Abstract
MicroRNAs (miRNAs) are a group of small non-coding RNA molecules predicted to control the activity of about 30 % of all protein-coding genes in mammals. The expression of microRNA-424-5p (miR-424-5p) has been shown to vary in multiple hematological and solid organ malignancies, such as pancreatic cancer. This study aimed to characterize the function of upregulated miR-424-5p in pancreatic cancer and show how downstream suppressor of cytokine-induced signaling 6 (SOCS6) is negatively regulated by miR-424-5p. MiR-424-5p and SOCS6 expression was detected using quantitative real-time PCR (qRT-PCR) in pancreatic cancer tissues and adjacent non-tumorous ductal epithelium tissues. Luciferase reporter assays were used to assess SOCS6 as a _target of miR-424-5p. The downstream effect of SOCS6 was measured by qRT-PCR after miR-424-5p inhibition and SOCS6 upregulation. The functions of miR-424-5p in vitro in pancreatic cancer cells were measured by migration and invasion assays and flow cytometry. Results suggested miR-424-5p was significantly upregulated in pancreatic cancer and suppress the expression of SOCS6, and miR-424-5p increased proliferation, migration and invasion of pancreatic cancer cells, while inhibited cell apoptosis. It was concluded that miR-424-5p is frequently upregulated in pancreatic cancer and modulates ERK1/2 signaling pathway by negatively regulating SOCS6.
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Li D, Xie K, Wolff R, Abbruzzese JL (2004) Pancreatic cancer. Lancet 363:1049
Guo X, Cui Z (2005) Current diagnosis and treatment of pancreatic cancer in China. Pancreas 31:13
Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ (2009) Cancer statistics, 2009. CA Cancer J Clin 59:225
Jemal A, Siegel R, Xu J, Ward E (2010) Cancer statistics, 2010. CA Cancer J Clin 60:277
Cameron JL, Riall TS, Coleman J, Belcher KA (2006) One thousand consecutive pancreaticoduodenectomies. Ann Surg 244:10
Wagner M, Redaelli C, Lietz M, Seiler CA, Friess H, Buchler MW (2004) Curative resection is the single most important factor determining outcome in patients with pancreatic adenocarcinoma. Br J Surg 91:586
Bartel DP (2004) MicroRNA’s: genomics biogenesis, mechanism, and function. Cell 116:281
Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J, Peck D, Sweet-Cordero A, Ebert BL, Mak RH, Ferrando AA, Downing JR, Jacks T, Horvitz HR, Golub TR (2005) MicroRNA expression profiles classify human cancers. Nature 435:834
Garzon R, Calin GA, Croce CM (2009) MicroRNAs in cancer. Annu Rev Med 60:167
Navon R, Wang H, Steinfeld I, Tsalenko A, Ben-Dor A, Yakhini Z (2009) Novel rank-based statistical methods reveal microRNAs with differential expression in multiple cancer types. PLoS One 4:e8003
Kozomara A, Griffiths-Jones S (2011) miRBase: integrating microRNA annotation and deep-sequencing data. Nucleic Acids Res 39:D152
Wang X, Wang J, Ma H, Zhang J, Zhou X (2012) Downregulation of miR-195 correlates with lymph node metastasis and poor prognosis in colorectal cancer. Med Oncol 29:919
Donnem T, Fenton CG, Lonvik K, Berg T, Eklo K, Andersen S, Stenvold H, Al-Shibli K, Al-Saad S, Bremnes RM, Busund LT (2012) MicroRNA signatures in tumor tissue related to angiogenesis in non-small cell lung cancer. PLoS One 7:e29671
Chen X, Hu H, Guan X, Xiong G, Wang Y, Wang K, Li J, Xu X, Yang K, Bai Y (2012) CpG island methylation status of miRNAs in esophageal squamous cell carcinoma. Int J Cancer 130:1607
Imig J, Motsch N, Zhu JY, Barth S, Okoniewski M, Reineke T, Tinguely M, Faggioni A, Trivedi P, Meister G, Renner C, Grässer FA (2011) microRNA profiling in Epstein-Barr virus-associated B-cell lymphoma. Nucleic Acids Res 39:1880
Shen Y, Li Y, Ye F, Wang F, Wan X, Lu W, Xie X (2011) Identification of miR-23a as a novel microRNA normalizer for relative quantification in human uterine cervical tissues. Exp Mol Med 43:358
Lee EJ, Gusev Y, Jiang J, Nuovo GJ, Lerner MR, Frankel WL, Morgan DL, Postier RG, Brackett DJ, Schmittgen TD (2007) Expression profiling identifies microRNA signature in pancreatic cancer. Int J Cancer 120:1046
Lai RH, Hsiao YW, Wang MJ, Lin HY, Wu CW, Chi CW, Li AF, Jou YS, Chen JY (2010) SOCS6, down-regulated in gastric cancer, inhibits cell proliferation and colony formation. Cancer Lett 288:75
