Expression and prognostic roles of beta-catenin in hepatocellular carcinoma: correlation with tumor progression and postoperative survival.

PURPOSE: Although hepatocellular carcinoma (HCC) is the most common primary malignant tumor of the human liver, the molecular changes and mechanisms that regulate its development and progression remain unclear. In the present study, we investigated the correlation between beta-catenin expression and clinical outcome in 51 patients with relatively small (maximal diameter < 30 mm), solitary HCCs. EXPERIMENTAL DESIGN: The tumors were classified according to histological tumor differentiation (grade I, 11 tumors; grade II, 28 tumors; grade III, 12 tumors). Using immunohistochemical methods to detect nuclear accumulation of beta-catenin, we investigated the correlation between beta-catenin expression and clinical outcome and compared the correlation with cyclin D1, Ki-67, and E-cadherin. RESULTS: Focal or generalized nuclear beta-catenin expression was observed in 36.4% (4 of 11) of the grade I tumors, 39.3% (11 of 28) of the grade II tumors, and 25% (3 of 12) of the grade III tumors. Nuclear beta-catenin-positive grade III tumors were associated with significantly poorer survival (P = 0.004), whereas none of the patients with nuclear beta-catenin-negative grade I tumors died. With regard to proliferative activity, positive nuclear beta-catenin staining correlated significantly with an increased Ki-67 labeling index in grade I (P < 0.0001) and grade III (P = 0.0045) tumors and with reduced epithelial cadherin expression in the cell membrane (P < 0.001). In contrast, no association with the expression of cyclin D1, one of the target factors of beta-catenin, was detected. CONCLUSIONS: Our present data suggest that beta-catenin plays important roles in promoting tumor progression by stimulating tumor cell proliferation and reducing the activity of cell adhesion systems and is associated with a poor prognosis, especially in patients with poorly differentiated HCCs.     

Expression of E-cadherin and beta-catenin in human non-small cell lung cancer and the clinical significance.

E-cadherin, a calcium-dependent cell-cell adhesion molecule, plays a key role in the maintenance of tissue integrity. The function of this molecule is partly mediated by alpha-/beta-/gamma-catenin. Loss or dysfunction of E-cadherin is associated with an invasive phenotype. We analyzed the expression of E-cadherin and beta-catenin in human lung cancer to determine the relationship to clinicopathological factors and prognosis. E-cadherin and beta-catenin expressions were evaluated in 331 lung cancer tissues in a immunohistochemical analysis. Reduced E-cadherin expression was evident in 138 (42%), and reduced beta-catenin expression was noted in 122 (37%). Reduced E-cadherin expression significantly correlated with lymph nodes metastasis (P = 0.0199). E-cadherin expression significantly correlated with increasing histological differentiation (P = 0.0403). Although reduced E-cadherin did not correlate with the prognosis (P = 0.0652), reduced beta-catenin expression did significantly correlate with a poor prognosis (P = 0.0001). When both were reduced, there was a significant unfavorable prognosis compared with either the reduced expression (P = 0.0493) and preserved expression (P = 0.0003). Multivariate analysis showed a significantly lower survival rate for patients with reduced beta-catenin (P < 0.0001). We interpret these data to mean that dysfunction of the cell-cell adhesion molecule has a role in the progression of lung cancer and that analysis of E-cadherin and beta-catenin expression can provide clinically important evidence on which to base treatment.     

Abnormal expression of the E-cadherin-catenin complex in dysplastic Barrett's oesophagus

It is now accepted that altered E-cadherin-catenin complex expression in oesophageal cancer correlates with clinical and pathological parameters, while abnormal E-cadherin expression occurs early in Barrett's oesophagus. We evaluated immunohistochemically the expression and cellular localization of alpha-, beta-, and gamma-catenin, and E-cadherin in 5 dysplastic and 26 non-dysplastic cases of Barrett's oesophagus. Usually all three catenins were localized at the cell membrane, as was E-cadherin. A similar staining pattern for E-cadherin and the catenins was observed in all cases of non-dysplastic Barrett's syndrome. However, 60% (3/5) of cases with dysplasia showed loss of membranous beta-catenin staining and diffuse cytoplasmic distribution, with predominantly nuclear localization in two cases. Membranous staining and concomitant cytoplasmic localization of E-cadherin, alpha-catenin and gamma-catenin were seen in one case with abnormal beta-catenin immunoreactivity. Our results indicate that altered subcellular distribution of beta-catenin occurs frequently in dysplastic Barrett's oesophagus and possibly reflects the signalling function of this molecule.     

