Transcriptional control of PAX4-regulated miR-144/451 modulates metastasis by suppressing ADAMs expression

Paired box gene 4 (PAX4) is a transcriptional modulator located on chromosome 7q32, and its expression is dysregulated in a variety of human cancers, suggesting that PAX4 may be important in multiple tumors as a driver gene. Here, we show that PAX4 promoted migration and invasion in human epithelial cancers by decreasing miR-144 and miR-451 (miR-144/451) expression levels. Accordingly, miR-144/451 suppressed the migratory and invasive phenotypes, even in PAX4-expressing cells. Mechanistically, miR-144/451 inhibits cancer metastasis by targeting the A disintegrin and metalloproteinase (ADAM) protein family members ADAMTS5 and ADAM10. Their dysregulation is associated with increased tumor invasiveness and metastasis, then reduced patient prognosis in certain epithelial cancers. This discovery suggests that a PAX4–miR-144/451–ADAMs axis regulates human epithelial cancer metastasis, thus opening up therapeutic possibilities and predicting prognosis for those cancer types.

[1]  P. Benfey.  Molecular biology: MicroRNA is here to stay , 2003, Nature.

[2]  K. Ichikawa,et al.  Expression of dominant negative form of PAX4 in human insulinoma. , 2001, Biochemical and biophysical research communications.

[3]  K. Mimori,et al.  Clinical significance of miR-144-ZFX axis in disseminated tumour cells in bone marrow in gastric cancer cases , 2012, British Journal of Cancer.

[4]  Chi Zhang,et al.  MicroRNA-144 Is Regulated by Activator Protein-1 (AP-1) and Decreases Expression of Alzheimer Disease-related A Disintegrin and Metalloprotease 10 (ADAM10)* , 2013, The Journal of Biological Chemistry.

[5]  Q. Sun,et al.  Loss of microRNA-143/145 disturbs cellular growth and apoptosis of human epithelial cancers by impairing the MDM2-p53 feedback loop , 2013, Oncogene.

[6]  R. Wynn,et al.  Identification of ADAM10 as a major source of HER2 ectodomain sheddase activity in HER2 overexpressing breast cancer cells , 2006, Cancer biology & therapy.

[7]  B. Katzenellenbogen,et al.  Tamoxifen down-regulation of miR-451 increases 14-3-3ζ and promotes breast cancer cell survival and endocrine resistance , 2011, Oncogene.

[8]  C. Wollheim,et al.  Association of childhood type 1 diabetes mellitus with a variant of PAX4: possible link to beta cell regenerative capacity , 2005, Diabetologia.

[9]  B. Johansson,et al.  Prognostic implications of cytogenetic aberrations in diffuse large B‐cell lymphomas , 1999, European journal of haematology.

[10]  G. Murphy.  The ADAMs: signalling scissors in the tumour microenvironment , 2008, Nature Reviews Cancer.

[11]  A. Luo,et al.  MicroRNA-34 suppresses breast cancer invasion and metastasis by directly targeting Fra-1 , 2013, Oncogene.

[12]  Yoshio Kato,et al.  MicroRNA-140 is expressed in differentiated human articular chondrocytes and modulates interleukin-1 responses. , 2009, Arthritis and rheumatism.

[13]  Qin Xu,et al.  Downregulation of miR-153 contributes to epithelial-mesenchymal transition and tumor metastasis in human epithelial cancer. , 2013, Carcinogenesis.

[14]  J. Steitz,et al.  Switching from Repression to Activation: MicroRNAs Can Up-Regulate Translation , 2007, Science.

[15]  H. Mehdorn,et al.  Matrix‐degrading proteases ADAMTS4 and ADAMTS5 (disintegrins and metalloproteinases with thrombospondin motifs 4 and 5) are expressed in human glioblastomas , 2006, International journal of cancer.

[16]  Anil G Jegga,et al.  Synergistic effects of the GATA-4-mediated miR-144/451 cluster in protection against simulated ischemia/reperfusion-induced cardiomyocyte death. , 2010, Journal of molecular and cellular cardiology.

[17]  Qin Xu,et al.  Dysregulated miR-363 affects head and neck cancer invasion and metastasis by targeting podoplanin. , 2013, The international journal of biochemistry & cell biology.

[18]  H. Samaratunga,et al.  Expression of the Disintegrin Metalloprotease, ADAM-10, in Prostate Cancer and Its Regulation by Dihydrotestosterone, Insulin-Like Growth Factor I, and Epidermal Growth Factor in the Prostate Cancer Cell Model LNCaP , 2004, Clinical Cancer Research.

[19]  M. Hirata,et al.  Transcriptional Induction of ADAMTS5 Protein by Nuclear Factor-κB (NF-κB) Family Member RelA/p65 in Chondrocytes during Osteoarthritis Development* , 2013, The Journal of Biological Chemistry.

