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Upregulation of ASCL1 and inhibition of Notch signaling pathway characterize progressive astrocytoma

Oncogene volume 24, pages 7073–7083 (2005)Cite this article

Abstract

Astrocytoma is the most common type of brain cancer constituting more than half of all brain tumors. With an aim to identify markers describing astrocytoma progression, we have carried out microarray analysis of astrocytoma samples of different grades using cDNA microarray containing 1152 cancer-specific genes. Data analysis identified several differentially regulated genes between normal brain tissue and astrocytoma as well as between grades II/III astrocytoma and glioblastoma multiforme (GBM; grade IV). We found several genes known to be involved in malignancy including Achaete-scute complex-like 1 (Drosophila) (ASCL1; Hash 1). As ASCL has been implicated in neuroendocrine, medullary thyroid and small-cell lung cancers, we chose to examine the role of ASCL1 in the astrocytoma development. Our data revealed that ASCL1 is overexpressed in progressive astrocytoma as evidenced by increased levels of ASCL1 transcripts in 85.71% (6/7) of grade II diffuse astrocytoma (DA), 90% (9/10) of grade III anaplastic astrocytoma (AA) and 87.5% (7/8) of secondary GBMs, while the majority of primary de novo GBMs expressed similar to or less than normal brain levels (66.67%; 8/12). ASCL1 upregulation in progressive astrocytoma is accompanied by inhibition of Notch signaling as seen by uninduced levels of HES1, a transcriptional target of Notch1, increased levels of HES6, a dominant-negative inhibitor of HES1-mediated repression of ASCL1, and increased levels of Notch ligand Delta1, which is capable of inhibiting Notch signaling by forming intracellular Notch ligand autonomous complexes. Our results imply that inhibition of Notch signaling may be an important early event in the development of grade II DA and subsequent progression to grade III AA and secondary GBM. Furthermore, ASCL1 appears to be a putative marker to distinguish primary GBM from secondary GBM.

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Abbreviations

ASCL1:

Achaete-scute complex-like 1 (Drosophila)

GBM:

glioblastoma multiforme

HES1:

Hairy and Enhancer of Split 1

HES6:

Hairy and Enhancer of Split 6

DA:

diffuse astrocytoma

AA:

anaplastic astrocytoma

References

  • Apelqvist A, Li H, Sommer L, Beatus P, Anderson DJ, Honjo T, Hrabe de Angelis M, Lendahl U and Edlund H . (1999). Nature, 400, 877–881.

  • Artavanis-Tsakonas S, Matsuno K and Fortini ME . (1995). Science, 268, 225–232.

  • Artavanis-Tsakonas S, Rand MD and Lake RJ . (1999). Science, 284, 770–776.

  • Bae SK, Bessho Y, Hojo M and Kageyama R . (2000). Development, 127, 2933–2943.

  • Ball DW, Azzoli CG, Baylin SB, Chi D, Dou S, Donis-Keller H, Cumaraswamy A, Borges M and Nelkin BD . (1993). Proc. Natl. Acad. Sci. USA, 90, 5648–5652.

  • Bonni A, Sun Y, Nadal-Vicens M, Bhatt A, Frank DA, Rozovsky I, Stahl N, Yancopoulos GD and Greenberg ME . (1997). Science, 278, 477–483.

  • Borges M, Linnoila RI, Van de Velde HJ, Chen H, Nelkin BD, Mabry M, Baylin SB and Ball DW . (1997). Nature, 386, 852–855.

  • Brock CS and Bower M . (1997). Med. Oncol., 14, 103–120.

  • Campomenosi P, Ottaggio L, Moro F, Urbini S, Bogliolo M, Zunino A, Camoriano A, Inga A, Gentile SL, Pellegata NS, Bonassi S, Bruzzone E, Iannone R, Pisani R, Menichini P, Ranzani GN, Bonatti S, Abbondandolo A and Fronza G . (1996). Cancer Genet. Cytogenet., 8, 95–102.

  • Casarosa S, Fode C and Guillemot F . (1999). Development, 126, 525–534.

  • Chen H, Thiagalingam A, Chopra H, Borges MW, Feder JN, Nelkin BD, Baylin SB and Ball DW . (1997). Proc. Natl. Acad. Sci. USA, 94, 5355–5360.

  • Davis F, Freels S, Grutsch J, Barlas S and Brem S . (1998). J. Neurosurg., 88, 1–10.

