Skip to main content
Top
Published in: Cancer Cell International 1/2013

Open Access 01-12-2013 | Primary research

Up-regulation of miR-224 promotes cancer cell proliferation and invasion and predicts relapse of colorectal cancer

Authors: Guang-jun Zhang, He Zhou, Hua-xu Xiao, Yu Li, Tong Zhou

Published in: Cancer Cell International | Issue 1/2013

Login to get access

Abstract

Background

MicroRNAs (miRNAs) are small, non-coding RNAs that can function as oncogenes or tumor suppressors in human cancer. Abnormally expressed miR-224 was found to play a fundamental role in several types of cancer. The aim of this study was to investigate the prognostic and biological values of miR-224 in colorectal cancer (CRC).

Methods

Quantitative RT-PCR (qRT-PCR) was used to evaluate expression levels of miR-224. The postoperative survival rate was analyzed with Kaplan–Meier method. The roles of miR-224 in cell proliferation, migration and invasion were analyzed with pre-miR-224 transfected cells. In addition, the regulation of SMAD4 by miR-224 was evaluated by qRT-PCR, Western blotting and luciferase reporter assays.

Results

In the present study, we demonstrated that miR-224 was significantly up-regulated in CRC tissue samples and associated with disease relapse and a relative poorer disease-free survival rate. Moreover, ectopic expression of miR-224 potently promoted tumor cell proliferation, migration and invasion in vitro. Furthermore, the over-expression of miR-224 in CRC cell lines decreased SMAD4 expression at the translational level and decreased SMAD4-driven luciferase-reporter activity.

