Abstract
Pancreatic cancer is one of the most aggressive malignancies with a very poor prognosis, partially due to its very low accessibility to resection and resistance to chemoradiotherapy. As such, it is reasonable to find more effective, specific therapies and the related therapeutic targets. The identification of certain genes contributing to the tumorigenesis and poor prognosis provides the specific targets for efficient silencing by RNA interference (RNAi). As a powerful tool to suppress gene expression in mammalian cells, RNAi can be directed against pancreatic cancer through various pathways, including the inhibition of overexpressed oncogenes, suppression of tumor growth, metastasis and enhancement of apoptosis. In combination with chemoradiotherapy agents, RNAi can also attenuate the chemoradiation resistance of pancreatic cancer. In addition, RNAi has been used to define the ‘loss of function’ of endogenous genes in pancreatic cancer. This review provides a brief introduction to recent developments of RNAi applications in pancreatic cancer studies and suggestions for further exploration. It substantially demonstrates that RNAi holds a promising therapeutic potential as a future treatment for pancreatic cancer.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, Hickey H et al. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med 2004; 350: 1200–1210.
Wray CJ, Ahmad SA, Matthews JB, Lowy AM . Surgery for pancreatic cancer: recent controversies and current practice. Gastroenterology 2005; 128: 1626–1641.
Jemal A, Murray T, Ward E, Samuels A, Tiwari RC, Ghafoor A et al. Cancer statistics, 2005. CA Cancer J Clin 2005; 55: 10–30.
de Braud F, Coscinu S, Gatta G . Cancer of pancreas. Crit Rev Oncol Hematol 2004; 50: 147–155.
Cowgill SM, Muscarella P . The genetics of pancreatic cancer. Am J Surg 2003; 186: 279–286.
Kopper L, Zalatnai A, Timar J . Genomics of pancreatic cancer: Does it make improvement in diagnosis, prognosis and therapy? Pathol Oncol Res 2005; 11: 69–73.
Jaffee EM, Hruban RH, Canto M, Kern SE . Focus on pancreas cancer. Cancer Cell 2002; 2: 25–28.
Furukawa T, Horii A . Molecular pathology of pancreatic cancer: in request of tumor suppressor genes. Pancreas 2004; 28: 253–256.
Couzin J . Break through of the year. Small RNAs make big splash. Science 2002; 298: 2296–2297.
Izquierdo M . Short interfering RNAs as a tool for cancer gene therapy. Cancer Gene Ther 2005; 12: 217–227.
Fire A, Xu S, Montgomery MK, Kostas SA, Driver SE, Mello CC . Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 1998; 391: 806–811.
Bernstein E, Caudy AA, Hammond SM, Hannon GJ . Role for a bidentate ribonuclease in the initiation step of RNA interference. Nature 2001; 409: 363–366.
Karagiannis TC, El-Osta A . RNA interference and potential therapeutic applications of short interfering RNAs. Cancer Gene Ther 2005; 12: 787–795.
Shankar P, Manjunath N, Lieberman J . The prospect of silencing disease using RNA interference. JAMA 2005; 293: 1367–1373.
Bertrand JR, Pottier M, Vekris A, Opolon P, Maksimenko A, Malvy C . Comparison of antisense oligonucleotides and siRNA in cell culture and in vivo. Biochem Biophys Res Commun 2002; 296: 100–1004.
Elbashir SM, Harborth J, Lendeckel W, Yalcin A, Weber K, Tuschl T . Duplexes of 21-nucleotide RNAs mediates RNA interference in cultured mammalian cells. Nature 2002; 411: 494–498.
Martinez LA, Naguibneva I, Lehrmann H, Vervisch A, Tchenio T, Lozano G et al. Synthetic small inhibiting RNAs; efficient tools to inactivate oncogenic mutations and restore p53 pathways. Proc Natl Acad Sci USA 2002; 99: 14849–14854.
