MicroRNA-217 functions as a prognosis predictor and inhibits colorectal cancer cell proliferation and invasion via an AEG-1 dependent mechanism

BackgroundRecent studies have indicated the possible function of miR-217 in tumorigenesis. However, the roles of miR-217 in colorectal cancer (CRC) are still largely unknown.MethodsWe examined the expression of miR-217 and AEG-1 in 50 CRC tissues and the corresponding noncancerous tissues by qRT-PCR. The clinical significance of miR-217 was analyzed. CRC cell lines with miR-217 upregulation and AEG-1 silencing were established and the effects on tumor growth in vitro and in vivo were assessed. Dual-luciferase reporter gene assays were also performed to investigate the interaction between miR-217 and AEG-1.ResultsOur data demonstrated that miR-217 was significantly downregulated in 50 pairs of colorectal cancer tissues. MiR-217 expression levels were closely correlated with tumor differentiation. Moreover, decreased miR-217 expression was also associated with shorter overall survival of CRC patients. MiR-217 overexpression significantly inhibited proliferation, colony formation and invasiveness of CRC cells by promoting apoptosis and G0/G1 phase arrest. Interestingly, ectopic miR-217 expression decreased AEG-1 expression and repressed luciferase reporter activity associated with the AEG-1 3′-untranslated region (UTR). AEG-1 silencing resulted in similar biological behavior changes to those associated with miR-217 overexpression. Finally, in a nude mouse xenografted tumor model, miR-217 overexpression significantly suppressed CRC cell growth.ConclusionsOur findings suggest that miR-217 has considerable value as a prognostic marker and potential therapeutic target in CRC.

[1]  Yu Qin,et al.  Astrocyte elevated gene-1 activates MMP9 to increase invasiveness of colorectal cancer , 2014, Tumor Biology.

[2]  Zhaohui Lu,et al.  The miR-217 microRNA functions as a potential tumor suppressor in pancreatic ductal adenocarcinoma by targeting KRAS. , 2010, Carcinogenesis.

[3]  J. Geng,et al.  Prognostic significance of AEG-1 expression in colorectal carcinoma , 2010, International Journal of Colorectal Disease.

[4]  G. Melino,et al.  MicroRNA 217 Modulates Endothelial Cell Senescence via Silent Information Regulator 1 , 2009, Circulation.

[5]  C. Mathers,et al.  Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008 , 2010, International journal of cancer.

[6]  Z. Su,et al.  Astrocyte elevated gene-1 contributes to the pathogenesis of neuroblastoma , 2009, Oncogene.

[7]  Gang Deng,et al.  Knockdown of astrocyte elevated gene-1 inhibits tumor growth and modifies microRNAs expression profiles in human colorectal cancer cells. , 2014, Biochemical and biophysical research communications.

[8]  Feipeng Zhao,et al.  MiR-124 suppresses tumor growth and metastasis by targeting Foxq1 in nasopharyngeal carcinoma , 2014, Molecular Cancer.

[9]  Z. Duan,et al.  Interleukin-6 signaling pathway in targeted therapy for cancer. , 2012, Cancer treatment reviews.

[10]  F. Guadagni,et al.  A metastatic nude-mouse model of human pancreatic cancer constructed orthotopically with histologically intact patient specimens. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[11]  D. Wells,et al.  CPEB1 Regulates the Expression of MTDH/AEG-1 and Glioblastoma Cell Migration , 2013, Molecular Cancer Research.

[12]  P. Fisher,et al.  Identification and cloning of human astrocyte genes displaying elevated expression after infection with HIV-1 or exposure to HIV-1 envelope glycoprotein by rapid subtraction hybridization, RaSH , 2002, Oncogene.

[13]  Y. Niu,et al.  miRNA-141, Downregulated in Pancreatic Cancer, Inhibits Cell Proliferation and Invasion by Directly Targeting MAP4K4 , 2013, Molecular Cancer Therapeutics.

[14]  M. Zhong,et al.  miR-217 inhibits invasion of hepatocellular carcinoma cells through direct suppression of E2F3 , 2014, Molecular and Cellular Biochemistry.

[15]  G. Packham,et al.  miR-153 supports colorectal cancer progression via pleiotropic effects that enhance invasion and chemotherapeutic resistance. , 2013, Cancer research.

[16]  Libing Song,et al.  Astrocyte elevated gene-1 is a proliferation promoter in breast cancer via suppressing transcriptional factor FOXO1 , 2009, Oncogene.

[17]  K. Shirouzu,et al.  Prognostic significance of isolated tumor cells in patients with colorectal cancer in recent 10-year studies. , 2013, Molecular and clinical oncology.