[20]  Anton J. Enright,et al.  The miR-144/451 locus is required for erythroid homeostasis , 2010, The Journal of experimental medicine.

[21]  T. Ninomiya,et al.  Diabetes mellitus and cancer risk: Review of the epidemiological evidence , 2013, Cancer science.

[22]  C. Kang,et al.  MicroRNA miR-451 downregulates the PI3K/AKT pathway through CAB39 in human glioma , 2011, International journal of oncology.

[23]  Ping Zhang,et al.  Plasma Membrane Proteomics of Tumor Spheres Identify CD166 as a Novel Marker for Cancer Stem-like Cells in Head and Neck Squamous Cell Carcinoma* , 2013, Molecular & Cellular Proteomics.

[24]  B. de Strooper,et al.  ADAM10 mediates E-cadherin shedding and regulates epithelial cell-cell adhesion, migration, and beta-catenin translocation. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[25]  G. Wakabayashi,et al.  Downregulation of miR-144 is associated with colorectal cancer progression via activation of mTOR signaling pathway. , 2012, Carcinogenesis.

[26]  S. Batra,et al.  Expression of ADAMs (a disintegrin and metalloproteases) and TIMP-3 (tissue inhibitor of metalloproteinase-3) in human prostatic adenocarcinomas. , 2003, International journal of oncology.

[27]  T. Murohara,et al.  Aberrant DNA demethylation in promoter region and aberrant expression of mRNA of PAX4 gene in hematologic malignancies. , 2006, Leukemia research.

[28]  Xiaowu Gai,et al.  A GATA-1-regulated microRNA locus essential for erythropoiesis , 2008, Proceedings of the National Academy of Sciences.

[29]  Saran Kumar,et al.  ADAMTS5 functions as an anti-angiogenic and anti-tumorigenic protein independent of its proteoglycanase activity. , 2012, The American journal of pathology.

[30]  Trevor Hastie,et al.  Gene expression patterns in ovarian carcinomas. , 2003, Molecular biology of the cell.

[31]  A. Aguzzi,et al.  Deregulated expression of PAX5 in medulloblastoma. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[32]  B. Sosa-Pineda.  The gene Pax4 is an essential regulator of pancreatic β-cell development , 2004 .

[33]  M. Scully,et al.  ADAM proteins - therapeutic potential in cancer. , 2008, Current cancer drug targets.

[34]  Y. M. Lee,et al.  Inhibition of Histone Deacetylase Attenuates Hypoxia-Induced Migration and Invasion of Cancer Cells via the Restoration of RECK Expression , 2010, Molecular Cancer Therapeutics.

[35]  J. Cigudosa,et al.  Cytogenetic analysis of 363 consecutively ascertained diffuse large B‐cell lymphomas , 1999, Genes, chromosomes & cancer.

[36]  B. Sosa-Pineda,et al.  The gene Pax4 is an essential regulator of pancreatic beta-cell development. , 2004, Molecules and cells.

[37]  D. Hayward,et al.  Pax gene diversity in the basal cnidarian Acropora millepora (Cnidaria, Anthozoa): implications for the evolution of the Pax gene family. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[38]  Gavin C. Jones.  ADAMTS proteinases: potential therapeutic targets? , 2006, Current pharmaceutical biotechnology.

[39]  N. Niikawa,et al.  Assignment of the human PAX4 gene to chromosome band 7q32 by fluorescence in situ hybridization. , 1994, Cytogenetics and cell genetics.

[40]  K. Jeong,et al.  Histone deacetylases 1, 6 and 8 are critical for invasion in breast cancer. , 2011, Oncology reports.

[41]  F. Hamdy,et al.  The expression and regulation of ADAMTS‐1, ‐4, ‐5, ‐9, and ‐15, and TIMP‐3 by TGFβ1 in prostate cells: relevance to the accumulation of versican , 2005, The Prostate.

[42]  Jianjun Zhang,et al.  Regulation of RAP1B by miR-139 suppresses human colorectal carcinoma cell proliferation. , 2012, The international journal of biochemistry & cell biology.

[43]  Jianjun Zhang,et al.  The regulation of toll-like receptor 2 by miR-143 suppresses the invasion and migration of a subset of human colorectal carcinoma cells , 2013, Molecular Cancer.

[44]  D. Notterman,et al.  Expression of L1-CAM and ADAM10 in human colon cancer cells induces metastasis. , 2007, Cancer research.

[45]  Toru Egashira,et al.  The Arg121Trp variant in PAX4 gene is associated with beta-cell dysfunction in Japanese subjects with type 2 diabetes mellitus. , 2006, Metabolism: clinical and experimental.

[46]  R. Lauro,et al.  Expression of thyroid-specific transcription factors TTF-1 and PAX-8 in human thyroid neoplasms. , 1994, Cancer research.

[47]  Vasilis Vasiliou,et al.  Evolutionary divergence and functions of the ADAM and ADAMTS gene families , 2009, Human Genomics.