Conclusions

Our data suggest that miR-224 could play an oncogenic role in the cellular processes of CRC and represent a novel biomarker for tumor relapse of CRC patients.
Appendix
Available only for authorised users
Literature
1.
go back to reference Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, Thun MJ: Cancer statistics, 2008. CA Cancer J Clin. 2008, 58 (2): 71-96. 10.3322/CA.2007.0010.CrossRefPubMed Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, Thun MJ: Cancer statistics, 2008. CA Cancer J Clin. 2008, 58 (2): 71-96. 10.3322/CA.2007.0010.CrossRefPubMed
2.
go back to reference Kobayashi H, Mochizuki H, Sugihara K, Morita T, Kotake K, Teramoto T, Kameoka S, Saito Y, Takahashi K, Hase K: Characteristics of recurrence and surveillance tools after curative resection for colorectal cancer: a multicenter study. Surgery. 2007, 141 (1): 67-75. 10.1016/j.surg.2006.07.020.CrossRefPubMed Kobayashi H, Mochizuki H, Sugihara K, Morita T, Kotake K, Teramoto T, Kameoka S, Saito Y, Takahashi K, Hase K: Characteristics of recurrence and surveillance tools after curative resection for colorectal cancer: a multicenter study. Surgery. 2007, 141 (1): 67-75. 10.1016/j.surg.2006.07.020.CrossRefPubMed
3.
go back to reference Bartel DP: MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004, 116 (2): 281-297. 10.1016/S0092-8674(04)00045-5.CrossRefPubMed Bartel DP: MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004, 116 (2): 281-297. 10.1016/S0092-8674(04)00045-5.CrossRefPubMed
5.
go back to reference Munker R, Calin GA: MicroRNA profiling in cancer. Clin Sci (Lond). 2011, 121 (4): 141-158. 10.1042/CS20110005.CrossRef Munker R, Calin GA: MicroRNA profiling in cancer. Clin Sci (Lond). 2011, 121 (4): 141-158. 10.1042/CS20110005.CrossRef
7.
go back to reference Lee DY, Deng Z, Wang CH, Yang BB: MicroRNA-378 promotes cell survival, tumor growth, and angiogenesis by targeting SuFu and Fus-1 expression. Proc Natl Acad Sci USA. 2007, 104 (51): 20350-20355. 10.1073/pnas.0706901104.PubMedCentralCrossRefPubMed Lee DY, Deng Z, Wang CH, Yang BB: MicroRNA-378 promotes cell survival, tumor growth, and angiogenesis by targeting SuFu and Fus-1 expression. Proc Natl Acad Sci USA. 2007, 104 (51): 20350-20355. 10.1073/pnas.0706901104.PubMedCentralCrossRefPubMed
8.
go back to reference Paterson EL, Kazenwadel J, Bert AG, Khew-Goodall Y, Ruszkiewicz A, Goodall GJ: Down-regulation of the miRNA-200 family at the invasive front of colorectal cancers with degraded basement membrane indicates EMT is involved in cancer progression. Neoplasia. 2013, 15 (2): 180-191.PubMedCentralCrossRefPubMed Paterson EL, Kazenwadel J, Bert AG, Khew-Goodall Y, Ruszkiewicz A, Goodall GJ: Down-regulation of the miRNA-200 family at the invasive front of colorectal cancers with degraded basement membrane indicates EMT is involved in cancer progression. Neoplasia. 2013, 15 (2): 180-191.PubMedCentralCrossRefPubMed
9.
go back to reference Zhang GJ, Xiao HX, Tian HP, Liu ZL, Xia SS, Zhou T: Upregulation of microRNA-155 promotes the migration and invasion of colorectal cancer cells through the regulation of claudin-1 expression. Int J Mol Med. 2013, 31 (6): 1375-1380.PubMed Zhang GJ, Xiao HX, Tian HP, Liu ZL, Xia SS, Zhou T: Upregulation of microRNA-155 promotes the migration and invasion of colorectal cancer cells through the regulation of claudin-1 expression. Int J Mol Med. 2013, 31 (6): 1375-1380.PubMed
10.
go back to reference Shen SN, Wang LF, Jia YF, Hao YQ, Zhang L, Wang H: Upregulation of microRNA-224 is associated with aggressive progression and poor prognosis in human cervical cancer. Diagn Pathol. 2013, 8: 69-10.1186/1746-1596-8-69.PubMedCentralCrossRefPubMed Shen SN, Wang LF, Jia YF, Hao YQ, Zhang L, Wang H: Upregulation of microRNA-224 is associated with aggressive progression and poor prognosis in human cervical cancer. Diagn Pathol. 2013, 8: 69-10.1186/1746-1596-8-69.PubMedCentralCrossRefPubMed
