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[Cancer Research 59, 1830-1833, April 15, 1999]
© 1999 American Association for Cancer Research

Advances in Brief

ß-Catenin Mutations Are Frequent in Hepatocellular Carcinomas but Absent in Adenomas Induced by Diethylnitrosamine in B6C3F1 Mice1

Katsuhiro Ogawa2, Yoshihisa Yamada, Kan Kishibe, Kenichi Ishizaki and Yoshihiko Tokusashi

Department of Pathology, Asahikawa Medical College, Asahikawa 078-8510, Japan


   ABSTRACT
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 ABSTRACT
Introduction
 Materials and Methods
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 Discussion
 REFERENCES
 
Activating mutations in the region of the ß-catenin gene corresponding to the NH2-terminal phosphorylation sites of glycogen synthetase kinase 3ß have been causally implicated in carcinogenesis. In this study, the ß-catenin exon 3 was examined in hepatic lesions induced by diethylnitrosamine in B6C3F1 mice. PCR and DNA sequencing detected seven ß-catenin mutations in 13 samples dissected from hepatocellular carcinoma tissues, but none in 14 hepatic adenomas. All of the mutations were found in codon 41 encoding a threonine residue, one of the possible glycogen synthetase kinase-3ß phosphorylation sites. Although ß-catenin protein was immunohistochemically stained mainly on the cell membrane in preneoplastic hepatocytic foci and most adenomas, as observed in normal hepatocytes, it was detected in the cytoplasm and nuclei in addition to the cell membrane, indicating stabilization of the protein in HCCs. This shift in staining was observed not only in tumors with mutations, but also in examples lacking exon 3 mutations. Our data demonstrate that ß-catenin alterations may be important for malignant progression during multistep hepatic carcinogenesis in mice.


   Introduction
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 ABSTRACT
 Introduction
Materials and Methods
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ß-Catenin mutations play a critical role in the development of some cancers in man (1, 2, 3, 4, 5, 6, 7) and in rodents (8 , 9) . The protein is involved with both cell proliferation through the Wnt-Tcf signaling pathway and cell adhesion by its association with epithelial cadherin (10) . ß-Catenin levels are regulated by phosphorylation of its NH2-terminal region by GSK-3ß3 (11) , the phosphorylated protein being rapidly degraded through the ubiquitin-proteasome pathway (12 , 13) . For phosphorylation to occur, ß-catenin needs to be assembled with the APC, Axin, and GSK-3ß complex (14) . Physiological expression of Wnt is associated with increased levels of hypophosphorylated-free ß-catenin (15) . Inactivation of APC or ß-catenin mutations also lead to elevated free ß-catenin (1 , 2 , 16) . Hypophosphorylated ß-catenin associates with members of the T-cell factor (Tcf) family (17 , 18) , and their complexes transactivate growth-promoting genes such as c-myc (19) .

Although the HCC is one of the major malignancies in man, the molecular mechanisms involved in its development remain obscure. High expression of oncogenes and growth factors such as c-myc, cyclin D1, and insulin-like growth factor II, and inactivation of tumor suppressor genes such as p53 and Rb have been reported (20) , but it is not known to what extent these changes are related to its pathogenesis. Recently, ß-catenin mutations were reported to be relatively frequent in human (7) and mouse HCCs (9) , the latter developing in transgenic mice with activated H-ras or c-myc genes. However, it is unknown whether mutations are also prevalent in HCCs induced by chemical carcinogens in mice and at what stage ß-catenin mutations occur during multistep hepatic carcinogenesis.

Administration of a single dose of DEN to newborn mice causes many preneoplastic hepatocytic foci to emerge during the early stage, and then hepatic adenomas develop before the final occurrence of HCC (21) . Focal HCCs are occasionally seen within adenomas. Although activating mutations of H-ras are frequently observed in the tumors (22) , no information is available regarding ß-catenin mutations. In this study, we, therefore, examined for the status of exon 3 of the ß-catenin gene and immunohistochemically investigated its protein localization in mouse hepatic lesions.


