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  • Original Paper
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Reduced expression of Hugl-1, the human homologue of Drosophila tumour suppressor gene lgl, contributes to progression of colorectal cancer

Abstract

The human gene, human giant larvae (Hugl-1/Llg1 /Lgl1) has significant homology to the Drosophila tumour suppressor gene lethal(2)giant larvae (lgl). The lgl gene codes for a cortical cytoskeleton protein, Lgl, that binds Myosin II and is involved in maintaining cell polarity and epithelial integrity. The human protein, Hugl-1 contains several conserved functional domains found in Lgl, suggesting that these proteins may have closely related functions. Whether loss of Hugl expression plays a role in human tumorigenesis has so far not been extensively investigated. Thus, we evaluated tumour tissues from 94 patients undergoing surgery for colorectal cancer (CRC) for loss of Hugl-1 transcription and compared our findings with the clinical data from each of these patients. We found that Hugl-1 was lost in 75% of tumour samples and these losses were associated with advanced stage and particularly with lymph node metastases. Reduced Hugl-1 expression during the adenoma-carcinoma sequence occurring as early as in colorectal adenomas was detected by both immunohistochemical and reverse transcription–polymerase chain reaction analysis. Functional assays with ecdysone-inducible cell lines revealed that Hugl-1 expression increased cell adhesion and decreased cell migration. Our studies thus indicate that downregulation of Hugl-1 contributes to CRC progression.

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Abbreviations

bp:

base pair

CRC:

colorectal carcinoma

Hugl :

human giant larvae

lgl :

lethal giant larvae

PCR:

polymerase chain reaction

RT:

reverse transcription

References

  • Agrawal N, Kango M, Mishra A and Sinha P . (1995). Dev. Biol., 172, 218–229.

  • Boulay JL, Mild G, Reuter J, Lagrange M, Terracciano L, Lowy A, Laffer U, Orth B, Metzger U, Stamm B, Martinoli S, Herrmann R and Rochlitz C . (2001). Genes Chromosomes Cancer, 31, 240–247.

  • Chen KS, Gunaratne PH, Hoheisel JD, Young IG, Miklos GL, Greenberg F, Shaffer LG, Campbell HD and Lupski JR . (1995). Am. J. Hum. Genet., 56, 175–182.

  • Cho KR and Vogelstein B . (1992). Cancer, 70, 1727–1731.

  • Dow LE, Brumby AM, Muratore R, Coombe ML, Sedelies KA, Trapani JA, Russell SM, Richardson HE and Humbert PO . (2003). Oncogene, 22, 9225–9230.

  • Fuja TJ, Lin F, Osann KE and Bryant PJ . (2004). Cancer Res., 64, 942–951.

  • Gateff E . (1978). Science, 200, 1448–1459.

  • Grifoni D, Garoia F, Schimanski CC, Schmitz G, Laurenti E, Galle PR, Pession A, Cavicchi S and Strand D . (2004). Oncogene, 23, 8688–8694.

  • Guanti G and Bukvic N . (2000). Acta. Chir. Iugosl., 47, 23–25.

  • Houlston RS, Collins A, Slack J and Morton NE . (1992). Ann. Hum. Genet., 56 (Part 2), 99–103.

  • Humbert PO, Russell S and Richardson HE . (2003). BioEssays, 25, 542–553.

  • Ishidate T, Matsumine A, Toyoshima K and Akiyama T . (2000). Oncogene, 19, 365–372.

  • Kagami M, Toh-e A and Matusui Y . (1998). Genetics, 149, 1717–1727.

  • Klezovitch O, Fernandez TE, Tapscott SJ and Vasioukhin V . (2004). Genes Dev., 18, 559–571.

  • Koyama K, Fukushima Y, Inazawa J, Tomotsune D, Takahashi N and Nakamura Y . (1996). Cytogenet. Cell Genet., 72, 78–82.

  • Krishan A . (1975). J. Cell Biol., 66, 188–193.

  • Larsson K, Bohl F, Sjostrom I, Akhtar N, Strand D, Mechler BM, Grabowski R and Adler L . (1998). J. Biol. Chem., 273, 33610–33618.

  • Leslie A, Pratt NR, Gillespie K, Sales M, Kernohan NM, Smith G, Wolf CR and Carey FA . (2003). Cancer Res., 63, 4656–4661.

  • Lin HT, Steller MA, Aish L, Hanada T and Chishti AH . (2004). Gynecol. Oncol., 93, 422–428.

  • Micheli A, Mugno E, Krogh V, Quinn MJ, Coleman M, Hakulinen T, Gatta G, Berrino F and Capocaccia R . (2002). Ann. Oncol., 13, 840–865.