Immunohistochemical prognostic factors in resected colorectal lung metastases using tissue microarray analysis.

AIMS: Immunohistochemical prognostic factors of pulmonary metastatic colorectal cancer lesions have not been well investigated. The study was conducted to identify the immunohistochemical prognostic factors of metastasized colorectal cancer. METHODS: We immunohistochemically investigated the expression of insulin-like growth factor-1 receptor (IGF1-R), E-cadherin, beta-catenin, and p53 using a tissue microarray in the surgical specimens of 86 metastatic lesions. RESULTS: The univariate analysis revealed E-cadherin and membrane beta-catenin positive to be prognostic factors. IGF1-R and p53 were not significantly associated with the patient's survival. In multivariate analysis, the reduced expression of E-cadherin, aerogenous spread with floating cancer cell clusters and vascular invasion were independent prognostic factors. CONCLUSIONS: The reduced expression of E-cadherin in the pulmonary metastatic lesions was an independent predictor of poor survival after pulmonary metastasectomy.     

Evaluation of myosin VI,E-cadherin and beta-catenin immunostaining in renal cell carcinoma

Background

Renal cell carcinoma (RCC) is a cancer of increasing incidence and mortality. Currently, there are no immunohistochemical prognostic markers for RCCs in routine use. The aim of this study was to examine for the first time the immunostaining of myosin VI in RCCs as well as its association with E-cadherin and beta-catenin immunostaining and the prognostic significance of these markers in RCCs.

Methods

Our study population consisted of 152 patients who underwent surgery for RCCs between 1990 and 1999. The tumours were examined with three immunohistochemical markers: myosin VI, E-cadherin and beta-catenin.

Results

The immunostaining for cytoplasmic myosin VI was common (72%). One-third of the tumours were immunopositive for nuclear myosin VI. Cytoplasmic myosin VI immunopositivity and nuclear beta-catenin immunostaining were associated with lower Fuhrman grades (p = 0.04 and p = 0.005, respectively), but not stages. There was no significant association between myosin VI immunostaining and the histological subtype of RCC. Nuclear myosin VI was associated with the nuclear expression of beta-catenin. A direct association could also be proven between membranous E-cadherin and cytoplasmic beta-catenin. Cytoplasmic myosin VI immunostaining was a marker of poorer prognosis in multivariate Cox regression model adjusted with stage and Fuhrman grade with hazard ratio 2.4 (95% confidence interval 1.1 to 5.0 with p = 0.024).

Conclusions

Cytoplasmic myosin VI immunopositivity and nuclear beta-catenin immunostaining were associated with lower Fuhrman grades, and there was a strong positive relationship between E-cadherin immunostaining and beta-catenin immunostaining in RCCs. Cytoplasmic myosin VI immunostaining was associated with poorer prognosis in RCCs.     