[18]  Peng Huang,et al.  Identification of MicroRNA‐214 as a negative regulator of colorectal cancer liver metastasis by way of regulation of fibroblast growth factor receptor 1 expression , 2014, Hepatology.

[19]  W. Ma,et al.  MicroRNA-217, down-regulated in clear cell renal cell carcinoma and associated with lower survival, suppresses cell proliferation and migration. , 2013, Neoplasma.

[20]  Xi Chen,et al.  A microRNA 221- and 222-Mediated Feedback Loop, via PDLIM2, Maintains Constitutive Activation of NFκB and STAT3 in Colorectal Cancer Cells , 2014 .

[21]  M. D'Angelica,et al.  Liver Resection for Metastatic Colorectal Cancer in the Presence of Extrahepatic Disease , 2009, Annals of Surgical Oncology.

[22]  RossellaMenghini,et al.  MicroRNA 217 Modulates Endothelial Cell Senescence via Silent Information Regulator 1 , 2009 .

[23]  R. Gregory,et al.  Many roads to maturity: microRNA biogenesis pathways and their regulation , 2009, Nature Cell Biology.

[24]  N. Kaminski,et al.  FACS-assisted microarray profiling implicates novel genes and pathways in zebrafish gastrointestinal tract development. , 2009, Gastroenterology.

[25]  G. Calin,et al.  MiR-200a regulates epithelial to mesenchymal transition-related gene expression and determines prognosis in colorectal cancer patients , 2014, British Journal of Cancer.

[26]  Yu Qin,et al.  Astrocyte Elevated Gene-1 Mediates Glycolysis and Tumorigenesis in Colorectal Carcinoma Cells via AMPK Signaling , 2014, Mediators of inflammation.

[27]  A. Jemal,et al.  Global cancer statistics , 2011, CA: a cancer journal for clinicians.

[28]  Sabine Tejpar,et al.  KRAS, BRAF, PIK3CA, and PTEN mutations: implications for targeted therapies in metastatic colorectal cancer. , 2011, The Lancet. Oncology.

[29]  Xijie Yu,et al.  MiR-335 Inhibits Small Cell Lung Cancer Bone Metastases via IGF-IR and RANKL Pathways , 2013, Molecular Cancer Research.

[30]  S. Curran,et al.  New insights into the roles of matrix metalloproteinases in colorectal cancer development and progression , 2003, The Journal of pathology.

[31]  Bo Wang,et al.  miR-148b Functions as a Tumor Suppressor in Pancreatic Cancer by Targeting AMPKα1 , 2012, Molecular Cancer Therapeutics.

[32]  Qiang Zhang,et al.  MiR-217 Promotes Tumor Proliferation in Breast Cancer via Targeting DACH1 , 2015, Journal of Cancer.

[33]  Hong Zhang,et al.  Expression of AEG-1 mRNA and protein in colorectal cancer patients and colon cancer cell lines , 2012, Journal of Translational Medicine.

[34]  N. Mukhopadhyay,et al.  Astrocyte elevated gene‐1 promotes hepatocarcinogenesis: Novel insights from a mouse model , 2012, Hepatology.

[35]  T. Ikezoe,et al.  Downregulation of miR-217 correlates with resistance of ph+ leukemia cells to ABL tyrosine kinase inhibitors , 2014, Cancer science.

[36]  M. Piris,et al.  miR-217 is an oncogene that enhances the germinal center reaction. , 2014, Blood.

[37]  Xing-Xing He,et al.  MicroRNA-375 targets AEG-1 in hepatocellular carcinoma and suppresses liver cancer cell growth in vitro and in vivo , 2012, Oncogene.

[38]  D. Bartel.  MicroRNAs Genomics, Biogenesis, Mechanism, and Function , 2004, Cell.

[39]  S. Cai,et al.  Uncontrolled inflammation induced by AEG-1 promotes gastric cancer and poor prognosis. , 2014, Cancer research.

[40]  Yong-Tae Kim,et al.  Identification of MicroRNA-21 as a Biomarker for Chemoresistance and Clinical Outcome Following Adjuvant Therapy in Resectable Pancreatic Cancer , 2010, PloS one.

[41]  M. Peter,et al.  Targeting of mRNAs by multiple miRNAs: the next step , 2010, Oncogene.

[42]  I. Liu,et al.  Astrocyte elevated gene-1 is associated with metastasis in head and neck squamous cell carcinoma through p65 phosphorylation and upregulation of MMP1 , 2013, Molecular Cancer.

[43]  B. Zhu,et al.  Knockdown of astrocyte elevated gene-1 (AEG-1) in cervical cancer cells decreases their invasiveness, epithelial to mesenchymal transition, and chemoresistance , 2014, Cell cycle.