  • Nicoletti I, Migliorati G, Pagliacci MC, Grignani F and Riccardi C . (1991). J. Immunol. Methods, 139, 271–279.

  • Ohshiro T, Yagami T, Zhang C and Matsuzaki F . (2000). Nature, 408, 593–596.

  • Parker SL, Tong T, Bolden S and Wingo PA . (1996). CA Cancer J. Clin., 46, 5–27.

  • Parkin DM, Pisani P and Ferlay J . (1993). Int. J. Cancer, 54, 594–606.

  • Plant PJ, Fawcett JP, Lin DC, Holdorf AD, Binns K, Kulkarni S and Pawson T . (2003). Nat. Cell Biol., 5, 301–308.

  • Roth S, Johansson M, Loukola A, Peltomaki P, Jarvinen H, Mecklin JP and Aaltonen LA . (2000). J. Med. Genet., 37, 298–300.

  • Scheurlen WG, Seranski P, Mincheva A, Kuhl J, Sorensen N, Krauss J, Lichter P, Poustka A and Wilgenbus KK . (1997). Genes Chromosomes Cancer, 18, 50–58.

  • Scheurlen WG, Schwabe GC, Seranski P, Joos S, Harbott J, Metzke S, Dohner H, Poustka A, Wilgenbus KK and Haas OA . (1999). Genes Chromosomes Cancer, 25, 230–240.

  • Smith G, Carey FA, Beattie J, Wilkie MJ, Lightfoot TJ, Coxhead J, Garner RC, Steele RJ and Wolf CR . (2002). Proc. Natl. Acad. Sci. USA., 99, 9433–9438.

  • Strand D . (1998). G Proteins, Cytoskeleton and Cancer Maruta H, Kohama K. (eds). R.G. Landes: Georgetwon, TX, pp. 61–78.

    Google Scholar 

  • Strand D, Jakobs R, Merdes G, Neumann B, Kalmes A, Heid HW, Husmann I and Mechler BM . (1994a). J. Cell Biol., 127, 1361–1373.

  • Strand D, Raska I and Mechler BM . (1994b). J. Cell Biol., 127, 1345–1360.

  • Strand D, Unger S, Corvi R, Hartenstein K, Schenkel H, Kalmes A, Merdes G, Neumann B, Krieg-Schneider F, Coy JF, Poustka A, Schwab M and Mechler BM . (1995). Oncogene, 11, 291–301.

  • Takagi Y, Koumura H, Futamura M, Aoki S, Ymaguchi K, Kida H, Tanemura H, Shimokawa K and Saji S . (1998). Br. J. Cancer, 78, 1152–1155.

  • Tanentzapf G and Tepass U . (2003). Nat. Cell Biol., 5, 46–52.

  • Thomas U, Phannavong B, Muller B, Garner CC and Gundelfinger ED . (1997). Mech. Dev., 62, 161–174.

  • Timmons L, Hersperger E, Woodhouse E, Xu J, Liu LZ and Shearn A . (1993). Dev. Biol., 158, 364–379.

  • Vogelstein B and Kinzler KW . (1993). Trends Genet., 9, 138–141.

  • Watson RA, Rollason TP, Reynolds GM, Murray PG, Banks L and Roberts S . (2002). Carcinogenesis, 23, 1791–1796.

  • Woodhouse E, Hersperger E and Shearn A . (1998). Dev. Genes Evol., 207, 542–550.

  • Woodhouse E, Hersperger E, Stetler-Stevenson WG, Liotta LA and Shearn A . (1994). Cell Growth Differ., 5, 151–159.

  • Yam JWP, Chan KW and Hsiao W . (2001). Oncogene, 20, 58–68.

  • Yamanaka T, Horikoshi Y, Sugiyama Y, Ishiyama C, Suzuki A, Hirose T, Iwamatsu A, Shinohara A and Ohno S . (2003). Curr. Biol., 13, 734–743.

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Acknowledgements

The expert technical assistance of Daniela Gottfried, Mirjam Weisser and Christina Grössgen is gratefully acknowledged. We thank Susanne Wallner for performing the immunohistochemistry. This work was supported by a grant to DS from the MAIFOR programme.

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Correspondence to Dennis Strand.

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Schimanski, C., Schmitz, G., Kashyap, A. et al. Reduced expression of Hugl-1, the human homologue of Drosophila tumour suppressor gene lgl, contributes to progression of colorectal cancer. Oncogene 24, 3100–3109 (2005). https://doi.org/10.1038/sj.onc.1208520

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