上皮型钙黏素基因启动子甲基化和β-链接素基因突变对鼻咽癌细胞侵袭转移的影响

目的　检测鼻咽原发癌和淋巴结转移癌组织中上皮型钙黏素基因启动子的甲基化和 β 链接素基因第 3外显子的突变 ,探讨鼻咽癌癌细胞早期发生组织侵袭和淋巴结转移的机制。方法采用DNA甲基化特异性聚合酶链反应、DNA直接测序法和免疫组化法 ,检测 2 1例鼻咽原发癌组织和 2 1例淋巴结转移癌组织中上皮型钙黏素基因启动子的甲基化程度、β 链接素基因第 3外显子的点突变以及 β 链接素蛋白的表达差异性。结果　 (1) 2 1例鼻咽原发癌组织中 ,2 3.8% (5 2 1)的病例可以检测到上皮型钙黏素基因启动子的甲基化 ,而在 2 1例淋巴结转移癌组织中则有 6 1.9% (13 2 1) ,二者差异有显著性 (P <0 .0 1)。 (2 ) 4 2例癌组织中 ,仅有 3例 (7.1% )检测到 β-链接素第 3外显子的 3处点突变 ,分别为密码子 37(TCT→GCT)、密码子 4 1(ACC→GCC)和密码子 4 7(AGT→ACT) ,但与癌细胞的侵袭转移无相关性 (P >0 .0 5 )。 (3) β 链接素蛋白在鼻咽原发癌和淋巴结转移癌组织中均有较高的表达量 ,其表达部位均为胞膜 ,未见到胞核表达者 (P >0 .0 5 )。结论　 (1)鼻咽癌组织中 ,上皮型钙黏素基因启动子的甲基化是导致上皮型钙黏素表达下调的主要原因 ,也可能是最终造成癌细胞分离移动的决定因素。 (2 ) β 链接素基因第 3外显子的突     

Alteration of beta-catenin expression in esophageal squamous-cell carcinoma

beta-catenin regulates cadherin-mediated cell-cell adhesion and also functions as a signaling molecule. In this study, we examined the expression pattern of E-cadherin, alpha-catenin and beta-catenin in 22 cases of esophageal squamous-cell carcinoma by Western-blot analysis. Expression of E-cadherin, alpha-catenin and beta-catenin was lower in carcinomas than in normal esophageal mucosa in 4 cases (18.2%) for E-cadherin, 6 cases (27.3%) for alpha-catenin and 9 cases (40.9%) for beta-catenin. Expression of beta-catenin was not always correlated with that of E-cadherin. Over-expression of beta-catenin was observed in 3 cases (13.6%). Of 3 cases that presented with over-expression of beta-catenin, 2 showed cytoplasmic staining by immunohistochemistry. Nuclear localization of beta-catenin was observed in one case that had higher beta-catenin level in tumor tissue (1.4-fold higher than normal mucosa). The genomic DNA sequences of the beta-catenin and the APC gene were analyzed. No mutation of the beta-catenin gene was observed in any cases. Silent mutation of the APC gene was found in all the cases that showed over-expression or nuclear localization of the beta-catenin protein. These results indicate that alterations of the cadherin-catenin complex may play an important role in a sub-set of esophageal carcinogenesis. Furthermore, it is suggested that beta-catenin over-expression is not caused by genetic alteration of either the beta-catenin or the APC gene.     

Density-dependent location and interactions of truncated APC and beta-catenin

Adenomatous polyposis coli (APC) is a multifunctional tumour suppressor protein, central to development and the mature organism. It is mutated in most cases of colorectal cancer, rendering it ineffective in mediating beta-catenin degradation. We show that localization of full-length APC in colon carcinoma and noncancer cell lines is independent of cell density. However, the location of truncated APC is a function of cell density and in high-density cells truncated APC is predominantly not nuclear. Although the distribution of truncated APC and beta-catenin is closely linked in subconfluent SW480 cells, at high cell density they are not colocalized. We postulated that in this cell line this could be due to an increase in beta-catenin bound to E-cadherin with formation of adherens junctions at high cell density. However, while in coimmunoprecipitation assays we observe an increase in binding between beta-catenin and E-cadherin and a corresponding decrease in binding between beta-catenin and APC at high cell density, we did not observe a strict colocalization of beta-catenin and E-cadherin at the membrane of all cells.     

Alteration of the E-cadherin/beta-catenin cell adhesion system is common in pulmonary neuroendocrine tumors and is an independent predictor of lymph node metastasis in atypical carcinoids