  • DeAngelis LM . (2001). N. Engl. J. Med., 344, 114–123.

  • Eisen MB, Spellman PT, Brown PO and Botstein D . (1998). Proc. Natl. Acad. Sci. USA, 95, 14863–14868.

  • Ellisen LW, Bird J, West DC, Soreng AL, Reynolds TC and Smith SD . (1991). Cell, 66, 649–661.

  • Fathallah-Shaykh HM, Rigen M, Zhao LJ, Bansal K, He B, Engelhard HH, Cerullo L, Von Roenn K, Byrne R, Munoz L, Rosseau GL, Glick R, Lichtor T and DiSavino E . (2002). Oncogene, 21, 7164–7174.

  • Fleming TP, Saxena A, Clark WC, Robertson JT, Oldfield EH, Aaronson SA and Ali IU . (1992). Cancer Res., 52, 4550–4553.

  • Frederick L, Wang XY, Eley G and James CD . (2000). Ann. Intern. Med., 138, 658–659.

  • Furukawa T, Mukherjee S, Bao ZZ, Morrow EM and Cepko CL . (2000). Neuron, 26, 383–394.

  • Ge W, Martinowich K, Wu X, He F, Miyamoto A, Fan G, Weinmaster G and Sun YE . (2002). J. Neurosci. Res., 69, 848–860.

  • Ghysen A, Dambly-Chaudiere C, Jan LY and Jan YN . (1993). Genes Dev., 7, 723–733.

  • Gibert JM and Simpson P . (2003). Int. J. Dev. Biol., 47, 643–651.

  • Godard S, Getz G, Delorenzi M, Farmer P, Kobayashi H, Desbaillets I, Michimasa N, Diserens AC, Hamou MF, Dietrich PY, Regli L, Janzer RC, Bucher P, Stupp R, de Tribolet N, Domany E and Hegi ME . (2003). Cancer Res., 63, 6613–6625.

  • Hall KT, Boumsell L, Schultze JL, Boussiotis VA, Dorfman DM, Cardoso AA, Bensussan A, Nadler LM and Freeman GJ . (1996). Proc. Natl. Acad. Sci. USA, 93, 11780–11785.

  • Haltiwanger RS and Stanley P . (2002). Biochim. Biophys. Acta., 1573, 328–335.

  • Heitzler P, Bourouis M, Ruel L, Carteret C and Simpson P . (1996). Development, 122, 161–171.

  • Hermanson MK, Funa M, Hartman L, Claesson-Welsh CH, Heldin B, Westermark M and Nistér M . (1992). Cancer Res., 52, 3213–3219.

  • Hermanson M, Funa K, Koopman J, Maintz D, Waha A, Westermark B, Heldin CH, Wiestler OD, Louis DN, von Deimling A and Nistér M . (1996). Cancer Res., 56, 164–171.

  • Hill JR, Kuriyama N, Kuriyama H and Israel MA . (1999). Arch. Neurol., 56, 439–441.

  • Ito T, Udaka N, Yazawa T, Okudela K, Hayashi H, Sudo T, Guillemot F, Kageyama R and Kitamura H . (2000). Development, 127, 3913–3921.

  • James CD, He J, Carlbom E, Nordenskjold M, Cavenee WK and Collins VP . (1991). Cancer Res., 51, 1684–1688.

  • Johe KK, Hazel TG, Muller T, Dugich-Djordjevic MM and McKay RD . (1996). Genes Dev., 10, 3129–3140.

  • Jordanova ES, Riemersma SA, Philippo K, Schuuring E and Kluin PM . (2003). Int. J. Cancer, 103, 393–398.

  • Kleihues P, Louis DN, Scheithauer BW, Rorke LB, Reifenberger G, Burger PC and Cavenee WK . (2002). J. Neuropathol. Exp. Neurol., 61, 215–225.

  • Kleihues P, Burger PC, Collins VP, Ohgaki H and Cavenee WK . (2000). Glioblastoma: In Pathology and Genetics of Tumors of Nervous System Kleihues P and Cavenee WK (eds) IARC Press: Lyon, pp 29–39.

    Google Scholar 

  • Kleihues P and Ohgaki H . (1999). Neurooncology, 1, 44–51.

  • Kumanogoh A, Marukawa S, Suzuki K, Takegahara N, Watanabe C, Ch'ng E, Ishida I, Fujimura H, Sakoda S, Yoshida K and Kikutani H . (2002). Nature, 419, 629–633.