11.
go back to reference Mees ST, Mardin WA, Sielker S, Willscher E, Senninger N, Schleicher C, Colombo-Benkmann M, Haier J: Involvement of CD40 targeting miR-224 and miR-486 on the progression of pancreatic ductal adenocarcinomas. Ann Surg Oncol. 2009, 16 (8): 2339-2350. 10.1245/s10434-009-0531-4.CrossRefPubMed Mees ST, Mardin WA, Sielker S, Willscher E, Senninger N, Schleicher C, Colombo-Benkmann M, Haier J: Involvement of CD40 targeting miR-224 and miR-486 on the progression of pancreatic ductal adenocarcinomas. Ann Surg Oncol. 2009, 16 (8): 2339-2350. 10.1245/s10434-009-0531-4.CrossRefPubMed
12.
go back to reference Huang L, Dai T, Lin X, Zhao X, Chen X, Wang C, Li X, Shen H, Wang X: MicroRNA-224 targets RKIP to control cell invasion and expression of metastasis genes in human breast cancer cells. Biochem Biophys Res Commun. 2012, 425 (2): 127-133. 10.1016/j.bbrc.2012.07.025.CrossRefPubMed Huang L, Dai T, Lin X, Zhao X, Chen X, Wang C, Li X, Shen H, Wang X: MicroRNA-224 targets RKIP to control cell invasion and expression of metastasis genes in human breast cancer cells. Biochem Biophys Res Commun. 2012, 425 (2): 127-133. 10.1016/j.bbrc.2012.07.025.CrossRefPubMed
13.
go back to reference Zhang Y, Takahashi S, Tasaka A, Yoshima T, Ochi H, Chayama K: Involvement of microRNA-224 in cell proliferation, migration, invasion, and anti-apoptosis in hepatocellular carcinoma. J Gastroenterol Hepatol. 2013, 28 (3): 565-575. 10.1111/j.1440-1746.2012.07271.x.CrossRefPubMed Zhang Y, Takahashi S, Tasaka A, Yoshima T, Ochi H, Chayama K: Involvement of microRNA-224 in cell proliferation, migration, invasion, and anti-apoptosis in hepatocellular carcinoma. J Gastroenterol Hepatol. 2013, 28 (3): 565-575. 10.1111/j.1440-1746.2012.07271.x.CrossRefPubMed
14.
go back to reference Motoyama K, Inoue H, Takatsuno Y, Tanaka F, Mimori K, Uetake H, Sugihara K, Mori M: Over- and under-expressed microRNAs in human colorectal cancer. Int J Oncol. 2009, 34 (4): 1069-1075.PubMed Motoyama K, Inoue H, Takatsuno Y, Tanaka F, Mimori K, Uetake H, Sugihara K, Mori M: Over- and under-expressed microRNAs in human colorectal cancer. Int J Oncol. 2009, 34 (4): 1069-1075.PubMed
15.
go back to reference Arndt GM, Dossey L, Cullen LM, Lai A, Druker R, Eisbacher M, Zhang C, Tran N, Fan H, Retzlaff K: Characterization of global microRNA expression reveals oncogenic potential of miR-145 in metastatic colorectal cancer. BMC cancer. 2009, 9: 374-10.1186/1471-2407-9-374.PubMedCentralCrossRefPubMed Arndt GM, Dossey L, Cullen LM, Lai A, Druker R, Eisbacher M, Zhang C, Tran N, Fan H, Retzlaff K: Characterization of global microRNA expression reveals oncogenic potential of miR-145 in metastatic colorectal cancer. BMC cancer. 2009, 9: 374-10.1186/1471-2407-9-374.PubMedCentralCrossRefPubMed
16.
go back to reference Mencia N, Selga E, Noe V, Ciudad CJ: Underexpression of miR-224 in methotrexate resistant human colon cancer cells. Biochem Pharmacol. 2011, 82 (11): 1572-1582. 10.1016/j.bcp.2011.08.009.CrossRefPubMed Mencia N, Selga E, Noe V, Ciudad CJ: Underexpression of miR-224 in methotrexate resistant human colon cancer cells. Biochem Pharmacol. 2011, 82 (11): 1572-1582. 10.1016/j.bcp.2011.08.009.CrossRefPubMed
17.
go back to reference Li S, Gao J, Gu J, Yuan J, Hua D, Shen L: MicroRNA-215 inhibits relapse of colorectal cancer patients following radical surgery. Medical oncology. 2013, 30 (2): 549-CrossRefPubMed Li S, Gao J, Gu J, Yuan J, Hua D, Shen L: MicroRNA-215 inhibits relapse of colorectal cancer patients following radical surgery. Medical oncology. 2013, 30 (2): 549-CrossRefPubMed
18.