BACKGROUND: To the authors' knowledge, little is known regarding the role of E-cadherin/beta-catenin system dysregulation in pulmonary neuroendocrine tumors. METHODS: E-cadherin and beta-catenin immunoreactivity was evaluated in 10 hyperplastic neuroendocrine tumorlets and 210 neuroendocrine tumors, including 96 typical carcinoids (CTs), 35 atypical carcinoids (ACTs), 49 large cell neuroendocrine carcinomas (LCNECs), and 30 small cell lung carcinomas (SCLCs). RESULTS: Normal and hyperplastic bronchial neuroendocrine cells expressed E-cadherin/beta-catenin with an orderly distribution along the cell membrane. Neuroendocrine tumors retained beta-catenin expression in all tumors and E-cadherin in most tumors, with the exception of 2% of LCNECs, 3% of SCLCs and 9% of ACTs. E-cadherin showed a prevalent membrane-associated, linear immunoreactivity in CTs, whereas membrane-disarrayed and cytoplasmic staining was seen in most ACTs, LCNECs, and SCLCs (P < 0.001). beta-Catenin exhibited similar immunoreactivity patterns according to tumor type and a close association with E-cadherin subcellular distribution (P < 0.001). Nuclear accumulation of beta-catenin was found only in seven LCNECs and in two SCLCs. In ACTs, disarrayed immunoreactivity for E-cadherin and/or beta-catenin was associated with a nontrabecular growth pattern, altered expression of the cell-motility marker fascin, and lymph node metastases. Furthermore, a disarrayed E-cadherin distribution pattern was associated with the pathologic lymph node classification and the number of involved lymph nodes. Multivariate analysis confirmed that a disarrayed E-cadherin or beta-catenin pattern was an independent predictor of lymph node metastases in patients with ACT. CONCLUSIONS: The subcellular compartmentalization of the E-cadherin/beta-catenin complex was altered in pulmonary neuroendocrine tumors. This likely affects the tumor growth pattern and cell motility of ACT and was correlated with the occurrence of lymph node metastases.     

Epithelial-cadherin and beta-catenin expression changes in pancreatic intraepithelial neoplasia.

PURPOSE: Cadherins and associated catenins are important mediators of epithelial cell-cell adhesion, as well as the Wnt-signaling pathway. Significant changes in their expression or structure have been implicated in malignancy. This study aimed to investigate the epithelial-cadherin (E-cadherin) and beta-catenin expression changes during multistage, pancreatic ductal carcinogenesis. EXPERIMENTAL DESIGN: Ninety-four Whipple resection specimens were retrieved from the surgical pathology files of the University Health Network (Toronto, Canada), from which tissue microarray blocks containing 36 pancreatic ductal adenocarcinomas, 34 PanIN-1A lesions, 28 PanIN-1B lesions, 27 PanIN-2 lesions, 16 PanIN-3 lesions, and 32 normal ducts were constructed. The E-cadherin, beta-catenin, and the phosphorylated glycogen synthase kinase-3beta of the Wnt/beta-catenin pathway were immunohistochemically evaluated in these duct/PanIN lesions. RESULTS: There was marked increase in the cytoplasmic E-cadherin expression in PanIN lesions (P < 0.0001) and adenocarcinoma (P = 0.005) compared with normal pancreatic ducts. In contrast, reduced/loss of E-cadherin membranous expression was also significant in ductal adenocarcinoma compared with both the PanIN lesions (P < 0.0001) and normal ducts (P = 0.05). The beta-catenin expression showed significantly more frequent aberrant nuclear localization in high-grade PanIN lesions, particularly PanIN2 and in adenocarcinoma compared with normal ducts or low grade PanIN lesions (P < 0.0001). However, there was a lack of correlation between phospho(Ser9)-glycogen synthase kinase-3beta cytoplasmic expression and beta-catenin aberrant nuclear expression (P = 0.07). CONCLUSIONS: Aberration in the expression of E-cadherin and its associated beta-catenin is evident in pre-invasive (PanIN) neoplastic pancreatic duct cells, suggesting involvement of pathways leading to beta-catenin stabilization during pancreatic duct cell carcinogenesis.     

