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PLOS ONE  2013 

TUSC1, a Putative Tumor Suppressor Gene, Reduces Tumor Cell Growth In Vitro and Tumor Growth In Vivo

DOI: 10.1371/journal.pone.0066114

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Abstract:

We previously reported the identification of TUSC1 (Tumor Suppressor Candidate 1), as a novel intronless gene isolated from a region of homozygous deletion at D9S126 on chromosome 9p in human lung cancer. In this study, we examine the differential expression of TUSC1 in human lung cancer cell lines by western blot and in a primary human lung cancer tissue microarray by immunohistochemical analysis. We also tested the functional activities and mechanisms of TUSC1 as a tumor suppressor gene through growth suppression in vitro and in vivo. The results showed no expression of TUSC1 in TUSC1 homozygously deleted cells and diminished expression in some tumor cell lines without TUSC1 deletion. Interestingly, the results from a primary human lung cancer tissue microarray suggested that higher expression of TUSC1 was correlated with increased survival times for lung cancer patients. Our data demonstrated that growth curves of tumor cell lines transfected with TUSC1 grew slower in vitro than those transfected with the empty vector. More importantly, xenograph tumors in nude mice grew significantly slower in vivo in cells stably transfected with TUSC1 than those transfected with empty vector. In addition, results from confocal microscopy and immunohistochemical analyses show distribution of TUSC1 in the cytoplasm and nucleus in tumor cell lines and in normal and tumor cells in the lung cancer tissue microarray. Taken together, our results support TUSC1 has tumor suppressor activity as a candidate tumor suppressor gene located on chromosome 9p.

References

[1]  American Cancer Society. Cancer Facts & Figures 2012 (2012) Atlanta: American Cancer Society.
[2]  Zochbauer-Muller S, Gazdar AF, Minna JD (2002) Molecular pathogenesis of lung cancer. Ann Rev Physiol 64: 681–708.
[3]  Howlader N, Noone AM, Krapcho M, Neyman N, Aminou R, et al.. (2012) SEER Cancer Statistics Review, 1975–2009 (Vintage 2009 Populations), National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2009_pop?s09/, based on November 2011 SEER data submission, posted to the SEER web site.
[4]  Cheng JQ, Jhanwar SC, Lu YY, Testa JR (1993) Homozygous deletions within 9p21-p22 identify a small critical region of chromosomal loss in human malignant mesotheliomas Cancer Res. 53: 4761–3.
[5]  Holland EA, Beaton SC, Edwards BG, Kefford RF, Mann GJ (1994) Loss of heterozygosity and homozygous deletions on 9p21–22 in melanoma. Oncogene 9: 1361–5.
[6]  Coleman A, Fountain JW, Nobori T, Olopade OI, Robertson G, et al. (1994) Distinct deletions of chromosome 9p associated with melanoma versus glioma, lung cancer, and leukemia. Cancer Res 54: 344–8.
[7]  Kamb A, Gruis NA, Weaver-Feldhaus J, Liu Q, Harshman K, et al. (1994) A cell cycle regulator potentially involved in genesis of many tumor types. Science 264: 436–440.
[8]  An HX, Niederacher D, Picard F, van Roeyen C, Bender HG, et al. (1996) Frequent allele loss on 9p21–22 defines a smallest common region in the vicinity of the CDKN2 gene in sporadic breast cancer. Genes Chromosomes Cancer 17: 14–20.
[9]  Mead LJ, Gillespie MT, Hung JY, Rane US, Rayeroux KC, et al. (1997) Frequent loss of heterozygosity in early non-small cell lung cancers at chromosome 9p21 proximal to the CDKN2a gene. Int J Cancer 71: 213–7.
[10]  Wiest JS, Franklin WA, Otstot JT, Forbey K, Varella-Garcia M, et al. (1997) Identification of a novel region of homozygous deletion on chromosome 9p in squamous cell carcinoma of the lung: the location of a putative tumor suppressor gene. Cancer Res 57: 1–6.
[11]  Takeuchi S, Koike M, Seriu T, Bartram CR, Slater J, et al. (1997) Homozygous deletions at 9p21 in childhood acute lymphoblastic leukemia detected by microsatellite analysis. Leukemia 11: 1636–40.
[12]  Sheu JC, Lin YW, Chou HC, Huang GT, Lee HS, et al. (1999) Loss of heterozygosity and microsatellite instability in hepatocellular carcinoma in Taiwan. Br J Cancer 80: 468–76.
[13]  Pollock PM, Welch J, Hayward NK (2001) Evidence for three tumor suppressor loci on chromosome 9p involved in melanoma development. Cancer Res 61: 1154–61.
[14]  Shan Z, Parker T, Wiest JS (2004) Identifying novel homozygous deletions by microsatellite analysis and characterization of tumor suppressor candidate 1 gene, TUSC1, on chromosome 9p in human lung cancer. Oncogene 23: 6612–20.
[15]  La Rochelle J, Klatte T, Dastane A, Rao N, Seligson D, et al. (2010) Chromosome 9p deletions identify an aggressive phenotype of clear cell renal cell carcinoma. Cancer 16: 4696–702.
[16]  Ploussard G, Dubosq F, Soliman H, Verine J, Desgrandchamps F, et al. (2010) Prognostic value of loss of heterozygosity at chromosome 9p in non-muscle-invasive bladder cancer. Urology 76: 513.e13–8.
[17]  Yang XR, Liang X, Pfeiffer RM, Wheeler W, Maeder D, et al.. (2010) Associations of 9p21 variants with cutaneous malignant melanoma, nevi, and pigmentation phenotypes in melanoma-prone families with and without CDKN2A mutations. Fam Cancer 625–33.
[18]  Serrano M, Hannon GJ, Beach D (1993) A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature 366: 704–707.
[19]  Quelle DE, Zindy F, Ashmun RA, Sherr CJ (1995) Alternative reading frames of the INK4a tumor suppressor gene encode two unrelated proteins capable of inducing cell cycle arrest. Cell 83: 993–1000.
[20]  Cairns P, Polascik TJ, Eby Y, Tokino K, Califano J, et al. (1995) Frequency of homozygous deletion at p16/CDKN2 in primary human tumours. Nat Genet 11: 210–2.
[21]  Merlo A, Herman JG, Mao L, Lee DJ, Gabrielson E, et al. (1995) 5′ CpG island methylation is associated with transcriptional silencing of the tumour suppressor p16/CDKN2/MTS1 in human cancers. Nat Med 7: 686–92.
[22]  Xiao S, Li D, Corson JM, Vijg J, Fletcher JA (1995) Codeletion of p15 and p16 genes in primary non-small cell lung carcinoma. Cancer Res 55: 2968–71.
[23]  Castellano M, Pollock PM, Walters MK, Sparrow LE, Down LM, et al. (1997) CDKN2A/p16 is inactivated in most melanoma cell lines. Cancer Res. 57: 4868–75.
[24]  Hamada K, Kohno T, Kawanishi M, Ohwada S, Yokota J (1998) Association of CDKN2A(p16)/CDKN2B(p15) alterations and homozygous chromosome arm 9p deletions in human lung carcinoma. Cancer 22: 232–40.
[25]  Hamada K, Kohno T, Takahashi M, Yamazaki M, Yamazaki M, et al. (2000) Two regions of homozygous deletion clusters at chromosome band 9p21 in human lung cancer. Genes Chromosomes Cancer 27: 308–18.
[26]  Fogh J, Trempe G (1975) New human tumor cell lines. In: Fogh J, ed. Human tumor cells in vitro. New York and London: Plenum, 115–159.
[27]  Carney DN, Gazdar AF, Bepler G, Guccion JG, Marangos PJ, et al. (1985) Establishment and identification of small cell lung cancer cell lines having classic and variant features. Cancer Res 45(6): 2913–23.
[28]  Pettijohn DE, Pfenninger O, Brown J, Duke R, Olsson L (1988) Tumorigenic human squamous lung cancer cells have defined cell surface carbohydrates that are absent from nontumorigenic cells. Proc Natl Acad Sci U S A 85(3): 802–6.
[29]  Goldsmith P, Gierschik P, Milligan G, Unson CG, Vinitsky R, et al. (1987) Antibodies directed against synthetic peptides distinguish between GTP-binding proteins in neutrophil and brain. J Biol Chem 262: 14683–8.
[30]  Fukuoka J, Fujii T, Shih JH, Dracheva T, Meerzaman D, et al. (2004) Chromatin remodeling factors and BRM/BRG1 expression as prognostic indicators in non-small cell lung cancer. Clin Cancer Res 10: 4314–24.
[31]  Wood LD, Parsons DW, Jones S, Lin J, Sj?blom T, et al. (2007) The genomic landscapes of human breast and colorectal cancers. Science 16: 1108–13.
[32]  Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, et al. (2008) Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 26: 1801–6.
[33]  Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, et al. (2008) An integrated genomic analysis of human glioblastoma multiforme. Science 26: 1807–12.
[34]  Parsons DW, Li M, Zhang X, Jones S, Leary RJ, et al. (2011) The genetic landscape of the childhood cancer medulloblastoma. Science 331: 435.

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