Abstract
Proline oxidase (POX) is a novel mitochondrial tumor suppressor that can suppress proliferation and induce apoptosis through the generation of reactive oxygen species (ROS) and decreasing hypoxia-inducible factor (HIF) signaling. Recent studies have shown the absence of expression of POX in human cancer tissues, including renal cancer. However, the mechanism for the loss of POX remains obscure. No genetic or epigenetic variation of POX gene was found. In this study, we identified the upregulated miR-23b* in renal cancer as an important regulator of POX. Ectopic overexpression of miR-23b* in normal renal cells resulted in striking downregulation of POX, whereas POX expression increased markedly when endogenous miR-23b* was knocked down by its antagomirs in renal cancer cells. Consistent with the POX-mediated tumor suppression pathway, these antagomirs induced ROS, inhibited HIF signaling and increased apoptosis. Furthermore, we confirmed the regulation of miR-23b* on POX and its function in the DLD1 Tet-off POX cell system. Using a luciferase reporter system, we verified the direct binding of miR-23b* to the POX mRNA 3′-untranslated region. In addition, pairs of human renal carcinoma and normal tissues showed a negative correlation between miR-23b* and POX protein expression, providing its clinical corroboration. Taken together, our results suggested that miR-23b*, by targeting POX, could function as an oncogene; decreasing miR-23b* expression may prove to be an effective way of inhibiting kidney tumor growth.
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References
Bartel DP . (2004). MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116: 281–297.
Chen K, Rajewsky N . (2007). The evolution of gene regulation by transcription factors and microRNAs. Nat Rev Genet 8: 93–103.
Chow TF YY, Lianidou E, Romaschin AD, Honey RJ, Stewart R, Pace KT et al. (2009). Differential expression profiling of microRNAs and their potential involvement in renal cell carcinoma pathogenesis. Clin Biochem 43: 150–158.
Denli AM, Tops BB, Plasterk RH, Ketting RF, Hannon GJ . (2004). Processing of primary microRNAs by the microprocessor complex. Nature 432: 231–235.
Donald SP, Sun XY, Hu CA, Yu J, Mei JM, Valle D et al. (2001). Proline oxidase, encoded by p53-induced gene-6, catalyzes the generation of proline-dependent reactive oxygen species. Cancer Res 61: 1810–1815.
Gandellini P, Folini M, Longoni N, Pennati M, Binda M, Colecchia M et al. (2009). miR-205 Exerts tumor-suppressive functions in human prostate through down-regulation of protein kinase Cepsilon. Cancer Res 69: 2287–2295.
Gao P, Tchernyshyov I, Chang TC, Lee YS, Kita K, Ochi T et al. (2009). c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature 458: 762–765.
Girgin C, Tarhan H, Hekimgil M, Sezer A, Gurel G . (2001). P53 mutations and other prognostic factors of renal cell carcinoma. Urol Int 66: 78–83.
Gottardo F, Liu CG, Ferracin M, Calin GA, Fassan M, Bassi P et al. (2007). Micro-RNA profiling in kidney and bladder cancers. Urol Oncol 25: 387–392.
Gregory RI, Yan KP, Amuthan G, Chendrimada T, Doratotaj B, Cooch N et al. (2004). The microprocessor complex mediates the genesis of microRNAs. Nature 432: 235–240.
Guimbellot JS, Erickson SW, Mehta T, Wen H, Page GP, Sorscher EJ et al. (2009). Correlation of microRNA levels during hypoxia with predicted target mRNAs through genome-wide microarray analysis. BMC Med Genomics 2: 15.
Iorio MV, Ferracin M, Liu CG, Veronese A, Spizzo R, Sabbioni S et al. (2005). MicroRNA gene expression deregulation in human breast cancer. Cancer Res 65: 7065–7070.
Johnson SM, Grosshans H, Shingara J, Byrom M, Jarvis R, Cheng A et al. (2005). RAS is regulated by the let-7 microRNA family. Cell 120: 635–647.
Kaelin Jr WG . (2009). Treatment of kidney cancer: insights provided by the VHL tumor-suppressor protein. Cancer 115: 2262–2272.
Kim S, Lee UJ, Kim MN, Lee EJ, Kim JY, Lee MY et al. (2008). MicroRNA miR-199a*regulates the MET proto-oncogene and the downstream extracellular signal-regulated kinase 2 (ERK2). J Biol Chem 283: 18158–18166.
Kondo K, Klco J, Nakamura E, Lechpammer M, Kaelin Jr WG . (2002). Inhibition of HIF is necessary for tumor suppression by the von Hippel-Lindau protein. Cancer Cell 1: 237–246.
Kulshreshtha R, Davuluri RV, Calin GA, Ivan M . (2008). A microRNA component of the hypoxic response. Cell Death Differ 15: 667–671.
Kulshreshtha R, Ferracin M, Wojcik SE, Garzon R, Alder H, Agosto-Perez FJ et al. (2007). A microRNA signature of hypoxia. Mol Cell Biol 27: 1859–1867.
Lewis BP, Burge CB, Bartel DP . (2005). Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 120: 15–20.
Lim LP, Lau NC, Garrett-Engele P, Grimson A, Schelter JM, Castle J et al. (2005). Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature 433: 769–773.
Liu Y, Borchert GL, Donald SP, Diwan BA, Anver M, Phang JM . (2009). Proline oxidase functions as a mitochondrial tumor suppressor in human cancers. Cancer Res 69: 6414–6422.
Liu Y, Borchert GL, Donald SP, Surazynski A, Hu CA, Weydert CJ et al. (2005). MnSOD inhibits proline oxidase-induced apoptosis in colorectal cancer cells. Carcinogenesis 26: 1335–1342.