Rubinson DA, Dillon CP, Kwiatkowski AV, Sievers C, Yang L, Kopinja J et al. A lentivirus-based system to functionally silence genes in primary mammalian cells, stem cells and transgenic mice by RNA interference. Nat Genet 2003; 33: 401–406.
Rozenblum E, Schutte M, Goggins M, Hahn SA, Panzer S, Zahurak M et al. Tumor-suppressive pathways in pancreatic carcinoma. Cancer Res 1997; 57: 1731–1734.
Ishimura N, Yamasawa K, Karim Rumi MA, Kadowaki Y, Ishihara S, Amano Y et al. BRAF and K-Ras gene mutations in human pancreatic cancers. Cancer Lett 2002; 199: 169–173.
Brummelkamp TR, Bernards R, Agami R . Stable suppression of tumorigenicity by virus-mediated RNA interference. Cancer Cell 2002; 2: 243–247.
Fleming JB, Shen GL, Holloway SE, Davis M, Brekken RA . Molecular consequences of silencing mutant K-Ras knockdown. Mol Cancer Res 2005; 3: 413–423.
Jantscheff P, Terracciano L, Lowy A, Glatz-Krieger K, Grunert F, Micheel B et al. Expression of CEACAM6 in resectable colorectal cancer: a factor of independent prognostic significance. J Clin Oncol 2003; 21: 3638–3646.
Ilantzis C, DeMarte L, Screaton RA, Stanners CP . Deregulated expression of the human tumor maker CEA and CEA family member CEACAM6 disrupts tissue architecture and blocks coloncyte differentiation. Neoplasia 2002; 4: 151–163.
Duxbury MS, Ito H, Zinner MJ, Ashley SW, Whang EE . CEACAM6 gene silencing impairs anoikis resistance and in vivo metastatic ability of pancreatic adenocarcinoma cells. Oncogene 2004; 23: 465–473.
Duxbury MS, Matros E, Ito H, Zinner MJ, Ashley SW, Whang EE . Systemic siRNA –mediated gene silencing. A new approach to targeted therapy of cancer. Ann Surg 2004; 240: 667–676.
Versteeg HH, Spek CA, Peppelenbosch MP, Richel DJ . Tissue Factor and cancer metastasis: The role of intracellular and extracellular signaling pathways. Mol Med 2004; 10: 6–11.
Kakkar AK, Lemoine NR, Scully MF, Tebbutt S, Williamson RC . Tissue factor expression correlates with histological grade in human pancreatic cancer. Br J Surg 1995; 82: 1101–1104.
Nitori N, Ino Y, Nakanishi Y, Yamada T, Honda K, Yanagihara K et al. Prognostic significance of Tissue Factor in pancreatic adenocarcinoma. Clin Cancer Res 2005; 11: 2531–2539.
Nakasaki T, Wada h, Shigemori C, Miki C, Gabazza EC, Nobori T et al. Expression of tissue factor and vascular endothelial growth is associated with angiogenesis in colorectal cancer. Am J Hematol 2002; 69: 247–254.
Poon RT, Lau CP, Ho JW, Yu WC, Fan ST, Wong J . Tissue factor expression correlates with tumor angiogenesis and invasiveness in human hepatocellular carcinoma. Clin Cancer Res 2003; 9: 5339–5345.
Ohta S, Wada H, Nakazaki T, Maeda Y, Nobori T, Shiku H et al. Expression of tissue factor is associated with clinical features and angiogenesis in prostate cancer. Anticancer Res 2002; 22: 2991–2996.
Sulman EP, Tang XX, Allen C, Biegel JA, Pleasure DE, Brodeur GM et al. ECK, a human EPH-related gene, maps to 1p36.1, a common region of alternation in human cancer. Genomics 1997; 40: 371–374.
Zelinski DP, Zantek ND, Stewart JC, Irizarry AR, Kinch MS . EphA2 overexpression cause tumorigenesis of mammary epithelial cells. Cancer Res 2004; 10: 5145–5150.