Decreased E-cadherin augments beta-catenin nuclear localization: studies in breast cancer cell lines

We showed that the YMB-1-derived breast cancer cell line YMB-S, which proliferates in suspension without aggregation, exhibits complete loss of cell-cell adhesion despite the presence of E-cadherin-catenin complex and expression of free beta-catenin in the cytoplasm. Here, we describe beta-catenin gene regulation, interaction with E-cadherin, immunocytochemical localization, and their relation to growth rate in the YMB-1-derived cell line YMB-A, which forms tight junctions and displays anchorage-dependent growth. YMB-A cells proliferated more slowly than YMB-S cells. E-cadherin and APC gene product expression in YMB-A cells was significantly higher than that in YMB-S cells, whereas expression of beta-catenin, MUC1, and c-myc was lower in YMB-A cells than in YMB-S cells. According to immunocytochemical analysis, beta-catenin in YMB-A cells displayed membranous or submembranous localization, indicating that beta-catenin is mostly tethered to E-cadherin. Inhibition of E-cadherin expression in YMB-A cells by an antisense oligonucleotide did not change expression of whole cell beta-catenin protein, but increased nuclear beta-catenin protein level, c-myc expression, and cell growth rate. These results suggest that decreased expression of E-cadherin and APC and increased amount of beta-catenin in YMB-S cells lead to accumulation of beta-catenin in the nucleus, activate beta-catenin-LEF/TCF signaling pathway, and trigger c-myc proto-oncogene expression. c-Myc overexpression in breast cancer may be related to activated Wnt independent beta-catenin-LEF/TCF signaling.     

乳腺癌组织中E-cadherin、β-catenin及cyclin D1表达的相关性研究

背景与目的上皮性钙粘素(E-cadherin)通过连接素(catenins)与细胞骨架相连介导细胞同质粘附反应,β-catenin除与E-cadherin结合介导细胞粘附反应外,还作为Wnt信号转导通路的重要成分与肿瘤发生密切相关。本研究通过检测乳腺癌组织中E-cadherin、β-catenin及cyclinD1的表达,探讨E-cadherin、β-catenin在乳腺癌发生、发展中的意义。方法采用免疫组织化学SP法检测60例乳腺癌组织中E-cadherin、β-catenin、cyclinD1的表达。结果乳腺癌组织中有29例(48.3%)E-cadherin、18例(30.0%)β-catenin正常表达,28例(46.7%)cyclinD1过度表达。E-cadherin正常表达病例中,31.0%(9/29)的病例呈现cyclinD1过度表达,而E-cadherin异常表达病例中,61.3%(19/31)的病例呈现cyclinD1过度表达,E-cadherin异常表达与cyclinD1的过度表达有显著的正相关性(rs=0.303,P<0.05)。有42例癌组织表现出β-catenin的异常表达,其中57.1%(24/42)的病例出现cyclinD1的过度表达,而β-catenin正常膜表达病例中,22.2%(4/18)的病例呈现cyclinD1的过度表达。β-catenin的异常表达与cyclinD1的过度表达有显著的正相关性(rs=0.321,P<0.05)。结论E-cadherin和β-catenin的异常表达可能通过促使或激活cyclinD1的过度表达导致乳腺癌的发生和发展。     

Significance of E-cadherin/beta-catenin complex and cyclin D1 in breast cancer

E-cadherin and beta-catenin are important epithelial adhesion molecules in normal epithelium. Loss of E-cadherin - beta-catenin adhesion is an important step in the progression of many epithelial malignancies. beta-catenin plays also a role in intracellular signaling and can function as an oncogene when binds to the T-cell factor 4 (Tcf4)-binding site in the promotor region of cyclin D1 and transactivates genes after translocation to the nucleus. We evaluated the immunohistochemical expression pattern of E-cadherin, beta-catenin in relationship with cyclin D1 overexpression, tumor stage, clinicopathologic parameters and patient survival in 128 mammary infiltrating duct carcinomas. The expression of E-cadherin/beta-catenin complex and beta-catenin/cyclin D1 double staining with confocal scanning laser microscope was evaluated. There were aberrant expressions in 78% of E-cadherin, 79% of beta-catenin, and 66% of cyclin D1 in breast cancer. There was correlation of aberrant expression of E-cadherin or beta-catenin with lymph node metastasis, survival rate, and survival length. However, there was no correlation of cyclin D1 overexpression with aberrant expression of E-cadherin or beta-catenin. No death was found in normal expression of beta-catenin, however lowest survival (50%) was found in nuclear beta-catenin expression. There was correlation of overexpression of cyclin D1 with survival rate and survival length. The highest survival rate and survival length were found in membranous normal beta-catenin expression group, however significant decrement of survival length was found in the groups of aberrant expression one or both of E-cadherin or/and beta-catenin. These results suggest that aberrant expression of E-cadherin, beta-catenin, and cyclin D1 may be involved in tumor metastasis, and analysis of the degree or the pattern of E-cadherin, beta-catenin, cyclin D1, and E-cadherin/beta-catenin complex may be good prognostic markers of mammary infiltrating duct carcinoma.     