go back to reference Tsai HL, Chu KS, Huang YH, Su YC, Wu JY, Kuo CH, Chen CW, Wang JY: Predictive factors of early relapse in UICC stage I-III colorectal cancer patients after curative resection. J Surg Oncol. 2009, 100 (8): 736-743. 10.1002/jso.21404.CrossRefPubMed Tsai HL, Chu KS, Huang YH, Su YC, Wu JY, Kuo CH, Chen CW, Wang JY: Predictive factors of early relapse in UICC stage I-III colorectal cancer patients after curative resection. J Surg Oncol. 2009, 100 (8): 736-743. 10.1002/jso.21404.CrossRefPubMed
19.
go back to reference Garzon R, Marcucci G: Potential of microRNAs for cancer diagnostics, prognostication and therapy. Curr Opin Oncol. 2012, 24 (6): 655-659. 10.1097/CCO.0b013e328358522c.CrossRefPubMed Garzon R, Marcucci G: Potential of microRNAs for cancer diagnostics, prognostication and therapy. Curr Opin Oncol. 2012, 24 (6): 655-659. 10.1097/CCO.0b013e328358522c.CrossRefPubMed
20.
go back to reference Albulescu R, Neagu M, Albulescu L, Tanase C: Tissular and soluble miRNAs for diagnostic and therapy improvement in digestive tract cancers. Expert Rev Mol Diagn. 2011, 11 (1): 101-120. 10.1586/erm.10.106.CrossRefPubMed Albulescu R, Neagu M, Albulescu L, Tanase C: Tissular and soluble miRNAs for diagnostic and therapy improvement in digestive tract cancers. Expert Rev Mol Diagn. 2011, 11 (1): 101-120. 10.1586/erm.10.106.CrossRefPubMed
21.
go back to reference Massague J, Chen YG: Controlling TGF-beta signaling. Genes Dev. 2000, 14 (6): 627-644.PubMed Massague J, Chen YG: Controlling TGF-beta signaling. Genes Dev. 2000, 14 (6): 627-644.PubMed
22.
go back to reference Wang LH, Kim SH, Lee JH, Choi YL, Kim YC, Park TS, Hong YC, Wu CF, Shin YK: Inactivation of SMAD4 tumor suppressor gene during gastric carcinoma progression. Clin Cancer Res. 2007, 13 (1): 102-110. 10.1158/1078-0432.CCR-06-1467.CrossRefPubMed Wang LH, Kim SH, Lee JH, Choi YL, Kim YC, Park TS, Hong YC, Wu CF, Shin YK: Inactivation of SMAD4 tumor suppressor gene during gastric carcinoma progression. Clin Cancer Res. 2007, 13 (1): 102-110. 10.1158/1078-0432.CCR-06-1467.CrossRefPubMed
23.
go back to reference Maitra A, Molberg K, Albores-Saavedra J, Lindberg G: Loss of Dpc4 expression in colonic adenocarcinomas correlates with the presence of metastatic disease. Am J Pathol. 2000, 157 (4): 1105-1111. 10.1016/S0002-9440(10)64625-1.PubMedCentralCrossRefPubMed Maitra A, Molberg K, Albores-Saavedra J, Lindberg G: Loss of Dpc4 expression in colonic adenocarcinomas correlates with the presence of metastatic disease. Am J Pathol. 2000, 157 (4): 1105-1111. 10.1016/S0002-9440(10)64625-1.PubMedCentralCrossRefPubMed
24.
go back to reference Alazzouzi H, Alhopuro P, Salovaara R, Sammalkorpi H, Jarvinen H, Mecklin JP, Hemminki A, Schwartz S, Aaltonen LA, Arango D: SMAD4 as a prognostic marker in colorectal cancer. Clin Cancer Res. 2005, 11 (7): 2606-2611. 10.1158/1078-0432.CCR-04-1458.CrossRefPubMed Alazzouzi H, Alhopuro P, Salovaara R, Sammalkorpi H, Jarvinen H, Mecklin JP, Hemminki A, Schwartz S, Aaltonen LA, Arango D: SMAD4 as a prognostic marker in colorectal cancer. Clin Cancer Res. 2005, 11 (7): 2606-2611. 10.1158/1078-0432.CCR-04-1458.CrossRefPubMed
25.
go back to reference Zhang B, Halder SK, Kashikar ND, Cho YJ, Datta A, Gorden DL, Datta PK: Antimetastatic role of Smad4 signaling in colorectal cancer. Gastroenterology. 2010, 138 (3): 969-980. 10.1053/j.gastro.2009.11.004. e961-963PubMedCentralCrossRefPubMed Zhang B, Halder SK, Kashikar ND, Cho YJ, Datta A, Gorden DL, Datta PK: Antimetastatic role of Smad4 signaling in colorectal cancer. Gastroenterology. 2010, 138 (3): 969-980. 10.1053/j.gastro.2009.11.004. e961-963PubMedCentralCrossRefPubMed
26.
go back to reference Muller N, Reinacher-Schick A, Baldus S, van Hengel J, Berx G, Baar A, van Roy F, Schmiegel W, Schwarte-Waldhoff I: Smad4 induces the tumor suppressor E-cadherin and P-cadherin in colon carcinoma cells. Oncogene. 2002, 21 (39): 6049-6058. 10.1038/sj.onc.1205766.CrossRefPubMed Muller N, Reinacher-Schick A, Baldus S, van Hengel J, Berx G, Baar A, van Roy F, Schmiegel W, Schwarte-Waldhoff I: Smad4 induces the tumor suppressor E-cadherin and P-cadherin in colon carcinoma cells. Oncogene. 2002, 21 (39): 6049-6058. 10.1038/sj.onc.1205766.CrossRefPubMed
