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High-frequency Alu-mediated genomic recombination/deletion within the caspase-activated DNase gene in human hepatoma

Oncogene volume 24, pages 6584–6589 (2005)Cite this article

Abstract

The Alu repetitive elements, which constitute 10% of human genome, may serve as bridges for genomic recombination. However, their roles in tumorigenesis remain to be elucidated. Caspase-activated DNase (CAD), whose gene (hCAD) is mapped at chromosome 1p36, a region frequently displaying hemizygote deletion in many human cancers, is the key enzyme for nucleosome fragmentation during apoptosis. Recently, we detected many aberrant mRNAs for hCAD in many human hepatoma cells. To elucidate the genetic basis leading to the mRNA aberration, we used PCR-based chromosome walking to clone the corresponding genomic DNA identifying a novel Alu/Alu homologous recombination/deletion within hCAD in HepG2 and Hep3B cells. We then detected similar recombination events in 13 out of the 20 hepatoma tissues and in eight of the para-cancerous cirrhotic livers. The recombination was inclined to occur in males (P=0.031) and had marginal association with high-grade hepatoma (P=0.070) and tumor recurrence (P=0.070). The recombination caused exon-3 deletion, which in turn led to exon-3 skipping or replacement with a partial Alu-sequence, and consequential C-truncation of CAD. Our findings of high frequency of Alu-mediated hCAD deletion in human hepatoma not only underscore the implication of hCAD in hepatocarcinogenesis, but also highlight the potential roles of human repetitive sequences in mediating genome instability in human cancers.

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References

  • Bader SA, Fasching C, Brodeur GM and Stanbridge EJ . (1991). Cell Growth Differ., 2, 245–255.

  • Batzer MA and Deininger PL . (2002). Nat. Rev. Genet., 3, 370–379.

  • Chen SJ, Chen Z, Font MP, d'Auriol L, Larsen CJ and Berger R . (1989). Nucleic Acids Res., 17, 7631–7642.

  • Cheng NC, Van Roy N, Chan A, Beitsma M, Westerveld A, Speleman F and Versteeg R . (1995). Oncogene, 10, 291–297.

  • Deininger PL and Batzer MA . (1999). Mol. Genet. Metabol., 67, 183–193.

  • Enari M, Sakahira H, Yokoyama H, Okawa K, Iwamatsu A and Nagata SA . (1998). Nature, 391, 43–50.

  • Halenbeck R, MacDonald H, Roulstone A, Chen TT, Conrou L and Williams LT . (1998). Curr. Biol., 8, 537–540.

  • Hanahan D and Weinberg RA . (2000). Cell, 100, 57–70.

  • Hsieh SY, Liaw SF, Lee SN, Hsieh PS, Chu CM and Liaw YF . (2003). Br. J. Cancer, 88, 210–216.

  • Hsieh SY, Yang PY, Chen HC and Liaw YF . (1997). Proc. Natl. Acad. Sci. USA, 94, 3206–3210.

  • Jeffs AR, Benjes SM, Smith TL, Sowerby SJ and Morris CM . (1998). Hum. Mol. Genet., 7, 767–776.

  • Kaghad M, Bonnet H, Yang A, Creancier K, Biscan JC, Valent A, Minty A, Chalon P, Lelias JM, Dumon X, Ferrara P, McKeon F and Caput D . (1997). Cell, 90, 809–819.

  • Kolomietz E, Al-Maghrabi J, Brennan S, Karaskova J, Minkin S, Lipton J and Squire JA . (2001). Blood, 97, 3581–3588.

  • Kuroki T, Fujivara Y, Tsuchiya E, Nakamori S, Imaoka S, Kanematsu T and Nakamura Y . (1995). Genes Chromosomes Cancer, 13, 163–167.

  • Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC, Baldwin J, Devon K, Dewar K, Doyle M, FitzHugh W, Funke R, Gage D, Harris K, Heaford A, Howland J, Kann L, Lehoczky J, LeVine R, McEwan P, McKernan K, Meldrim J, Mesirov JP, Miranda C, Morris W, Naylor J, Raymond C, Rosetti M, Santos R, Sheridan A, Sougnez C, Stange-Thomann N, Stojanovic N, Subramanian A, Wyman D, Rogers J, Sulston J, Ainscough R, Beck S, Bentley D, Burton J, Clee C, Carter N, Coulson A, Deadman R, Deloukas P, Dunham A, Dunham I, Durbin R, French L, Grafham D, Gregory S, Hubbard T, Humphray S, Hunt A, Jones M, Lloyd C, McMurray A, Matthews L, Mercer S, Milne S, Mullikin JC, Mungall A, Plumb R, Ross M, Shownkeen R, Sims S, Waterston RH, Wilson RK, Hillier LW, McPherson JD, Marra MA, Mardis ER, Fulton LA, Chinwalla AT, Pepin KH, Gish WR, Chissoe SL, Wendl MC, Delehaunty KD, Miner TL, Delehaunty A, Kramer JB, Cook LL, Fulton RS, Johnson DL, Minx PJ, Clifton SW, Hawkins T, Branscomb E, Predki P, Richardson P, Wenning S, Slezak T, Doggett N, Cheng JF, Olsen A, Lucas S, Elkin C, Uberbacher E, Frazier M, Gibbs RA, Muzny DM, Scherer SE, Bouck JB, Sodergren EJ, Worley KC, Rives CM, Gorrell JH, Metzker ML, Naylor SL, Kucherlapati RS, Nelson DL, Weinstock GM, Sakaki Y, Fujiyama A, Hattori M, Yada T, Toyoda A, Itoh T, Kawagoe C, Watanabe H, Totoki Y, Taylor T, Weissenbach J, Heilig R, Saurin W, Artiguenave F, Brottier P, Bruls T, Pelletier E, Robert C, Wincker P, Smith DR, Doucette-Stamm L, Rubenfield M, Weinstock K, Lee HM, Dubois J, Rosenthal A, Platzer M, Nyakatura G, Taudien S, Rump A, Yang H, Yu J, Wang J, Huang G, Gu J, Hood L, Rowen L, Madan A, Qin S, Davis RW, Federspiel NA, Abola AP, Proctor MJ, Myers RM, Schmutz J, Dickson M, Grimwood J, Cox DR, Olson MV, Kaul R, Raymond C, Shimizu N, Kawasaki K, Minoshima S, Evans GA, Athanasiou M, Schultz R, Roe BA, Chen F, Pan H, Ramser J, Lehrach H, Reinhardt R, McCombie WR, de la Bastide M, Dedhia N, Blocker H, Hornischer K, Nordsiek G, Agarwala R, Aravind L, Bailey JA, Bateman A, Batzoglou S, Bimey E, Bork P, Brown DG, Burge CB, Cerutti L, Chen HC, Church D, Clamp M, Copley RR, Doerks T, Eddy SR, Eichler EE, Furey TS, Galagan J, Gilbert JG, Harmon C, Hayashizaki Y, Haussier D, Hermjakob H, Hokamp K, Jang W, Johnson LS, Jones TA, Kasif S, Kaspryzk A, Kennedy S, Kent WJ, Kitts P, Koonin EV, Korf I, Kulp D, Lancet D, Lowe TM, McLysaght A, Mikkelsen T, Moran JV, Mulder N, Pollara VJ, Ponting CP, Schuler G, Schultz J, Slater G, Smit AF, Stupka E, Szustakowski J, Thierry-Mieg D, Thierry-Mieg J, Wagner L, Wallis J, Wheeler R, Williams A, Wolf YI, Wolfe KH, Yang SP, Yeh RF, Collins F, Guyer MS, Peterson J, Felsenfeld A, Wetterstrand KA, Patrinos A, Morgan MJ, de Jong P, Catanese JJ, Osoegawa K, Shizuya H, Choi S, Chen YJ and International Human Geome Sequencing Consortium. (2001). Nature, 409, 860–921.

    Article  CAS  Google Scholar 

  • Lehrman MA, Russel DW, Goldstein JL and Brown MS . (1987). J. Bio. Chem., 262, 3354–3361.

  • Lin CH, Hsieh SY, Sheen IS, Lee WC, Chen TC, Shyu WC and Liaw YF . (2001). Cancer Res., 61, 4238–4243.

  • Liu X, Li P, Widlak P, Zou H, Luo X, Garrard WT and Wang X . (1998). Proc. Natl. Acad. Sci. USA, 95, 8461–8466.

