Proliferation, but Not Apoptosis, Is Associated with Distinct β-Catenin Expression Patterns in Non-Small-Cell Lung Carcinomas
2002; Elsevier BV; Volume: 161; Issue: 5 Linguagem: Inglês
10.1016/s0002-9440(10)64440-9
ISSN1525-2191
AutoresAthamassios Kotsinas, Konstantinos Evangelou, Panayotis Zacharatos, Christos Kittas, Vassilis G. Gorgoulis,
Tópico(s)Kruppel-like factors research
Resumoβ-catenin (β-cat) is a versatile component of homotypic cell adhesion and signaling. Its subcellular localization and cytoplasmic levels are tightly regulated by the adenomatous polyposis coli (APC) protein. Mutations in β-cat (exon 3) or APC (MCR) result in β-cat aberrant overexpression that is associated with its nuclear accumulation and improper gene activation. Data from experimental models have shown that β-cat overexpression has a multitude of effects on cell-cycle behavior. In many of these aspects its function depends on major G1 phase regulators. To the best of our knowledge, most of these issues have never been addressed concurrently in tumors. For this reason we investigated in a panel of 92 non-small-cell lung carcinomas, β-cat and APC expression, and their relationship with cell-cycle kinetics (PI and AI) and ploidy status. Moreover, the above correlations were examined in relation to the main G1/S-phase checkpoint regulators. Four β-cat immunohistochemical expression patterns [membranous (11.1%), membranous-cytoplasmic (54.3%), cytoplasmic (9.9%), cytoplasmic-nuclear (24.7%)] and three APC immunohistochemical expression patterns [cytoplasmic (37.7%), cytoplasmic-nuclear (58%), nuclear (4.3%)] were observed, which were further confirmed by Western blot analysis on subcellular fractions in representative samples. The frequent presence of β-cat in the cytoplasm is an indication of aberrant expression, whereas membranous and nuclear localization were inversely related. Absence of mutations in β-cat (exon 3) and APC (MCR) suggest that β-cat destruction mechanisms may be functional. However, expression analysis revealed attenuated levels for APC, indicating a residual ability to degrade β-cat. Decreased levels were associated with loss of heterozygosity at the APC region in 24% of the cases suggesting that additional silencing mechanisms may be involved. Interestingly, the 90-kd APC isoform associated with apoptosis, was found to be the predominant isoform in normal and cancerous lung tissues. The most important finding in our study, was the correlation of nuclear β-cat immunohistochemical localization with increased proliferation, overexpression of E2F1 and MDM2, aberrant p53, and low expression of p27KIP, providing for the first time in vivo evidence that β-cat-associated proliferation correlates with release of E2F1 activity and loss of p53- and p27KIP-dependent cell-cycle checkpoints. Loss of these checkpoints is accompanied by low levels of APC, which possibly reflects a diminished ability to degrade β-cat. Taken together our data indicate that cases with nuclear β-cat immunohistochemical expression represent a subset of non-small-cell lung carcinomas that have gained an increased proliferation advantage in contrast to the other β-cat immunohistochemical expression profiles. β-catenin (β-cat) is a versatile component of homotypic cell adhesion and signaling. Its subcellular localization and cytoplasmic levels are tightly regulated by the adenomatous polyposis coli (APC) protein. Mutations in β-cat (exon 3) or APC (MCR) result in β-cat aberrant overexpression that is associated with its nuclear accumulation and improper gene activation. Data from experimental models have shown that β-cat overexpression has a multitude of effects on cell-cycle behavior. In many of these aspects its function depends on major G1 phase regulators. To the best of our knowledge, most of these issues have never been addressed concurrently in tumors. For this reason we investigated in a panel of 92 non-small-cell lung carcinomas, β-cat and APC expression, and their relationship with cell-cycle kinetics (PI and AI) and ploidy status. Moreover, the above correlations were examined in relation to the main G1/S-phase checkpoint regulators. Four β-cat immunohistochemical expression patterns [membranous (11.1%), membranous-cytoplasmic (54.3%), cytoplasmic (9.9%), cytoplasmic-nuclear (24.7%)] and three APC immunohistochemical expression patterns [cytoplasmic (37.7%), cytoplasmic-nuclear (58%), nuclear (4.3%)] were observed, which were further confirmed by Western blot analysis on subcellular fractions in representative samples. The frequent presence of β-cat in the cytoplasm is an indication of aberrant