Adriamycin activates E-cadherin-mediated cell-cell adhesion in human breast cancer cells

E-cadherin-mediated cell-cell adhesion plays a crucial role in intercellular communication, which is related to the regulation of cell proliferation, differentiation, and apoptosis. Our previous study showed that decreased expression of MUC1 can induce E-cadherin-mediated cell-cell adhesion in human breast cancer cell lines proliferating in suspension without aggregation. Using such a cell line (YMB-S), we observed the effects of an anticancer agent, adriamycin, on cell-cell adhesion and expression of E-cadherin-catenin complex and MUC1. The cells showed E-cadherin-mediated cell-cell adhesion after 48 h exposure to 0.4 micromol/l adriamycin. And in these cells, expression of E-cadherin and beta-catenin mRNA obviously began to increase, while expression of MUC1 mRNA decreased, as demonstrated by Northern blot analysis. Such change in mRNA levels were followed by increases in E-cadherin and beta-catenin protein levels and a decrease in MUC1 protein level. Though expression of alpha-catenin mRNA began to increase on day 2, its protein level did not change. In immunohistochemical analysis, beta-catenin protein in untreated cells showed diffuse cytoplasmic localization, whereas beta-catenin in treated cells was present in cytoplasm with a clear submembranous localization, indicating that increased beta-catenin mainly bound with E-cadherin, participating in cell-cell adhesion. These findings show for the first time that adriamycin can induce E-cadherin-mediated cell-cell adhesion by increasing expression of E-cadherin and beta-catenin and decreasing expression of MUC1 during breast cancer cell apoptosis induced by this drug.     

Thiazolidinedione,a peroxisome proliferator-activated receptor-gamma ligand,modulates the E-cadherin/beta-catenin system in a human pancreatic cancer cell line,BxPC-3

Activation of peroxisome proliferator-activated receptor (PPAR)-gamma induces terminal differentiation and growth inhibition associated with G1 cell cycle arrest in some cancer cells. The multifunctional molecule beta-catenin performs important roles in intercellular adhesion and signal transduction. However, no report has focused on actions of PPAR-gamma in regulating the E-cadherin/beta-catenin system. We examined whether thiazolidinedione (TZD), a potent PPAR-gamma ligand, could modulate the E-cadherin/beta-catenin system in a human pancreatic cancer cell line, BxPC-3, that has been found to express PPAR-gamma. According to Western blotting, TZD markedly increased differentiation markers including E-cadherin and carcinoembryonic antigen, while beta-catenin did not change significantly. In untreated cells, fluorescence immunostaining demonstrated beta-catenin predominantly in the cytoplasm and/or nucleus; in TZD-treated cells, beta-catenin localization had dramatically shifted to the plasma membrane, in association with increased E-cadherin at this site. Thus, a PPAR-gamma ligand appears to participate not only in induction of differentiation in pancreatic cancer cells, but also in the regulation of the E-cadherin/beta-catenin system. Such ligands may prove clinically useful as cytostatic anticancer agents.     

Bottom-up histogenesis of colorectal adenomas: origin in the monocryptal adenoma and initial expansion by crypt fission