Thaker PH, Deavers M, Celestino J, Thornton A, Fletcher MS, Landen CN et al. EphA2 expression is associated with aggressive feature in ovarian carcinoma. Clin Cancer Res 2004; 10: 5145–5150.
Duxbury MS, Ito H, Zinner MJ, Ashley SW, Whang EE . EphA2: a determinant of malignant cellular behavior and a potential therapeutic target in pancreatic adenocarcinoma. Oncogene 2004; 23: 1448–1456.
Landen Jr CN, Chavez-Reyes A, Bucana C, Schmandt R, Deavers MT, Lopez-Berestein G et al. Therapeutic EphA2 gene targeting in vivo using neutral liposomal small interfering RNA delivery. Cancer Res 2005; 65: 6910–6918.
Haber RS, Rathan A, Weiser KR, Pritsker A, Itzkowitz SH, Bodian C et al. GLUT1 glucose transporter expression in colorectal carcinoma: a marker for poor prognosis. Cancer 1998; 83: 34–40.
Kalir T, Wang BY, Goldfisher M, Haber RS, Reder I, Demopoulos R et al. Immunohistochemical staining of GLUT1 in benign, borderline, and malignant ovarian epithelia. Cancer 2002; 94: 1078–1082.
Chandler JD, Williams ED, Slavin JL, Best JD, Rogers S . Expression and localization of GLUT1 an GLUT12 in prostate carcinoma. Cancer 2003; 97: 2035–2042.
Kawamura T, Kusakabe T, Sugino T, Watanabe K, Fukuda T, Nashimoto A et al. Expression of glucose transporter-1 in human gastric carcinoma: association with tumor aggressiveness, metastasis and patient survival. Cancer 2002; 92: 634–641.
Ito H, Duxbury M, Zinner MJ, Ashley SW, Whang EE . Glucose transporter-1 gene expression is associated with pancreatic cancer invasiveness and MMP-2 activity. Surgery 2004; 136: 548–556.
Liu B, Staren ED, Iwamura T, Appert HE, Howard JM . Mechanisms of taxotere-related drug resistance in pancreatic carcinoma. J Surg Res 2002; 99: 179–186.
Westphal S, Kalthoof H . Apoptosis: targets in pancreatic cancer. Mol Cancer 2003; 2: 6–38.
Nieth C, Priebsch A, Stege A, Lage H . Modulation of the classical multidrug resistance(MDR) phenotype by RNA interference(RNAi). FEBS Lett 2003; 545: 144–150.
Xu D, Kang H, Fisher M, Juliano RL . Strategies for inhibition of MDR1 gene expression. Mol Pharmacol 2004; 66: 268–275.
Wu H, Hait WN, Yang JM . Small interfering RNA-induced suppression of MDR1(P-glycoprotein) restores sensitivity to multidrug-resistant cancer cells. Cancer Res 2003; 63: 1515–1519.
Peng Z, Xiao Z, Wang Y, Liu P, Cai Y, Lu S et al. Reversal of P-glycoprotein-mediated multidrug resistance with small interference RNA(RNAi) in leukemia cells. Cancer Gene Ther 2004; 11: 707–712.
Yague E, Higgins CF, Raguz S . Complete reversal of multidrug resistance by stable expression of small interfering RNAs targeting MDR. Gene Therapy 2004; 11: 1170–1174.
Nachmias B, Ashhab Y, Ben-Yehuda D . The inhibitor of apoptosis protein family(IAPs): an emerging therapeutic target in cancer. Semin Cancer Biol 2004; 14: 231–243.
Yang L, Cao Z, Yan H, Wood WC . Coexistence of high levels of apoptosis signaling and inhibitor of apoptosis proteins in human tumor cells: Implication for cancer specific therapy. Cancer Res 2003; 63: 6815–6824.
