GHR, PEX5 AND AXIN2 ARE NEW TARGETS FOR MIR-195 IN- VOLVING IN LONGEVITY, INCREASING BIOLOGICAL ACTIVI- TIES AND EMT OF CANCER CELLS FOR HEPATOCELLULAR CARCINOMA CELLS
Abstract
Recently, micro RNAs have been shown to regulate gene expression of genes in many organisms. They bind to target mRNA transcripts. In a sequence specific manner, including mRNA degradation, translational repression or endonucleolytic cleavage. Some studies showed that miRNA expression correlates with various cancers. Combination of multiple properties e.g. free-energy, sequence pattern, hairpin shaped precursor rather than miRNAs complementarity to their targets provide a more desirable accuracy in miRNA target prediction. Different programs were used to predict novel targets for differentially expressed miRNA in cancers tissues. Luciferase assay for PEX5, GHR and AXIN2 showed a significant decrease in luciferase production in the presence of both miR-195 and PEX5-3'UTR, GHR-3'YTR and AXIN2-3'UTR. The results emphasize that both PEX5, GHR or AXIN2 are real targets for miR-195. This confirms and verifies the prediction method that were used on this study and our previous studies. These genes are suggested to have a major role in regulation of Wnt signaling pathway, epithelial-mesenchymal transition, AKT Signaling Pathway, peroxisomal protein import and cell longevity.References
Amer M, Elhefnawi M., El-Ahwany E., Awad A. F., Gawad Zada N. A. S., Tawab F. M., (2014). Has-mir-195 targets pcmt1 in hepatocellular carcinoma that increases tumor life span. Tumor Bol., 35:11301-11309.
Bereikov E., Van Tereing G., Verheul M., Van De Belt J., Van Laake L., Vos J., Veloop R., Van De Wtring M., Guryev V., Takada Sm Van Zonneveld A. J., Mano H., Platerk R., Cuppen E., (2006). Many novel mammalian microrna candidates identified by extensive cloning and rake analysis. Genome Res., 16:1289-1298.
Berezikov E, Thuemmler F., Van Laake LW., Knodova I., Bontrop R., Cuppen E., Plastek R., H (2006). Divrsity of Micrornas in human and chimpanzee brain. Nat. Genet., 38: 1375-1377.
Bluher M., Kahn B. B., Kahn C. R., (2003). Extended longevity in mice lacking the insulin receptor in adipose tissue. Science, 299: 572-574.
Croce C. M., (2009). Causes and consequrnces of microrna dysregulation in cancer. Nat. Rev. Genet, 10:704-714.
De Benedetti A., Harris A. l., (1999). Eit4e expression in tumors: Its possible role in progression of malignancies. Int. J. Biochem. Cell Biol., 31:59-72.
DeFeo-Jones D., Barenett S. F., Fu S., Hancock P. J., Haskell K. M., Leander K. R., McAvoy E., Robinson R. G., Duggan M. E., Lindsley C. W., Zhao Z., Huber H. E., Jones R. E., (2005). Tumor cell sensitization to apoptotic stimuli by selective inhibition of specific akt/pkb family members. Mol. Cancer Ther., 4: 271-279.
Dodt G., Bravman N., Wong C., Mosr A., Moser H. W., Watkins P., Valle D., Gould S. J., (1995). Mutations in the pts1 receptor gene, pxr1, define complementation group 2 of the peroxisome biogenesis disorders. Nat. Genet., 9: 115-125.
El-Hefnawi M., Soliman B., Abu-Shahba N., Amer M., (2013). An intergrative meta-analysis of micrornas in hepatocellular carcinoma. Genomics Proteomics Bioinformatics,11: 354-367.
Fransen M., Bres C., Baumgrat E., Vanhooren J. C., Bas M., Mannaerts G.P., Van Veldhoven P. P., (1995). Identification and characterization of the putative human peroxisomal c-teminal targeting signal import receptor. J. Biol. Chem., 270: 7731-7736.
Garzon R., Fabbri M., Cimmino A., Calin G. A., Croce C. M., 2006. Microrna expression and function in cancer. Trends Mol. Med., 12: 580-587.
Graff J. R., Konicek B. W., Carter J. H., Marcusson E. G., (2008). Targeting the eukaryotic translation initiation factor 4e for cancer therapy. Cancer Res., 68: 631-634.
Graff J. R., Konicek B. W., Lynch R. L., Dumstorf C. A., Dowless M. S., McNulty A. M., Parsons S. H., Brail L. H., Colligan B. M., Koop JW, Hurst B. M., Deddens J. A., Neubauer B. L., Stancato LF, Carter HW, Douglass L. E., Carter J. H., (2009). Eif4e activation is commonly elevated in advanced human prostate cancer and significantly related to reduced patient survival. Cancer Res., 69: 3866-3873.
Holzenberger M., Dupont J., Ducos B., Leneuve P., Geloen A., Even P. C., Cervera P., Le Bouc Y., (2003). Igf-1 receptor regulates lifespan and resistance to oxidative stress in mice. Naur.,421: 182-187.
Hrington J., Carter-Su C., (2001). Signaling pathways activated by the growth hormone receptor. Trends Endocrinol. Metab., 12: 252-257.
Hugang S. M., Mishina Y. M., Liu S., Chung A., Stegmeier F., Michaud G. A., Charlat O., Wiellete E., Zhang Y., Wiessner S., Hild M., Shi X., Wilson C. J., Mickanin C., Myer V., Fazal A., Tomlinson R., Serluca F., Shao W., Cheng H., Shultz M., Rau C., Schile M., Schlel J., Ghidelli S., Fawell S., Lu C., Curtis D., Kirschner M. W., Lengauer C., Finan P. M., Tallarico J. A., Bouwmeester T., Porter J. A., Bauer A., Cong F., (2009). Tankyrase inhibition stabilizes axin and antagonizes wnt signalling. Nature, 461: 614-620.