  • Landis SH, Murray T, Bolden S and Wingo PA . (1999). Cancer J. Clin., 49, 8–31.

  • Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang S, Puc J, Miliaresis C, Rodgers L, McCombie R, Bigner S, Giovanella B, Ittmann M, Tycko B, Hibshoosh H, Wigler M and Parsons R . (1997). Science, 275, 1943–1947.

  • Liau LM, Lallone RL, Seitz RS, Buznikov A, Gregg JP, Kornblum HI, Nelson SF and Bronstein JM . (2000). Cancer Res., 60, 1353–1360.

  • Ljubimova JY, Lakhter AJ, Loksh A, Yong WH, Riedinger MS, Miner JH, Sorokin LM, Ljubimova AV and Black KL . (2001). Cancer Res., 61, 5601–5610.

  • Louis DN and Gusella JF . (1995). Trends Genet., 11, 412–415.

  • Maher EA, Furnari FB, Bachoo RM, Rowitch DH, Louis DN, Cavenee WK and DePinho RA . (2001). Genes Dev., 15, 1311–1333.

  • Maxwell M, Naber SP, Wolfe HJ, Galanopoulos T, Hedley-Whyte ET, Black P and Antoniades N . (1990). J. Clin. Invest., 85, 131–140.

  • Mischel PS and Vinters HV . (2001). Brain Tumor Immunotherapy. Liau L Mea (ed) Humana Press: Totowa, NJ. pp 3–45.

    Book  Google Scholar 

  • Mitelman F, Johansson B and Mertens F (eds). (2002). http://cgap.ci.nih.gov/Chromosomes/Mitelman.

  • Moloney DJ, Panin VM, Johnston SH, Chen J, Shao L, Wilson R, Wang Y, Stanley P, Irvine KD, Haltiwanger RS and Vogt TF . (2000). Nature, 406, 369–375.

  • Morrison SJ, Perez SE, Qiao Z, Verdi JM, Hicks C, Weinmaster G and Anderson DJ . (2000). Cell, 101, 499–510.

  • Muller P, Kietz S, Gustafsson JA and Strom A . (2002). J. Biol. Chem., 277, 28376–28379.

  • Nagane M, Su Huang HJ and Cavenee WK . (1997). Curr. Opin. Oncol., 9, 215–222.

  • Nair P, Somasundaram K and Krishna S . (2003). J. Virol., 77, 7106–7112.

  • Nicolas M, Wolfer A, Raj K, Kummer JA, Mill P, van Noort M, Hui CC, Clevers H, Dotto GP and Radtke F . (2003). Nat. Genet., 33, 416–421.

  • Nieto M, Schuurmans C, Britz O and Guillemot F . (2001). Neuron, 29, 401–413.

  • Novitch BG, Chen AI and Jessell TM . (2001). Neuron, 31, 773–789.

  • Nutt CL, Mani DR, Betensky RA, Tamayo P, Cairncross JG, Ladd C, Pohl U, Hartmann C, McLaughlin ME, Batchelor TT, Black PM, von Deimling A, Pomeroy SL, Golub TR and Louis DN . (2003). Cancer Res., 63, 1602–1607.

  • Olopade OI, Jenkins RB, Ransom DT, Malik K, Pomykala H, Nobori T, Cowan JM, Rowley JD and Diaz MO . (1992). Cancer Res., 52, 2523–2529.

  • Pfaffl MW . (2001). Nucleic Acids Res., 29, 2002–2006.

  • Phatak P, Kalai Selvi S, Divya T, Hegde AS, Hegde S and Somasundaram K . (2002). J. Biosci., 27, 673–686.

  • Post LC, Ternet M and Hogan BL . (2000). Mech. Dev., 98, 95–98.

  • Qian X, Shen Q, Goderie SK, He W, Capela A, Davis AA and Temple S . (2000). Neuron, 28, 69–80.

  • Rangarajan A, Talora C, Okuyama R, Nicolas M, Mammucari C, Oh H, Aster JC, Krishna S, Metzger D, Chambon P, Miele L, Aguet M, Radtke F and Dotto GP . (2001). EMBO J., 20, 3427–3436.

  • Rickman DS, Bobek MP, Misek DE, Kuick R, Blaivas M, Kurnit DM, Taylor J and Hanash SM . (2001). Cancer Res., 61, 6885–6891.