Yagihashi A, Asanuma K, Tsuji N, Torigoe T, Sato N, Hirata K et al. Detection of anti-livin antibody in gastrointestinal cancer patients. Clin Chem 2003; 49: 1206–1208.
Kami K, Doi R, Koizumi M, Toyada E, Mori T, Ito D et al. Survivin expression is a prognostic marker in pancreatic cancer patients. Surgery 2004; 136: 443–448.
Asanuma K, Kobayashi D, Furuya D, Tsuji N, Yagihashi A, Watanabe N . A role for survivin in radioresistance of pancreatic cancer cells. Jpn J Cancer Res 2002; 93: 1057–1062.
Kami K, Doi R, Koizumi M, Toyoda E, Mori T, Ito D et al. Downregulation of survivin by siRNA diminishes radioresistance of pancreatic cancer cells. Surgery 2005; 138: 299–305.
Tsuji N, Asanuma K, Kobayashi D, Yagihashi A, Watanzbe N . Introduction of a survivin gene-specific small inhibitory RNA inhibits growth of pancreatic cancer cells. Anticancer Res 2005; 25: 3967–3972.
Crnkovic-Mertens I, Hoppe-Seyler F, Butz K . Induction of apoptosis in tumor by siRNA-medicated silencing of the livin/ML-IAP/KIAP gene. Oncogene 2003; 22: 8330–8336.
Mcmanus DC, Lefebvre CA, Cherton-Horvat G, St-Jean M, Kandimalla ER, Agrawal S et al. Loss of XIAP protein expression by RNAi and antisense approaches sensitizes cancer cells to functionally diverse chemotherapeutics. Oncogene 2004; 23: 8105–8117.
Ning S, Fuessel S, Kotzsch M, Kraemer K, Kappler M, Schmidt U et al. siRNA-mediated downregulation of survivin inhibits bladder cancer cell growth. Int J Oncol 2004; 25: 1065–1071.
Uchida H, Tanaka T, Sasaki K, Kato K, Dehari H, Ito Y et al. Adenovirus-mediated transfer of siRNA against survivin induced apoptosis and attenuated tumor growth in vitro and in vivo. Mol Ther 2004; 10: 162–171.
Crnkovic-Mertens I, Semzow J, Hoppe-Seyler F, Butz K . Isoform-specific silencing of the Livin gene by RNA interference defines Livin beta as key mediator of apoptosis inhibition in HeLa cells. J Mol Med 2006; 84: 232–240.
Yoganathan N, Yee A, Zhang Z, Leung D, Yan J, Fazli L et al. Integrin-linked kinase, a promising cancer therapeutic target: biochemical and biological properties. Pharmacol Ther 2002; 93: 233–242.
Ahmed N, Riley C, Oliva K, Stutt E, Rice GE, Quinn MA . Integrin-linked kinase expression increase with ovarian tumor grade and is sustained by peritoneal tumor fluid. J Pathol 2003; 211: 229–237.
Marotta A, Parhar K, Owen D, Dedhar S, Salh B . Characterisation of integrin-linked kinase signaling in sporadic human colon cancer. Br J Cancer 2003; 88: 1755–1762.
Ito R, Oue N, Zhu X, Yoshida K, Nakayama H, Yokozaki H et al. Expression of integrin-linked kinase is closely correlated with invasion and metastasis of gastric carcinoma. Virchows Arch 2003; 442: 118–123.
Graff JR, Deddens JA, Konicek BW, Colligan BM, Hurst BM, Cater HW et al. Integrin-linked kinase expression increase with prostate tumor grade. Clin Cancer Res 2002; 7: 1987–1991.
Dai DL, Makretsov N, Campos EI, Huang C, Zhou Y, Huntsman D et al. Increased expression of integrin-linked kinase is correlated with melanoma progression and poor patient survival. Clin Cancer Res 2003; 9: 4409–4414.
