Abnormal b-Catenin and Reduced Axin Expression in NSCLC
Abnormal b-Catenin and Reduced Axin Expression in NSCLC
We studied the expression of axin and β-catenin and their relation to clinicopathologic factors in 100 non-small cell lung cancers (NSCLCs) by immunohistochemical analysis. The mutation in exon 3 of the β-catenin gene was examined by polymerase chain reaction and direct sequencing. Preserved axin expression was significantly higher in well- and moderately differentiated NSCLC samples than in poorly differentiated ones. Reduced membranous expression of β-catenin was shown in 80 cases, whereas 26 cases had aberrant nuclear expression. Poor differentiation and lymph node metastasis were associated significantly with reduced β-catenin expression. Lower axin expression was related significantly to higher nuclear β-catenin expression. However, this study failed to detect any exon 3 mutation in the β-catenin gene in the 100 NSCLC samples. We conclude that reduced β-catenin and axin expression might predict poor differentiation in NSCLC. Reduced axin expression, but not mutation in exon 3, might be an important explanation for the abnormal β-catenin expression in NSCLC.
The wingless/int (WNT) signaling pathway regulates cellular proliferation and differentiation in vertebrates and invertebrates and has an important role in tumor progression. β-Catenin is a double-functional molecule in the WNT signaling pathway and the E-cadherin-catenin complex. When it accumulates in the nucleus, β-catenin loses its function as a cell-adhesion molecule, which activates the WNT signaling pathway and switches on transcription of target genes such as c-myc or cyclin D1, resulting in proliferation and metastasis of tumor cells.
Axin, an important regulator of the WNT signaling pathway, promotes phosphorylation of serine or threonine in exon 3 of the β-catenin gene by forming a complex with adenomatous polyposis coli (APC) and glycogen synthase kinase-3β (GSK-3β). Phosphorylated β-catenin is degraded quickly via a ubiquitin-proteasome pathway in the cytoplasm. When the activity or expression of the axin complex decreases, β-catenin accumulates in the cytoplasm and nucleus, owing to the suppression of β-catenin phosphorylation. This aberrant accumulation of nuclear β-catenin further activates target oncogenes.
As candidate mechanisms for the aberrant accumulation of nuclear β-catenin, mutations at phosphorylation sites in exon 3 of the β-catenin gene have been documented in several tumor types, such as hepatocellular carcinomas, carcinomas of the prostate, and endometrial carcinomas. Recent studies have indicated that mutations in axin also might be responsible for aberrant β-catenin accumulation in nuclei. However, knowledge of axin and β-catenin expression in the same tumor tissues is limited. We studied the expression of axin and β-catenin in 100 samples of non-small cell lung cancer (NSCLC), explored the relationship between the expression of axin and β-catenin and their possible relationship to clinicopathologic factors, and further tested whether the mutation of exon 3 in β-catenin is related to alterations in abnormal β-catenin expression.
Abstract and Introduction
Abstract
We studied the expression of axin and β-catenin and their relation to clinicopathologic factors in 100 non-small cell lung cancers (NSCLCs) by immunohistochemical analysis. The mutation in exon 3 of the β-catenin gene was examined by polymerase chain reaction and direct sequencing. Preserved axin expression was significantly higher in well- and moderately differentiated NSCLC samples than in poorly differentiated ones. Reduced membranous expression of β-catenin was shown in 80 cases, whereas 26 cases had aberrant nuclear expression. Poor differentiation and lymph node metastasis were associated significantly with reduced β-catenin expression. Lower axin expression was related significantly to higher nuclear β-catenin expression. However, this study failed to detect any exon 3 mutation in the β-catenin gene in the 100 NSCLC samples. We conclude that reduced β-catenin and axin expression might predict poor differentiation in NSCLC. Reduced axin expression, but not mutation in exon 3, might be an important explanation for the abnormal β-catenin expression in NSCLC.
Introduction
The wingless/int (WNT) signaling pathway regulates cellular proliferation and differentiation in vertebrates and invertebrates and has an important role in tumor progression. β-Catenin is a double-functional molecule in the WNT signaling pathway and the E-cadherin-catenin complex. When it accumulates in the nucleus, β-catenin loses its function as a cell-adhesion molecule, which activates the WNT signaling pathway and switches on transcription of target genes such as c-myc or cyclin D1, resulting in proliferation and metastasis of tumor cells.
Axin, an important regulator of the WNT signaling pathway, promotes phosphorylation of serine or threonine in exon 3 of the β-catenin gene by forming a complex with adenomatous polyposis coli (APC) and glycogen synthase kinase-3β (GSK-3β). Phosphorylated β-catenin is degraded quickly via a ubiquitin-proteasome pathway in the cytoplasm. When the activity or expression of the axin complex decreases, β-catenin accumulates in the cytoplasm and nucleus, owing to the suppression of β-catenin phosphorylation. This aberrant accumulation of nuclear β-catenin further activates target oncogenes.
As candidate mechanisms for the aberrant accumulation of nuclear β-catenin, mutations at phosphorylation sites in exon 3 of the β-catenin gene have been documented in several tumor types, such as hepatocellular carcinomas, carcinomas of the prostate, and endometrial carcinomas. Recent studies have indicated that mutations in axin also might be responsible for aberrant β-catenin accumulation in nuclei. However, knowledge of axin and β-catenin expression in the same tumor tissues is limited. We studied the expression of axin and β-catenin in 100 samples of non-small cell lung cancer (NSCLC), explored the relationship between the expression of axin and β-catenin and their possible relationship to clinicopathologic factors, and further tested whether the mutation of exon 3 in β-catenin is related to alterations in abnormal β-catenin expression.
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