  • Sakamoto K, Ohara O, Takagi M, Takeda S and Katsube K . (2002). Dev. Biol., 241, 313–326.

  • Sallinen SL, Sallinen PK, Haapasalo HK, Helin HJ, Helen PT, Schraml P, Kallioniemi OP and Kononen J . (2000). Cancer Res., 60, 6617–6622.

  • Satow T, Bae SK, Inoue T, Inoue C, Miyoshi G, Tomita K, Bessho Y, Hashimoto N and Kageyama R . (2001). J. Neurosci., 21, 1265–1273.

  • Scheffer GL, de Jong MC, Monks A, Flens MJ, Hose CD, Izquierdo MA, Shoemaker RH and Scheper RJ . (2002). Br. J. Cancer, 86, 1943–1950.

  • Schmidt MC, Antweiler S, Urban N, Mueller W, Kuklik A, Meyer-Puttlitz B, Wiestler OD, Louis DN, Fimmers R and von Deimling A . (2002). J. Neuropathol. Exp. Neurol., 61, 321–328.

  • Strom A, Arai N, Leers J and Gustafsson JA . (2000). Oncogene, 19, 5951–5953.

  • Sun Y, Nadal-Vicens M, Misono S, Lin MZ, Zubiaga A, Hua X, Fan G and Greenberg ME . (2001). Cell, 104, 365–376.

  • Swearingen ML, Sun D, Bourner M and Weinstein EJ . (2003). Cancer Lett., 198, 229–239.

  • Tanigaki K, Nogaki F, Takahashi J, Tashiro K, Kurooka H and Honjo T . (2001). Neuron, 29, 45–55.

  • Tanwar MK, Gilbert MR and Holland EC . (2002). Cancer Res., 62, 4364–4368.

  • Tomita K, Moriyoshi K, Nakanishi S, Guillemot F and Kageyama R . (2000). EMBO J., 19, 5460–5472.

  • Wang H, Wang H, Shen W, Huang H, Hu L, Ramdas L, Zhou Y, Liao WSL, Fuller GN and Zhang W . (2003). Cancer Res., 63, 4315–4321.

  • Watanabe K, Sato K, Biernat W, Tachibana O, von Ammon K, Ogata N, Yonekawa Y, Kleihues P and Ohgaki H . (1997). Clin. Cancer Res., 3, 523–530.

  • Watson MA, Perry A, Budhjara V, Hicks C, Shannon WD and Rich KM . (2001). Cancer Res., 61, 1825–1829.

  • Weinmaster G . (1997). Mol. Cell. Neurosci., 9, 91–102.

  • Westermark B, Heldin CH and Nistér M . (1995). Glia, 15, 257–263.

  • Zhou S, Fujimuro M, Hsieh JJ, Chen L, Miyamoto A, Weinmaster G and Hayward SD . (2000). Mol. Cell. Biol., 20, 2400–2410.

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Acknowledgements

This study was supported by a grant from CSIR, Government of India under the NMITLI program. The DBT funded facilities at IISc is acknowledged.

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Authors and Affiliations

  1. Department of Microbiology and Cell Biology, Indian Institute of Science, Malleswaram, Bangalore, 560012, India

    Kumaravel Somasundaram

  2. Department of Biochemistry, Indian Institute of Science, Malleswaram, Bangalore, 560012, India

    Sreekanth P Reddy, Katyayni Vinnakota, Ramona Britto, Madhavan Subbarayan, Sandeep Nambiar, Aparna Hebbar, Hari Kishore Sreepathi & M R S Rao

  3. Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Malleswaram, Bangalore, 560012, India

    Paturu Kondaiah

  4. Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, 560064, India

    M R S Rao

  5. Department of Neuropathology, National Institute of Mental Health and Neuro Sciences, Bangalore, 560029, India

    Vani Santosh

  6. Sri Satya Sai Institute of Higher Medical Sciences, Bangalore, 560066, India

    Alangar Sathyaranjandas Hegde

  7. Manipal Hospital, Bangalore, 560017, India

    Cini Samuel, Mitesh Shetty & Sridevi Hegde

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Somasundaram, K., Reddy, S., Vinnakota, K. et al. Upregulation of ASCL1 and inhibition of Notch signaling pathway characterize progressive astrocytoma. Oncogene 24, 7073–7083 (2005). https://doi.org/10.1038/sj.onc.1208865

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