Yau CY, Wheeler JJ, Sutton KL, Hedley DW . Inhibition of integrin-linked kinase by a selective small molecule inhibitor., QLTO254, inhibits the PI3K/PKB/mTOR, stat3 and FKHR pathways and tumor growth, and enhances Gemcitabine-induced apoptosis in human orthotopic primary pancreatic cancer xenografts. Cancer Res 2005; 65: 1497–1504.
Duxbury MS, Ito H, Benoit E, Waseem T, Ashley SW, Whang EE . RNA interference demonstrates a novel role for integrin-linked kinase as a determinant of pancreatic adenocarcinoma cell gemcitabine chemoresistance. Clin Cancer Res 2005; 11: 3433–3438.
Jung CP, Motwani MV, Schwartz GK . Flavopiridol increase sensitization to gemcitabine in human gastrointestinal cancer cell lines and correlated with down-regulation of ribonucleotide reductase M2 subunit. Clin Cancer Res 2001; 7: 2527–2536.
Zhou BS, Tsai P, Ker R, Tsai J, Ho R, Yu J et al. Overexpression of transfected human ribonucleotide reductase M2 subunit in human cancer cells enhances their invasive potential. Clin Exp Metastasis 1998; 16: 43–49.
Duxbury MS, Ito H, Zinner MJ, Ashley SW, Whang EE . RNA interference targeting the M2 subunit of ribonucleotide reductase enhances pancreatic adenocarcinoma chemosensitivity to gemcitabine. Oncogene 2004; 23: 1539–1548.
Duxbury MS, Ito H, Benoit E, Zinner MJ, Ashley SW, Whang EE . Retrovirally mediated RNA interference targeting the M2 subunit of ribonucleotide reductase: A novel therapeutic strategy in pancreatic cancer. Surgery 2004; 136: 261–269.
Vankayalapati H, Bearss DJ, Saldanha JW, Munoz RM, Rojanala S, Von Hoff DD et al. Targeting Aurora2 kinase in oncogenesis: A structural bioinformatics approach to target validation and rational drug design. Mol Cancer Ther 2003; 2: 283–294.
Han H, Bearss DJ, Browne LW, Calauce R, Nagle RB, Von Hoff DD . Identification of differentially expressed genes in pancreatic cancer cells using cDNA microarray. Cancer Res 2002; 62: 2890–2896.
Hata T, Furukawa T, Sunamura M, Egawa S, Motoi F, Ohmura N et al. RNA interference targeting Auroka Kinase A suppresses tumor growth and enhances the taxane chemosensitivity in human pancreatic cancer cells. Cancer Res 2005; 65: 2899–2905.
Mclean GW, Carragher NO, Avizienyte E, Evans J, Brunton VG, Frame MC . The role of focal-adhesion kinase in cancer-a new therapeutic opportunity. Nat Rev Cancer 2005; 5: 505–515.
Recher C, Ysebaert L, Beyne-Rauzy O, Mansat-De Mas V, Ruidavets JB, Cariven P et al. Expression of focal adhesion kinase in acute myeloid leukemia is associated with enhanced blast migration, increased cellularity and poor prognosis. Cancer Res 2004; 64: 3191–3197.
Duxbury MS, Ito H, Benoit E, Zinner MJ, Ashley SW, Whang EE . RNA interference targeting focal adhesion kinase enhances pancreatic adenocarcinoma gemcitabine chemosensitivity. Biochem Biophys Res Commun 2003; 311: 786–792.
Golubovskaya VM, Gross S, Kaur AS, Wilson RI, Xu LH, Yang XH et al. Simultaneous inhibition of focal adhesion kinase and SRC enhances detachment of apoptosis in colon cancer cell lines. Mol Cancer Res 2003; 1: 755–764.
Duxbury MS, Ito H, Zinner MJ, Ashley SW, Whang EE . Focal adhesion kinase gene silencing promotes anoikis and suppresses metastasis of human pancreatic adenocarcinoma cells. Surgery 2004; 135: 555–560.