Klaus A., Birchmeier W., (2008). Wnt signaling and its impact on development and cancer. Nat Rev Cancer, 8: 387-398.
Lee J. S., Thorgeirsson S. S., (2006). Comparative and integrative functional genomics of hcc. Oncogene, 25:3801-3809.
Lee R. C., Feinbaum R. L., Ambros V., (1993). The C Elegans hetochronic gene lin-4 encdes small rnas with antisense complementarity to lin-14. Cell;75: 843-854.
Lemmer E. R., Friedman S. L., LIovet J. M., (2006). Molecular diagnosis of chronic liver disease and hepato-cellular carcinoma: The potential of gene expression profiling. Semin Liver Dis., 26: 373-384.
Ling H, Krassnig L., Bullock M. D., Pichler M., (2016). Micronas in testicular cancer diagnosis and prognosis. Urol Clin Norh Am., 43: 127-134.
Liu Y., Bjokman J., Urquhart A., Wanders R. J., Crane D. I., Gould S. J., (1999). Pex13 is mutated in complementation group 13 of the peroxisome- biogenesis disorders. Am. J. Hum. Genet., 65: 621-634.
Lu J., Getz G., Miska E. A., Avarez-Saavedra E., Lamb J., Peck D., Sweet-Cordero A., Ebert B. L., Mak R. H., Ferrando A. A., Downing J., Jacks T., Hoorvitz H. R., Golub T. R., (2005). Micorna expression profiles classify human cancers. Nature, 435: 834-838.
Melo S. A., Easteller M., (2010). Dysregulation of micrornas in cancer: Playing with fire. EBS Lett.,585: 2087-2099.
Nana-Sinkam S. P., Croce C. M., (2011). Micrornas as therapeutic targets in cancer. Transl Rs.,157:216-225.
Salido-Guadarrama A. l., Morales-Montor J. G., Rangel –Escareno C., Langley E., Pralta-Zaragoza O., Cruz Colin J. L., Rodiguez-Dorantes M., (2016). Urinary micron-based signature improves accuracy of detection of clinically relevant prostate cancer within the prostate-specific antigen gry zone. Mol. Med. Rep., 13: 4549-4560.
Shimozawa N., Suzuki Y., Zhang Z., Imamura A., Toyama R., Mukai S., Fujiki Y., Tsukamoto T., Osumi T., Orii T., Wanders R. J., Kondo N., (1999). Nonsense and temperature-sensitive mutations in pex13 are the cause of complementation group h of peroxisome biogenesis disorders. Hum. Mol. Genet., 8: 1077-1083.
Song G, Ouyang G., Bao S., (2005). The activation of akt/pkb signaling pathway and cell survival. J. Cell Mol. Med., 9: 59-71.
Varnholt H., Drebber U., Schulze, Wedemeyer I., Schimacher P., Dienes H. P., Odenthal M., (2008). Microrna gene expression profile of hepatitis c virus-associated hepatocellur carcinoma. Hepatology, 47: 1223-1232.
Volinia S., Calin GA., Liu C. G., Ambs S., Cimmino A., Petrocca F., Visone R., Iorio M., Roldo C., Ferracin M., Prueitt R. L., Yanaihara N., Lanza G., Scarpa A., Vecchione A., Negrini M., Harris C. C., Croce C. M., (2006). Amicrorna expression signature of human solid tumors defines cancer gene targets. Proc. Nati. Acad. Sci. USA, 103: 2257-2261.
Waaler J., Machon O., Tumova L., Dinh H., Korinek V., Wilson S. R., Paulsen J. E., Pedersen N. M., Eide T. J., Machonova O., Gradl D., Voronkov A., Von Kries J. P., Krauss S., (2012). A novel tankyrase inhibitor decreases canonical wnt signaling in colon carcinoma cells and reduces tumor growth in conditional apc mutant mice. Cancer Res., 72: 2822-2832.
Wiemer E. A., Nuttley W. M., Bertolaet B. L., Li X., Francke U., Wheelock MJ, Anne UK, Johnson K. R., Subramani S., (1995).Human peroxisomal targeting signal-1 receptor restores peroxisome protein import in cells from patients with fatal peroxisomal disorders. J. Cell Biol., 130: 51-65.
Williams C., Distel B., (2006). Pex13p: Docking or cargo handling protein? Biochim Biophys Acta., 1763: 1585-1591.
Wu Z. Q., Brabletz T., Fearon E., Willis A. L., Hu C. Y., Li X. Y., Weiss S. J., (2012). Canonical wnt suppressor, axin2, promotes colon carcinoma oncongenic activity. Proc. Natl. Acad. Sci. U S A, 109: 11312-11317.
Yanaihara N., Calpen N., Bowman E., Seike M., Kumamoto K., Yi M., Stephens R. M., Okamoto A., Yokota J., Tanaka T., Calin G. A., Liu C. G., Croce C. M., Haris C. C., (2006). Unique microrna molecular profiles in lung cancer diagnosis and prognosis. Cancer Cell, 9: 189-198.
Zhou X, Zhang X., Yang Y., Li Z., Du L., Dong Z., Qu A., Jiang X., Li P., Wang C., (2014). Urinary cell-free microrna-106b as novel biomarker for detection of bladder cancer. Med. Oncol., 3: 197.