  • Liu X, Zou H, Slaughter C and Wang X . (1997). Cell, 89, 175–184.

  • Lobachev KS, Stenger JE, Kazyreva OG, Jurka J, Gordenin DA and Resnick MA . (2000). EMBO J., 19, 3822–3830.

  • Mighell AJ, Markham AF and Robinson PA . (1997). FEBS Lett., 417, 1–5.

  • Mukae N, Enari M, Sakahira H, Fukuda Y, Inazawa J, Toh H and Nagata S . (1998). Proc. Natl. Acad. Sci., USA, 95, 9123–9128.

  • Nagai H, Pineau P, Tiollais P, Buendia MA and Dejean A . (1997). Oncogene, 14, 2927–2933.

  • Nagase H, Fukuyama H, Tanaka T, Kawane K and Nagata S . (2003). Cell Death Differ., 10, 142–143.

  • Nagata S, Nagase H, Kawane K and Fukuyama H . (2003). Cell Death Differ., 10, 108–116.

  • Rohlfs EM, Puget N, Graham ML, Weber BL, Garber JE, Skrzynia C, Halperin JL, Lenior GM, Silverman LM and Mazoyer S . (2000). Genes Chromosome Cancer, 28, 300–307.

  • Rowold DJ and Herrera RJ . (2000). Genetica, 108, 57–72.

  • Rudiger NS, Gregersen N and Kielland-Brandt MC . (1995). NucleicAcids Res., 23, 256–260.

  • Sakahira H, Enari M and Nagata S . (1998). Nature, 391, 96–99.

  • Schmid CW . (1996). Prog. Nucleic Acid Res. Mol. Biol., 53, 283–319.

  • Simon D, Knowles BB and Weith A . (1991). Oncogene, 6, 765–770.

  • Smit AF . (1999). Curr. Opin. Genet. Dev., 9, 657–663.

  • Stenger JE, Lobachev KS, Gordeni D, Darden TA, Jurka J and Resnick MA . (2001). Genome Res., 11, 2–27.

  • Stoppa-Lyonnet D, Carter PE, Meo T and Tosi M . (1990). Proc. Natl. Acad. Sci. USA, 87, 1551–1555.

  • Tanaka K, Yanoshita R, Konishi M, Oshimura M, Maeda Y, Mori T and Miyaki M . (1993). Oncogene, 8, 2253–2258.