Hwang MN, Min CH, Kim HS, Lee H, Yoon KA, Park SY, Lee ES, Yoon S (2007) The nuclear localization of SOCS6 requires the n-terminal region and negatively regulates Stat3 protein levels. Biochem Biophys Res Commun 360:333
Storojeva I, Boulay JL, Ballabeni P, Buess M, Terracciano L, Laffer U, Mild G, Herrmann R, Rochlitz C (2005) Prognostic and predictive relevance of DNAM-1, SOCS6 and CADH-7 genes on chromosome 18q in colorectal cancer. Oncology 68:246
Sasi W, Jiang WG, Sharma A, Mokbel K (2010) Higher expression levels of SOCS 1,3,4,7 are associated with earlier tumour stage and better clinical outcome in human breast cancer. BMC Cancer 10:178
Bayle J, Letard S, Frank R, Dubreuil P, De Sepulveda P (2004) Suppressor of cytokine signaling 6 associates with KIT and regulates KIT receptor signaling. J Biol Chem 279:12249
Krebs DL, Uren RT, Metcalf D, Rakar S, Zhang JG, Starr R, De Souza DP, Hanzinikolas K, Eyles J, Connolly LM, Simpson RJ, Nicola NA, Nicholson SE, Baca M, Hilton DJ, Alexander WS (2002) SOCS-6 binds to insulin receptor substrate 4, and mice lacking the SOCS-6 gene exhibit mild growth retardation. Mol Cell Biol 22:4567
Boucher MJ, Morisset J, Vachon PH, Reed JC, Lainé J, Rivard N (2000) MEK/ERK signaling pathway regulates the expression of Bcl-2, Bcl-X(L), and Mcl-1 and promotessurvival of human pancreatic cancer cells. J Cell Biochem 79:355
Mardin WA, Mees ST (2009) MicroRNAs: novel diagnostic and therapeutic tools for pancreatic ductal adenocarcinoma? Ann Surg Oncol 16:3183
Rachagani S, Kumar S, Batra SK (2010) MicroRNA in pancreatic cancer, pathological, diagnostic and therapeutic implications. Cancer Lett 292:8
Wang YX, Zhang XY, Zhang BF, Yang CQ, Chen XM, Gao HJ (2010) Initial study of microRNA expression profiles of colonic cancer without lymph node metastasis. J Dig Dis 11:50
Pallasch CP, Patz M, Park YJ, Hagist S, Eggle D, Claus R, Debey-Pascher S, Schulz A, Frenzel LP, Claasen J, Kutsch N, Krause G, Mayr C, Rosenwald A, Plass C, Schultze JL, Hallek M, Wendtner CM (2009) miRNA deregulation by epigenetic silencing disrupts suppression of the oncogene PLAG1 in chronic lymphocytic leukemia. Blood 114:3255
Xu J, Li Y, Wang F, Wang X, Cheng B, Ye F, Xie X, Zhou C, Lu W (2012) Suppressed miR-424 expression via upregulation of _target gene Chk1 contributes to the progression of cervical cancer. Oncogene. doi:10.1038/onc.2012.121
Fulci V, Colombo T, Chiaretti S, Messina M, Citarella F, Tavolaro S, Guarini A, Foà R, Macino G (2009) Characterization of B- and T-lineage acute lymphoblastic leukemia by integrated analysis of MicroRNA and mRNA expression profiles. Genes Chromosomes Cancer 48:1069
Forrest AR, Kanamori-Katayama M, Tomaru Y, Lassmann T, Ninomiya N, Takahashi Y, de Hoon MJ, Kubosaki A, Kaiho A, Suzuki M, Yasuda J, Kawai J, Hayashizaki Y, Hume DA, Suzuki H (2010) Induction of microRNAs, mir-155, mir-222, miR-424 and mir-503, promotes monocytic differentiation through combinatorial regulation. Leukemia 24:460
Schmeier S, MacPherson CR, Essack M, Kaur M, Schaefer U, Suzuki H, Hayashizaki Y, Bajic VB (2009) Deciphering the transcriptional circuitry of microRNA genes expressed during human monocytic differentiation. BMC Genom 10:595
Rosa A, Ballarino M, Sorrentino A, Sthandier O, De Angelis FG, Marchioni M, Masella B, Guarini A, Fatica A, Peschle C, Bozzoni I (2007) The interplay between the master transcription factor PU.1 and miR-424 regulates human monocyte/macrophage differentiation. Proc Natl Acad Sci U S A 104:19849
Krebs DL, Hilton DJ (2000) SOCS: physiological suppressors of cytokine signaling. J Cell Sci 113:2813
Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Kamiyama H, Jimeno A, Hong SM, Fu B, Lin MT, Calhoun ES, Kamiyama M, Walter K, Nikolskaya T, Nikolsky Y, Hartigan J, Smith DR, Hidalgo M, Leach SD, Klein AP, Jaffee EM, Goggins M, Maitra A, Iacobuzio-Donahue C, Eshleman JR, Kern SE, Hruban RH, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, Kinzler KW (2008) Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 321:1801–1806
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Wu, K., Hu, G., He, X. et al. MicroRNA-424-5p Suppresses the Expression of SOCS6 in Pancreatic Cancer. Pathol. Oncol. Res. 19, 739–748 (2013). https://doi.org/10.1007/s12253-013-9637-x
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DOI: https://doi.org/10.1007/s12253-013-9637-x