The adenoma:carcinoma sequence is well established. Understanding the molecular pathology of the adenoma is therefore important. There is great controversy within the field. The Vogelstein group champions the "top-down" theory (colorectal adenomas arise and grow across the mucosal surface and down into the crypts), whereas other studies, including our own, propose "bottom-up" spread. Serial sections of 40 small (<3 mm) sporadic colorectal adenomas were stained with H&E, MIB-1, and for beta-catenin. 10 early adenomas were Feulgen-stained and microdissected. We also examined the flat mucosa of three patients who had undergone colectomies for familial adenomatous polyposis (FAP) and specimens from a XO/XY individual with FAP, the latter using in situ hybridization for the Y chromosome. In the earliest sporadic adenomas, there were crypts entirely filled with adenomatous epithelium, which showed proliferative activity and nuclear localization of beta-catenin. There was a sharp cutoff between crypt epithelial cells showing nuclear beta-catenin and surface cells with membrane staining. In slightly larger lesions, adenomatous spread from above was seen. Microdissected adenomas showed multiple fission events, with proliferation distributed equally throughout. In FAP tissue, numerous isolated monocryptal adenomas, which were clonal in origin, were seen. Examination of adenomas in the XO/XY individual showed no instances of XY or XO adenomatous epithelium growing down into crypts of the other genotype. Both sporadic and FAP adenomas start as a unicryptal adenomas and grow initially by crypt fission--a bottom-up pattern. Later, in sporadic adenomas, there is evidence of growth down into adjacent crypts (top-down).     

Activation of beta-catenin in epithelial and mesenchymal hepatoblastomas

Wnt/beta-catenin signaling is frequently activated in cancer cells by stabilizing mutations of beta-catenin or loss-of-function mutations of the APC tumor suppressor gene. We have analysed the role of beta-catenin in the pathogenesis of hepatoblastoma (HB), an embryonic liver tumor occurring mainly in children under 2 years of age. Sequence analysis of the beta-catenin NH2-terminal domain in 18 epithelial and mixed HBs revealed missense mutations in the GSK3beta phosphorylation motif or interstitial deletions in 12 tumors (67%). In the remaining cases, no truncating mutation of APC could be evidenced. Immunohistochemical analysis of beta-catenin in 11 HBs demonstrated nuclear/cytoplasmic accumulation of the protein in all tumors analysed, with predominant nuclear beta-catenin immunostaining in undifferentiated cells. Membranous beta-catenin localization was preserved only in fetal-type tumoral hepatocytes and was associated with E-cadherin expression. Moreover, we show that beta-catenin is aberrantly overexpressed in a large spectrum of tumor components, including hepatocyte-like cells at various differentiation stages and heterologous elements such as squamous, osteoid and chrondroid tissues, and in occasional other mesenchymally-derived cells. These data strongly suggest that activation of beta-catenin signaling is an obligatory step in HB pathogenesis, and raise the possibility that it interferes with developmental signals that specify different tissue types at early stages of hepatic differentiation.     

beta-Catenin mutation and overexpression in hepatocellular carcinoma: clinicopathologic and prognostic significance.

BACKGROUND: beta-Catenin has been recognized as a critical member of the Wnt signaling pathway, and inappropriate activation of this pathway has been implicated in carcinogenesis. METHODS: To determine the clinical significance of beta-catenin in hepatocellular carcinoma (HCC), we performed mutational analysis at exon 3 of the gene, investigated the subcellular protein expression, and analyzed their clinicopathologic and prognostic significance in 60 patients with resected primary HCC. RESULTS: By direct DNA sequencing, somatic mutations of the beta-catenin gene were detected in 7 (12%) HCCs. All the mutations were found at the region (exon 3) responsible for phosphorylation and ubiquitination, therefore likely to result in stabilization of free cytoplasmic beta-catenin. Nuclear accumulation of the beta-catenin protein, similar to the response to the Wnt signal, was found in 10 (17%) HCCs and was closely associated with gene mutation (P < 0.001). In the remaining cases, nonnuclear type overexpression, that is, overexpression in the cytoplasm and/or cytoplasmic membrane, was observed in 31 (62%) HCCs, thus suggesting that the mechanisms leading to beta-catenin overexpression may be heterogeneous. HCCs with a nonnuclear type of beta-catenin overexpression were more frequently larger than 5 cm in diameter (P = 0.022) and had poorer cellular differentiation (P = 0.037), and the patients had significantly shorter disease-free survival lengths (P = 0.041). Review of the data from previous studies in HCC showed that beta-catenin mutations were more frequent in HCV-associated HCC than in HBV-associated ones. CONCLUSIONS: beta-catenin mutation and deregulation may play an important role in hepatocarcinogenesis. Nonnuclear type beta-catenin overexpression appeared to have pathologic and prognostic significance.