  • Venter JC, Adams MD, Myers EW, Li PW, Mural RJ, Sutton GG, Smith HO, Yandell M, Evans CA, Holt RA, Gocayne JD, Amanatides P, Ballew RM, Huson DH, Wortman JR, Zhang Q, Kodira CD, Zheng XH, Chen L, Skupski M, Subramanian G, Thomas PD, Zhang J, Gabor Miklos GL, Nelson C, Broder S, Clark AG, Nadeau J, McKusick VA, Zinder N, Levine AJ, Roberts RJ, Simon M, Slayman C, Hunkapiller M, Bolanos R, Delcher A, Dew I, Fasulo D, Flanigan M, Florea L, Halpern A, Hannenhalli S, Kravitz S, Levy S, Mobarry C, Reinert K, Remington K, Abu-Threideh J, Beasley E, Biddick K, Bonazzi V, Brandon R, Cargill M, Chandramouliswaran I, Charlab R, Chaturvedi K, Deng Z, Di Francesco V, Dunn P, Eilbeck K, Evangelista C, Gabrielian AE, Gan W, Ge W, Gong F, Gu Z, Guan P, Heiman TJ, Higgins ME, Ji RR, Ke Z, Ketchum KA, Lai Z, Lei Y, Li Z, Li J, Liang Y, Lin X, Lu F, Merkulov GV, Milshina N, Moore HM, Naik AK, Narayan VA, Neelam B, Nusskern D, Rusch DB, Salzberg S, Shao W, Shue B, Sun J, Wang Z, Wang A, Wang X, Wang J, Wei M, Wides R, Xiao C, Yan C, Yao A, Ye J, Zhan M, Zhang W, Zhang H, Zhao Q, Zheng L, Zhong F, Zhong W, Zhu S, Zhao S, Gilbert D, Baumhueter S, Spier G, Carter C, Cravchik A, Woodage T, Ali F, An H, Awe A, Baldwin D, Baden H, Barnstead M, Barrow I, Beeson K, Busam D, Carver A, Center A, Cheng ML, Curry L, Danaher S, Davenport L, Desilets R, Dietz S, Dodson K, Doup L, Ferriera S, Garg N, Gluecksmann A, Hart B, Haynes J, Haynes C, Heiner C, Hladun S, Hostin D, Houck J, Howland T, Ibegwam C, Johnson J, Kalush F, Kline L, Koduru S, Love A, Mann F, May D, McCawley S, Mclntosh T, McMullen I, Moy M, Moy L, Murphy B, Nelson K, Pfannkoch C, Pratts E, Puri V, Qureshi H, Reardon M, Rodriguez R, Rogers YH, Romblad D, Ruhfel B, Scott R, Sitter C, Smallwood M, Stewart E, Strong R, Suh E, Thomas R, Tint NN, Tse S, Vech C, Wang G, Wetter J, Williams S, Williams M, Windsor S, Winn-Deen E, Wolfe K, Zaveri J, Zaveri K, Abril JF, Guigo R, Campbell MJ, Sjolander KV, Karlak B, Kejariwal A, Mi H, Lazareva B, Hatton T, Narechania A, Diemer K, Muruganujan A, Guo N, Sato S, Bafna V, Istrail S, Lippert R, Schwartz R, Walenz B, Yooseph S, Allen D, Basu A, Baxendale J, Blick L, Caminha M, Carnes-Stine J, Caulk P, Chiang YH, Coyne M, Dahike C, Mays A, Dombroski M, Donnelly M, Ely D, Esparham S, Fosler C, Gire H, Glanowski S, Glasser K, Glodek A, Gorokhov M, Graham K, Gropman B, Harris M, Heil J, Henderson S, Hoover J, Jennings D, Jordan C, Jordan J, Kasha J, Kagan L, Kraft C, Levitsky A, Lewis M, Liu X, Lopez J, Ma D, Majoros W, McDaniel J, Murphy S, Newman M, Nguyen T, Nguyen N, Nodell M, Pan S, Peck J, Peterson M, Rowe W, Sanders R, Scott J, Simpson M, Smith T, Sprague A, Stockwell T, Turner R, Venter E, Wang M, Wen M, Wu D, Wu M, Xia A, Zandieh A and Zhu X . (2001). Science, 291, 1304–1351.

  • Yeh SH, Chen PJ, Shau WY, Chen YW, Lee PH, Chen JT and Chen DS . (2001). Gastroenterology, 121, 699–709.

  • Zhang J, Liu X, Scherer DC, van Kaer L, Wand X and Xu M . (1998). Proc. Natl. Acad. Sci. USA, 95, 12480–121485.

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Acknowledgements

We thank Professor Jao-Ming Lien for the critical reading of this manuscript, and Miss Su-Chen Ji for help in preparation of this manuscript. This work was supported by a research grant from Chang Gung Memorial Hospital (CTRP).

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Authors and Affiliations

  1. Liver Research Unit, Chang Gung Memorial Hospital, No 5, Fu-Hsin Road, Kwei-San, 333, Tao-Yuan, Taiwan

    Sen-Yung Hsieh, Wai-Ying Chen & I-Shyan Sheen

  2. Clinical Proteomics Center, Chang Gung Memorial Hospital, 333, Tao-Yuan, Taiwan

    Sen-Yung Hsieh & Wai-Ying Chen

  3. Department of Microbiology and Immunology, School of Medicine, Chang Gung University, 333, Tao-Yuan, Taiwan

    Sen-Yung Hsieh

  4. Department of General Surgery, Chang Gung Memorial Hospital, 333, Tao-Yuan, Taiwan

    Ta-Sen Yeh

  5. Division of Molecular and Genomic Medicine, National Health Research Institute, 115, Taipei, Taiwan

    Shiu-Feng Huang

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Hsieh, SY., Chen, WY., Yeh, TS. et al. High-frequency Alu-mediated genomic recombination/deletion within the caspase-activated DNase gene in human hepatoma. Oncogene 24, 6584–6589 (2005). https://doi.org/10.1038/sj.onc.1208803

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