Liu Y, Borchert GL, Surazynski A, Hu CA, Phang JM . (2006). Proline oxidase activates both intrinsic and extrinsic pathways for apoptosis: the role of ROS/superoxides, NFAT and MEK/ERK signaling. Oncogene 25: 5640–5647.
Liu Y, Borchert GL, Surazynski A, Phang JM . (2008). Proline oxidase, a p53-induced gene, targets COX-2/PGE2 signaling to induce apoptosis and inhibit tumor growth in colorectal cancers. Oncogene 27: 6729–6737.
Lodygin D, Tarasov V, Epanchintsev A, Berking C, Knyazeva T, Korner H et al. (2008). Inactivation of miR-34a by aberrant CpG methylation in multiple types of cancer. Cell Cycle 7: 2591–2600.
Ma L, Teruya-Feldstein J, Weinberg RA . (2007). Tumour invasion and metastasis initiated by microRNA-10b in breast cancer. Nature 449: 682–688.
Maranchie JK, Vasselli JR, Riss J, Bonifacino JS, Linehan WM, Klausner RD . (2002). The contribution of VHL substrate binding and HIF1-alpha to the phenotype of VHL loss in renal cell carcinoma. Cancer Cell 1: 247–255.
Maxwell SA, Rivera A . (2003). Proline oxidase induces apoptosis in tumor cells, and its expression is frequently absent or reduced in renal carcinomas. J Biol Chem 278: 9784–9789.
Migliore C, Petrelli A, Ghiso E, Corso S, Capparuccia L, Eramo A et al. (2008). MicroRNAs impair MET-mediated invasive growth. Cancer Res 68: 10128–10136.
Miranda KC, Huynh T, Tay Y, Ang YS, Tam WL, Thomson AM et al. (2006). A pattern-based method for the identification of microRNA binding sites and their corresponding heteroduplexes. Cell 126: 1203–1217.
Nakada C, Matsuura K, Tsukamoto Y, Tanigawa M, Yoshimoto T, Narimatsu T et al. (2008). Genome-wide microRNA expression profiling in renal cell carcinoma: significant down-regulation of miR-141 and miR-200c. J Pathol 216: 418–427.
Nass D, Rosenwald S, Meiri E, Gilad S, Tabibian-Keissar H, Schlosberg A et al. (2009). MiR-92b and miR-9/9*are specifically expressed in brain primary tumors and can be used to differentiate primary from metastatic brain tumors. Brain Pathol 19: 375–383.
Northcott PA, Fernandez LA, Hagan JP, Ellison DW, Grajkowska W, Gillespie Y et al. (2009). The miR-17/92 polycistron is up-regulated in sonic hedgehog-driven medulloblastomas and induced by N-myc in sonic hedgehog-treated cerebellar neural precursors. Cancer Res 69: 3249–3255.
Pandhare J, Cooper SK, Phang JM . (2006). Proline oxidase, a proapoptotic gene, is induced by troglitazone: evidence for both peroxisome proliferator-activated receptor gamma-dependent and -independent mechanisms. J Biol Chem 281: 2044–2052.
Phang JM . (1985). The regulatory functions of proline and pyrroline-5-carboxylic acid. Curr Top Cell Regul 25: 91–132.
Phang JM, Pandhare J, Liu Y . (2008). The metabolism of proline as microenvironmental stress substrate. J Nutr 138: 2008S–2015S.
Polyak K, Xia Y, Zweier JL, Kinzler KW, Vogelstein B . (1997). A model for p53-induced apoptosis. Nature 389: 300–305.
Smaldone MC, Maranchie JK . (2009). Clinical implications of hypoxia inducible factor in renal cell carcinoma. Urol Oncol 27: 238–245.
Sowter HM, Raval RR, Moore JW, Ratcliffe PJ, Harris AL . (2003). Predominant role of hypoxia-inducible transcription factor (Hif)-1alpha versus Hif-2alpha in regulation of the transcriptional response to hypoxia. Cancer Res 63: 6130–6134.
Suzuki Y, Tamura G, Satodate R, Fujioka T . (1992). Infrequent mutation of p53 gene in human renal cell carcinoma detected by polymerase chain reaction single-strand conformation polymorphism analysis. Jpn J Cancer Res 83: 233–235.
Williams AE . (2008). Functional aspects of animal microRNAs. Cell Mol Life Sci 65: 545–562.
Yang H, Kong W, He L, Zhao JJ, O'Donnell JD, Wang J et al. (2008). MicroRNA expression profiling in human ovarian cancer: miR-214 induces cell survival and cisplatin resistance by targeting PTEN. Cancer Res 68: 425–433.
Zhang H, Gao P, Fukuda R, Kumar G, Krishnamachary B, Zeller KI et al. (2007). HIF-1 inhibits mitochondrial biogenesis and cellular respiration in VHL-deficient renal cell carcinoma by repression of C-MYC activity. Cancer Cell 11: 407–420.
Acknowledgements
We thank Dr Anna E Maciag for insightful comments, Dr Matthew J Fivash for statistical analysis, Dr Miriam R Anver for evaluating POX immunohistochemical staining and miR-23b* in situ hybridization, Dr Chang H Kim for his help with the miRNA microarray. This research was supported (in part) by the Intramural Research Program of the NIH, the National Cancer Institute, Center for Cancer Research. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government.
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Liu, W., Zabirnyk, O., Wang, H. et al. miR-23b* targets proline oxidase, a novel tumor suppressor protein in renal cancer. Oncogene 29, 4914–4924 (2010). https://doi.org/10.1038/onc.2010.237
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DOI: https://doi.org/10.1038/onc.2010.237
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