expression, whereas membranous and nuclear localization were inversely related. Absence of mutations in β-cat (exon 3) and APC (MCR) suggest that β-cat destruction mechanisms may be functional. However, expression analysis revealed attenuated levels for APC, indicating a residual ability to degrade β-cat. Decreased levels were associated with loss of heterozygosity at the APC region in 24% of the cases suggesting that additional silencing mechanisms may be involved. Interestingly, the 90-kd APC isoform associated with apoptosis, was found to be the predominant isoform in normal and cancerous lung tissues. The most important finding in our study, was the correlation of nuclear β-cat immunohistochemical localization with increased proliferation, overexpression of E2F1 and MDM2, aberrant p53, and low expression of p27KIP, providing for the first time in vivo evidence that β-cat-associated proliferation correlates with release of E2F1 activity and loss of p53- and p27KIP-dependent cell-cycle checkpoints. Loss of these checkpoints is accompanied by low levels of APC, which possibly reflects a diminished ability to degrade β-cat. Taken together our data indicate that cases with nuclear β-cat immunohistochemical expression represent a subset of non-small-cell lung carcinomas that have gained an increased proliferation advantage in contrast to the other β-cat immunohistochemical expression profiles. Current models of carcinogenesis describe the progressive accumulation of alterations in critical genes necessary for normal cell physiology.1Hanahan D Weinberg RA The hallmarks of cancer.Cell. 2000; 100: 57-70Abstract Full Text Full Text PDF PubMed Scopus (21638) Google Scholar Among these are genes whose products are involved in multiple cellular functions. β-catenin (β-cat) and adenomatous polyposis coli (APC) genes represent such an example.2Peifer M Polakis P Wnt signaling in oncogenesis and embryogenesis—a look outside the nucleus.Science. 2000; 287: 1606-1609Crossref PubMed Scopus (1131) Google Scholar The β-cat gene maps to 3p21 and encodes a 92- to 97-kd protein, that belongs to the mammalian homologues of armadillo.3Ilyas M Tomlinson IPM The interactions of APC, E-cadherin and β-catenin in tumor development and progression.J Pathol. 1997; 182: 128-137Crossref PubMed Scopus (177) Google Scholar It participates in two disparate cellular functions.4Morin PJ β-catenin signaling and cancer.BioEssays. 1999; 21: 1021-1030Crossref PubMed Scopus (806) Google Scholar, 5Barker N Clevers H Catenins, Wnt signaling and cancer.BioEssays. 2000; 22: 961-965Crossref PubMed Scopus (207) Google Scholar, 6Ben-Ze'ev A Shtutman M Zhurinsky J The integration of cell adhesion with gene expression: the role of β-catenin.Exp Cell Res. 2000; 261: 75-82Crossref PubMed Scopus (89) Google Scholar, 7Miller JR Hocking AM Brown JD Moon RT Mechanism and function of signal transduction by the Wnt/β-catenin and Wnt/Ca2+ pathways.Oncogene. 1999; 18: 7860-7872Crossref PubMed Scopus (601) Google Scholar The first one concerns homotypic cell-cell interactions, by complexing with E-cadherin (E-cad)3Ilyas M Tomlinson IPM The interactions of APC, E-cadherin and β-catenin in tumor development and progression.J Pathol. 1997; 182: 128-137Crossref PubMed Scopus (177) Google Scholar, 4Morin PJ β-catenin signaling and cancer.BioEssays. 1999; 21: 1021-1030Crossref PubMed Scopus (806) Google Scholar whereas, the second one involves signal transduction pathways that are activated by the Wnt-wingless, the integrin-associated tyrosine kinases, integrin-linked kinase (ILK), and focal adhesion kinase (FAK), as well as presenilins.7Miller JR Hocking AM Brown JD Moon RT Mechanism and function of signal transduction by the Wnt/β-catenin and Wnt/Ca2+ pathways.Oncogene. 1999; 18: 7860-7872Crossref PubMed Scopus (601) Google Scholar, 8Persad S Troussard AA McPhee TR Mulholland DJ Dedhar S Tumor suppressor PTEN inhibits nuclear accumulation of beta-catenin and T cell/lymphoid enhancer factor 1-mediated transcriptional activation.J Cell Biol. 2001; 153: 1161-1174Crossref PubMed Scopus (207) Google Scholar Cytoplasmic β-cat that is not incorporated in cell adhesion or signaling, is regulated by two proteasome degradation complexes.9Polakis P More than one way to skin a catenin.Cell. 2001; 105: 563-566Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar The first complex, suspected to be the default mechanism, requires GSK-3β-dependent phosphorylation of β-cat at N-terminus for destruction. The second complex, responds to p53-induced cell-cycle arrest. Both mechanisms require APC as a scaffold. 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