De Schrijver E, Brusselmans K, Heyns W, Verhoever G, Swinnen JV . RNA interference-mediated silencing of the fatty acid synthase attenuates growth and induced morphological changes and apoptosis of LNCaP prostate cancer cells. Cancer Res 2003; 63: 3799–3804.
Feagan-Shaw S, Ahmad N . Silencing of polo-like kinase (PIK) 1 via siRNA causes induction of apoptosis and impairment of mitosis machinery in human prostate cancer cells: implications for the treatment of prostate cancer. FASEB J 2005; 19: 611–613.
Wannenes F, Ciafre SA, Niola F, Frajese G, Farace MG . Vector-based RNA interference against vascular endothelial growth factor-A significantly limits vascularization and growth of prostate cancer in vivo. Cancer Gene Ther 2005; 12: 926–934.
Chen Z, Varney ML, Backora MW, Cowan K, Solheim Jc, Talmadge JE . Down-regulation of vascular endothelial cell growth factor-C expression using small interfering RNA vectors in mammary tumors inhibits tumor lymphangiogenesis and spontaneous metastasis and enhances survival. Cancer Res 2005; 65: 9004–9011.
Leung RKM, Whittaker PA . RNA interference: from gene silencing to gene-specific therapeutics. Pharmacol Ther 2005; 107: 222–239.
Jazag A, Ijichi H, Kanai F, Imamura T, Guleng B, Ohta M et al. Smad4 silencing in pancreatic cancer cell lines using stable RNA interference and gene expression profiles induced by transforming growth factor-β. Oncogene 2005; 24: 662–671.
Downward J . RNA interference-based genomics in cancer research –an introduction. Oncogene 2004; 23: 8334–8335.
Silva J, Chang K, Hannon GJ, Rivas FV . RNA interference-based functional genomics in mammalian cells: reverse genetics coming age. Oncogene 2004; 23: 8401–8409.
Bhattacharyya M, Lemoine NR . Gene therapy developments for pancreatic cancer. Best Pract Res Clin Gastroenterol 2006; 20: 285–298.
Caldas H, Holloway MP, Hall BM, Qualman SJ, Altura RA . Survivin-directed RNA interference cocktail is a potent suppressor of tumor growth in vivo. J Med Genet 2006; 43: 119–128.
Hemann MT, Fridman JS, Zilfou JT, Hernando E, paddison PJ, Cordon-Cardo C et al. An epi-allelic series of p53 hypomorphs created by stable RNAi produces distinct tumor phenotypes in vivo. Nat Genet 2003; 33: 396–400.
Kunath T, Gish G, Lickert H, Jones N, Pawson T, Rossant J . Transgenic RNA interference in ES cell-derived embryos recapitulates a genetic null phenotype. Nat Biotechnol 2003; 21: 559–561.
Lois C, Hong EJ, Pease S, Brown EJ, Baltimore D . Germline transmission and tissue-specific expressing of transgenes delivered by lentiviral vectors. Science 2002; 295: 868–872.
Acknowledgements
I thank Ken Mitchell and Becky Mitchell for editing this manuscript. This work was supported by the grants from the Department of Health, Shandong, PR China, (2005ZD03; 2003-34).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Chang, H. RNAi-mediated knockdown of target genes: a promising strategy for pancreatic cancer research. Cancer Gene Ther 14, 677–685 (2007). https://doi.org/10.1038/sj.cgt.7701063
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.cgt.7701063
Keywords
This article is cited by
-
RETRACTED ARTICLE: siRNA-participated chemotherapy: an efficient and specific therapeutic against gastric cancer
Journal of Cancer Research and Clinical Oncology (2013)
-
Influence of osteopontin short hairpin RNA on the proliferation and activity of rat vascular smooth muscle cells
Journal of Huazhong University of Science and Technology [Medical Sciences] (2009)