Skip to main content
Top
Published in: Pathology & Oncology Research 4/2013

01-10-2013 | Research

MicroRNA-424-5p Suppresses the Expression of SOCS6 in Pancreatic Cancer

Authors: Kemin Wu, Guohuang Hu, Xin He, Peng Zhou, Jian Li, Bin He, Weijia Sun

Published in: Pathology & Oncology Research | Issue 4/2013

Login to get access

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.
Literature
2.
3.
go back to reference Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ (2009) Cancer statistics, 2009. CA Cancer J Clin 59:225PubMedCrossRef Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ (2009) Cancer statistics, 2009. CA Cancer J Clin 59:225PubMedCrossRef
5.
go back to reference Cameron JL, Riall TS, Coleman J, Belcher KA (2006) One thousand consecutive pancreaticoduodenectomies. Ann Surg 244:10PubMedCrossRef Cameron JL, Riall TS, Coleman J, Belcher KA (2006) One thousand consecutive pancreaticoduodenectomies. Ann Surg 244:10PubMedCrossRef
6.
go back to reference 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 91:586PubMedCrossRef 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 91:586PubMedCrossRef
8.
go back to reference 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 435:834PubMedCrossRef 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 435:834PubMedCrossRef
10.
go back to reference 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:e8003PubMedCrossRef 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:e8003PubMedCrossRef
11.
go back to reference Kozomara A, Griffiths-Jones S (2011) miRBase: integrating microRNA annotation and deep-sequencing data. Nucleic Acids Res 39:D152PubMedCrossRef Kozomara A, Griffiths-Jones S (2011) miRBase: integrating microRNA annotation and deep-sequencing data. Nucleic Acids Res 39:D152PubMedCrossRef
12.
go back to reference 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 29:919PubMedCrossRef 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 29:919PubMedCrossRef
13.
go back to reference 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:e29671PubMedCrossRef 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:e29671PubMedCrossRef
14.
go back to reference 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 130:1607PubMedCrossRef 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 130:1607PubMedCrossRef
15.
go back to reference 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 39:1880PubMedCrossRef 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 39:1880PubMedCrossRef
16.
go back to reference 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 43:358PubMedCrossRef 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 43:358PubMedCrossRef
17.
go back to reference 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 120:1046PubMedCrossRef 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 120:1046PubMedCrossRef
18.
go back to reference 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 288:75PubMedCrossRef 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 288:75PubMedCrossRef
19.
go back to reference 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 360:333PubMedCrossRef 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 360:333PubMedCrossRef
20.
go back to reference 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 68:246PubMedCrossRef 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 68:246PubMedCrossRef
21.
go back to reference 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 10:178PubMedCrossRef 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 10:178PubMedCrossRef
22.
go back to reference 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 279:12249PubMedCrossRef 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 279:12249PubMedCrossRef
23.
go back to reference 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 22:4567PubMedCrossRef 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 22:4567PubMedCrossRef
24.
go back to reference 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 79:355PubMedCrossRef 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 79:355PubMedCrossRef
25.
go back to reference Mardin WA, Mees ST (2009) MicroRNAs: novel diagnostic and therapeutic tools for pancreatic ductal adenocarcinoma? Ann Surg Oncol 16:3183PubMedCrossRef Mardin WA, Mees ST (2009) MicroRNAs: novel diagnostic and therapeutic tools for pancreatic ductal adenocarcinoma? Ann Surg Oncol 16:3183PubMedCrossRef
26.
go back to reference Rachagani S, Kumar S, Batra SK (2010) MicroRNA in pancreatic cancer, pathological, diagnostic and therapeutic implications. Cancer Lett 292:8PubMedCrossRef Rachagani S, Kumar S, Batra SK (2010) MicroRNA in pancreatic cancer, pathological, diagnostic and therapeutic implications. Cancer Lett 292:8PubMedCrossRef
27.
go back to reference 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 11:50PubMedCrossRef 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 11:50PubMedCrossRef
28.
go back to reference 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 114:3255PubMedCrossRef 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 114:3255PubMedCrossRef
29.
go back to reference 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 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
30.
go back to reference 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 48:1069PubMedCrossRef 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 48:1069PubMedCrossRef
31.
go back to reference 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 24:460PubMedCrossRef 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 24:460PubMedCrossRef
32.
go back to reference 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 10:595CrossRef 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 10:595CrossRef
33.
go back to reference 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 104:19849PubMedCrossRef 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 104:19849PubMedCrossRef
34.
go back to reference Krebs DL, Hilton DJ (2000) SOCS: physiological suppressors of cytokine signaling. J Cell Sci 113:2813PubMed Krebs DL, Hilton DJ (2000) SOCS: physiological suppressors of cytokine signaling. J Cell Sci 113:2813PubMed
35.
go back to reference 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 321:1801–1806PubMedCrossRef 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 321:1801–1806PubMedCrossRef
Metadata
Title
MicroRNA-424-5p Suppresses the Expression of SOCS6 in Pancreatic Cancer
Authors
Kemin Wu
Guohuang Hu
Xin He
Peng Zhou
Jian Li
Bin He
Weijia Sun
Publication date
01-10-2013
Publisher
Springer Netherlands
Published in
Pathology & Oncology Research / Issue 4/2013
Print ISSN: 1219-4956
Electronic ISSN: 1532-2807
DOI
https://doi.org/10.1007/s12253-013-9637-x

Other articles of this Issue 4/2013

Pathology & Oncology Research 4/2013 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine