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Journal of Cancer Research and Clinical Oncology

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01.06.2004 | Original Paper

Overexpression of E2F1 associated with LOH at RB locus and hyperphosphorylation of RB in non-small cell lung carcinoma

verfasst von: Miwa Akasofu Imai, Yoshio Oda, Makoto Oda, Isao Nakanishi, Ei Kawahara

Erschienen in: Journal of Cancer Research and Clinical Oncology | Ausgabe 6/2004

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Abstract

Purpose

E2F1 plays a critical role in cell proliferation, and its function is controlled by the retinoblastoma (RB) protein. We examined the expression of E2F1 and the aberration of RB gene and protein to elucidate what factors contribute to the overexpression of E2F1 in non-small cell lung carcinomas.

Methods

The expression level of E2F1 in tissues of non-small cell lung carcinomas was measured by means of quantitative reverse transcription-polymerase chain reaction and immunohistochemistry. For RB, we examined loss of heterozygosity (LOH) by PCR-restriction fragment length polymorphism and a variable number of tandem repeats, and protein expression by immunohistochemistry.

Results

Fifteen cases of carcinoma (46%) showed high transcription levels of E2F1 gene. Immunohistochemically, almost all (14 of 15) cases overexpressing E2F1 mRNA were positive for E2F1 protein. LOH at the RB locus was found in 13 of 30 informative cases. In 13 cases with LOH, ten showed overexpression of E2F1 mRNA and protein. Immunohistochemical positivity for phosphorylated RB protein was also closely correlated with overexpression of E2F1.

Conclusions

Our results suggest that overexpression of E2F1, induced both by LOH at the RB locus and anomalous phosphorylation of the RB protein, is involved in the development of non-small cell lung carcinoma.

Bookstein R, Lai C-C, To H, Lee WH (1990) PCR-based detection of polymorphic BamHI site in intron 1 of the human retinoblastoma (RB) gene. Nucl Acids Res 18:1660

Brambilla E, Moro D, Gazzeri S, Brambilla C (1999) Alterations of expression of Rb p16 (INK4A) and cyclin D1 in non-small cell lung carcinoma and their clinical significance. J Pathol 188:351–360CrossRefPubMed

Chen JT, Chen YC, Wang YC, Tseng RC, Chen CY, Wang YC (2002) Alterations of the p16(ink4a) gene in resected nonsmall cell lung tumors and exfoliated cells within sputum. Int J Cancer 98:724–731CrossRefPubMed

Dyson N (1995) The regulation of E2F by pRB-family proteins. Genes Dev 12:2245–2262

Eymin B, Gazzeri S, Brambilla C, Brambilla E (2001) Distinct pattern of E2F1 expression in human lung tumors: E2F1 is upregulated in small lung carcinoma. Oncogene 20:1678–1687CrossRefPubMed

Gorgoulis VG, Zacharatos P, Mariatos G, Kotsinas A, Bouda M, Kletsas D, Asimacopoulos PJ, Agnantis N, Kittas C, Papavassiliou AG (2002) Transcriptional factor E2F-1 acts as a growth-promoting factor and is associated with adverse prognosis in non-small cell lung carcinomas. J Pathol 198:142–156CrossRefPubMed

Gouyer V, Gazzeri S, Brambilla E, Bolon I, Moro D, Perron P, Benabid AL, Brambilla C (1994) Loss of heterozygosity at the RB locus correlates with loss of RB protein in primary malignant neuroendocrine lung carcinomas. Int J Cancer 58:818–824PubMed

Helin K, Lees JA, Vidal M, Dyson N, Harlow E, Fattaey A (1992) A cDNA encoding a pRB-binding protein with protein with properties of the transcription factor E2F. Cell 70:337–350PubMed

Higashiyama M, Doi O, Kodama K, Yokouchi H, Tateishi R (1994) Retinoblastoma protein expression in lung cancer: an immunohistochemical analysis. Oncology 51:544–551PubMed

Ikeda M, Orimo H, Moriyama H, Nakajima E, Matsubara N, Mibu R, Tanaka N, Shimada T, Kimura A, Shimizu K (1998) Close correlation between mutations of E2F4 and hMSH3 genes in colorectal cancers with microsatellite instability. Cancer Res 58:594–598PubMed

Johnson DG, Cress WD, Jakoi L, Nevins JR (1994a) Oncogenic capacity of the E2F1 gene. Proc Natl Acad Sci USA 91:12823–12827PubMed

Johnson DG, Ohtani K, Nevins JR (1994b) Autoregulatory control of E2F1 expression in response to positive and negative regulators of cell cycle progression. Genes Dev 8:1514–1525PubMed

Kawahara E, Okada Y, Nakanishi I, Iwata K, Kojima S, Kumagai S, Yamamoto E (1993) The expression of invasive behavior of differentiated squamous carcinoma cell line evaluated by an in vitro invasion model. Jpn J Cancer Res 84:409–418PubMed

Kaye FJ (2002) RB and cyclin dependent kinase pathways: defining a distinction between RB and p16 loss in lung cancer. Oncogene 21:6908–6914CrossRefPubMed

Kurakawa E, Shimamoto T, Utsumi K, Hirano T, Kato H, Ohyashiki K (2001) Hypermethylation of p16 (INK4a) and p15 (INK4b) genes in non-small cell lung cancer. Int J Oncol 19:277–281PubMed

Lai R, Medeiros LJ, Coupl R, McCourty A, Brynes RK (1998) Immunohistochemical detection of E2F1 in non-Hodgkin’s lymphomas a survey of 124 cases. Mod Pathol 11:457–463PubMed

Lee C, Chang JH, Lee HS, Cho Y (2002) Structural basis for the recognition of the E2F transactivation domain by the retinoblastoma tumor suppressor. Genes Dev 16:3199–3212CrossRefPubMed

Liu Y, Szekely L, Grandér D, Söderhäll S, Juliusson G, Gahrton G, Linder S, Einhorn S (1993) Chronic lymphocytic leukemia cells with allelic deletions at 13q14 commonly have one intact RB1 gene: evidence for a role of an adjacent locus. Proc Natl Acad Sci USA 90:8697–8701PubMed

Matsumura K, Kallioniemi A, Kallioniemi O, Chen L, Smith HS, Pinkel D, Gray J, Waldman FM (1992) Deletion of chromosome 17q loci in breast cancer cells detected by fluorescence in situ hybridization. Cancer Res 52:3474–3477PubMed

McGee TL, Cowley GS, Yandell DW, Dryja TP (1990) Detection of the XbaI RFLP within the retinoblastoma locus by PCR. Nucl Acids Res 18:207

Mori N, Yokota J, Akiyama T, Sameshima Y, Okamoto A, Mizoguchi H, Toyoshima K, Sugimura T, Terada M (1990) Variable mutations of the RB gene in small-cell lung carcinoma. Oncogene 5:1713–1717PubMed

Nevins JR (1990) E2F: a link between the Rb tumor suppressor protein and viral oncoprotein. Science 258:424–429

Noonan KE, Beck C, Holzmayer TA, Chin JE, Wunder JS, Andrulis IL, Gazdar AF, Willman CL, Griffith B, Von Hoff DD, Roninson IB (1990) Quantitative analysis of MDR1 (multidrug resistance) gene expression in human tumors by polymerase chain reaction. Proc Natl Acad Sci USA 87:7160–7164PubMed

Rabbani F, Richon VM, Orlow I, Lu M-L, Drobnjak M, Dudas M, Charytonowicz E, Dalbagni G, Cordon-Cardo C (1999) Prognostic significance of transcription factor E2F1 in bladder cancer genotypic and phenotypic characterization. J Natl Cancer Inst 91:874–881CrossRefPubMed

Reissmann PT, Koga H, Takahashi R, Figlin RA, Holmes C, Piantadosi S, Cordon-Cardo C, Slamon DJ, the Lung Cancer Study Group (1993) Inactivation of the retinoblastoma susceptibility gene in non-small-cell lung cancer. Oncogene 8:1913–1919PubMed

Riedy MC, Timm EA, Stewart CC (1995) Quantitative RT-PCR for measuring gene expression. Biotechniques 18:70–76PubMed

Sachse R, Murakami Y, Shiraishi M, Hayashi K, Sekiya T (1994) DNA aberrations at the retinoblastoma gene locus in human squamous cell carcinomas of the lung. Oncogene 9:39–47PubMed

Saito M, Helin K, Valentine MB, Griffith BB, Willman CL, Harlow E, Look AT (1995) Amplification of the E2F1 transcription factor gene in the HEL erythroleukemia cell line. Genomics 25:130–138CrossRefPubMed

Sellers WR, Rodgers JW, Kaelin WG (1995) A potent trans-repression domain in the retinoblastoma protein induces cell cycle arrest when bound to E2F sites. Proc Natl Acad Sci USA 92:11544–11548PubMed

Suzuki T, Yasui W, Yokozaki H, Naka K, Ishikawa T, Tahara E (1999) Expression of the E2F family in human gastrointestinal carcinomas. Int J Cancer 81:535–538CrossRefPubMed

Tamura K, Zhang X, Murakami Y, Hirohashi S, Xu H-J, Hu S-X, Benedict WF, Sekiya T (1997) Deletion of three distinct regions on chromosome 13q in human non-small-cell lung cancer. Int J Cancer 74:45–49CrossRefPubMed

Wadayama B, Toguchida J, Shimizu T, Ishizaki K, Sasaki MS, Kotoura Y, Yamamuro T (1994) Mutation spectrum of the retinoblastoma gene in osteosarcomas. Cancer Res 54:3042–3048PubMed

Weinberg RA (1995) The retinoblastoma protein and cell cycle control. Cell 81:323–330PubMed

Xu G, Livingston DM, Krek W (1995) Multiple members of the E2F transcription factor family are the products of oncogenes. Proc Natl Acad Sci USA 92:1357–1361PubMed

Xu H-J, Hu S-X, Cagle PT, Moore GE, Benedict WF (1991) Absence of retinoblastoma protein expression in primary non-small cell lung carcinoma. Cancer Res 51:2735–2739PubMed

Xu Q, Dyson N, Harlow E (1990) The regions of the retinoblastoma binding to adenovirus E1A or SV40 large T antigen are common sites for mutations. EMBO J 9:1147–1155PubMed

Zhang SY, Liu SC, Al-Saleem LF, Holloran D, Babb J, Guo X, Klein-Szanto AJ (2000) E2F1: a proliferative marker of breast neoplasia. Cancer Epidemiol Biomarkers Prev 9:395–401PubMed

Zöchbauer-Müller S, Gazdar AF, Minna JD (2002) Molecular pathogenesis of lung cancer. Ann Rev Physiol 64:681–708CrossRef

Titel: Overexpression of E2F1 associated with LOH at RB locus and hyperphosphorylation of RB in non-small cell lung carcinoma
verfasst von: Miwa Akasofu Imai
Yoshio Oda
Makoto Oda
Isao Nakanishi
Ei Kawahara
Publikationsdatum: 01.06.2004
Verlag: Springer-Verlag
Erschienen in: Journal of Cancer Research and Clinical Oncology / Ausgabe 6/2004
Print ISSN: 0171-5216
Elektronische ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-003-0538-3

Springer Medizin

Overexpression of E2F1 associated with LOH at RB locus and hyperphosphorylation of RB in non-small cell lung carcinoma

Abstract

Purpose

Methods

Results

Conclusions

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Springer Medizin

Abstract

Purpose

Methods

Results

Conclusions

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