27.
go back to reference Pohl M, Radacz Y, Pawlik N, Schoeneck A, Baldus SE, Munding J, Schmiegel W, Schwarte-Waldhoff I, Reinacher-Schick A: SMAD4 mediates mesenchymal- epithelial reversion in SW480 colon carcinoma cells. Anticancer Res. 2010, 30 (7): 2603-2613.PubMed Pohl M, Radacz Y, Pawlik N, Schoeneck A, Baldus SE, Munding J, Schmiegel W, Schwarte-Waldhoff I, Reinacher-Schick A: SMAD4 mediates mesenchymal- epithelial reversion in SW480 colon carcinoma cells. Anticancer Res. 2010, 30 (7): 2603-2613.PubMed
28.
go back to reference Yao G, Yin M, Lian J, Tian H, Liu L, Li X, Sun F: MicroRNA-224 is involved in transforming growth factor-beta-mediated mouse granulosa cell proliferation and granulosa cell function by targeting Smad4. Mol Endocrinol. 2010, 24 (3): 540-551. 10.1210/me.2009-0432.CrossRefPubMed Yao G, Yin M, Lian J, Tian H, Liu L, Li X, Sun F: MicroRNA-224 is involved in transforming growth factor-beta-mediated mouse granulosa cell proliferation and granulosa cell function by targeting Smad4. Mol Endocrinol. 2010, 24 (3): 540-551. 10.1210/me.2009-0432.CrossRefPubMed
29.
go back to reference Xu XT, Xu Q, Tong JL, Zhu MM, Nie F, Chen X, Xiao SD, Ran ZH: MicroRNA expression profiling identifies miR-328 regulates cancer stem cell-like SP cells in colorectal cancer. Br J Cancer. 2012, 106 (7): 1320-1330. 10.1038/bjc.2012.88.PubMedCentralCrossRefPubMed Xu XT, Xu Q, Tong JL, Zhu MM, Nie F, Chen X, Xiao SD, Ran ZH: MicroRNA expression profiling identifies miR-328 regulates cancer stem cell-like SP cells in colorectal cancer. Br J Cancer. 2012, 106 (7): 1320-1330. 10.1038/bjc.2012.88.PubMedCentralCrossRefPubMed
30.
go back to reference Fang Y, Gu X, Li Z, Xiang J, Chen Z: miR-449b inhibits the proliferation of SW1116 colon cancer stem cells through downregulation of CCND1 andE2F3 expression. Oncol Rep. 2013, 30 (1): 399-406.PubMed Fang Y, Gu X, Li Z, Xiang J, Chen Z: miR-449b inhibits the proliferation of SW1116 colon cancer stem cells through downregulation of CCND1 andE2F3 expression. Oncol Rep. 2013, 30 (1): 399-406.PubMed
31.
go back to reference Fellenberg J, Saehr H, Lehner B, Depeweg D: A microRNA signature differentiates between giant cell tumor derived neoplastic stromal cells and mesenchymal stem cells. Cancer Lett. 2012, 321 (2): 162-168. 10.1016/j.canlet.2012.01.043.CrossRefPubMed Fellenberg J, Saehr H, Lehner B, Depeweg D: A microRNA signature differentiates between giant cell tumor derived neoplastic stromal cells and mesenchymal stem cells. Cancer Lett. 2012, 321 (2): 162-168. 10.1016/j.canlet.2012.01.043.CrossRefPubMed
32.
go back to reference Li R, Liang J, Ni S, Zhou T, Qing X, Li H, He W, Chen J, Li F, Zhuang Q: A mesenchymal-to-epithelial transition initiates and is required for the nuclear reprogramming of mouse fibroblasts. Cell Stem Cell. 2010, 7 (1): 51-63. 10.1016/j.stem.2010.04.014.CrossRefPubMed Li R, Liang J, Ni S, Zhou T, Qing X, Li H, He W, Chen J, Li F, Zhuang Q: A mesenchymal-to-epithelial transition initiates and is required for the nuclear reprogramming of mouse fibroblasts. Cell Stem Cell. 2010, 7 (1): 51-63. 10.1016/j.stem.2010.04.014.CrossRefPubMed
Metadata
Title
Up-regulation of miR-224 promotes cancer cell proliferation and invasion and predicts relapse of colorectal cancer
Authors
Guang-jun Zhang
He Zhou
Hua-xu Xiao
Yu Li
Tong Zhou
Publication date
01-12-2013
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2013
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/1475-2867-13-104

Other articles of this Issue 1/2013

Cancer Cell International 1/2013 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