridgeJA, ShawLet al.Potent and persistent in vivo anti-HBV activity of chemically modified siRNAs[J]Nat Biotechnol, 2005; 23:1002.
110.
FedorovY, AndersonEM, BirminghamAet al.Off-target effects by siRNA can induce toxic phenotype[J]RNA, 2006; 12:1188.
111.
TsudaN, IshiyamaS, LiYet al.Synthetic microRNA designed to target glioma-associated antigen 1 transcription factor inhibits division and induces late apoptosis in pancreatic tumor cells[J]Clin Cancer Res, 2006; 12:6557.
MaY, YuS, ZhaoWet al.miR-27a regulates the growth, colony formation and migration of pancreatic cancer cells by targeting Sprouty2[J]Cancer Lett, 2010; 298:150.
114.
PatersonEL, KolesnikoffN, GregoryPAet al.The microRNA-200 family regulates epithelial to mesenchymal transition[J]Sci World J, 2008; 8:901.
115.
TorrisaniJ, BournetB, du RieuMCet al.let-7 MicroRNA transfer in pancreatic cancer-derived cells inhibits in vitro cell proliferation but fails to alter tumor progression[J]Hum Gene Ther, 2009; 20:831.