   Materials and Methods
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 Materials and Methods
Results
 Discussion
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Treatment of Animals and Tissue Preparation.
Male B6C3F1 mice (Clea Japan, Tokyo, Japan), a cross between female C57BL/6J and male C3H/HeJ mice were given i.p. DEN at a dose of 10 µg/g body weight at the age of 3 weeks. The animals were then fed on normal diet and water ad libitum for 1–1.5 years. At sacrifice, the livers were perfusion-fixed through the portal vein or vena cava with 4% formaldehyde solution, embedded in paraffin, and examined histologically. Fresh HCC samples were also isolated at the 1.5 years time point for preparation of RNA, frozen in liquid nitrogen, and stored at -80°C until use. As control, six samples of normal hepatic tissues of untreated mice were frozen and stored.

Immunohistochemistry.
Deparaffinized tissue sections were incubated in 3% H2O2 dissolved in methanol for 30 min and then microwaved in 0.01 M citrate buffer (pH 6.0) for 10 min in an electric oven. After washing in PBS, the anti-ß-catenin monoclonal antibody (Transduction Laboratories, Lexington, KY) was applied to the sections at a dilution of 1:100 for 30 min. Then, antibody binding was visualized by the avidin-biotin method using a Histofine kit (Nichirei, Tokyo, Japan). As negative controls, the sections were immunostained without application of the primary antibody.

Preparation of DNAs and RNAs.
Fourteen adenomas and 13 HCCs were microdissected from deparaffinized sections, and DNAs were isolated from the tissues by incubation in 0.2 mg/ml proteinase K solution for 1 h at 37°C without further purification. Regarding HCCs, areas showing cytoplasmic and nuclear staining for ß-catenin were chosen for dissection. Five DNA samples were also prepared from normal hepatic tissues. Total RNAs were isolated from the six frozen normal livers and the whole mass of seven HCC samples using a TRIzol reagent kit (Life Technologies, Grand Island, NY).

PCR.
A 150-bp fragment emcompassing the GSK-3ß phosphorylation sites in ß-catenin exon 3 was amplified by PCR using DNA isolated from tissue sections. The PCR primer sequences were 5'-GGAGTTGGACATGGCCATGG-3' (forward) and 5'-TCAACATCTTCTTCCTCAGG-3' (reverse). PCR was carried out in a reaction volume of 50 µl for 4 min at 94°C for initial denaturation, followed by 35 cycles of 94°C for 30 s, 60°C for 30 s, and 72°C for 30 s with a thermal cycler (MJ Research, Watertown, MA).

RT-PCR.
Total RNA was reverse-transcribed for generation of first strand cDNA using oligo(dT)16 primers, and aliquots of the reaction mixtures were used for the subsequent PCR. The forward PCR primer (5'-GCGTGGACAATGGCTACTCAAG-3') targeted the end of exon 2, and the reverse primer (5'-GTCATTGCATACTGCCCGTCAA-3') the beginning of exon 4. The PCR conditions were the same as above, except for the extension temperature of 55°C.

DNA Sequencing.
PCR and RT-PCR products were purified from agarose gels using a QIAEXII gel extraction kit (Qiagen, Inc., Chatsworth, CA) and sequenced using dye terminator cycle sequencing chemistry with AmpliTaq polymerase FS (Applied Biosystems, Foster City, CA), according to the manufacturer’s instructions. Sequencing was performed in both directions using the PCR primers detailed above. The sequence reactions were run on a fluorescence automated DNA sequencer (Prism 377; Applied Biosystems), and the data collected were analyzed using Applied Biosystems sequencing analysis software.

Statistical Analysis.
Statistical differences in this study were analyzed using two-tailed {chi}2 tests.


   Results
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Discussion
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Immunohistochemistry.
Immunohistochemical staining of normal hepatic tissue revealed ß-catenin to be positive in hepatocytes, bile duct epithelium, and sinusoidal lining cells. In hepatocytes, the staining was localized predominantly on the membranes facing the sinusoids and the recesses between neighboring hepatocytes (Fig. 1A)Citation . The liver of mice treated with DEN contained preneoplastic hepatocytic foci, hepatic adenomas, and HCC at 1 and 1.5 years after the DEN treatment. These lesions were classified according to established criteria (23) . In preneoplastic foci and most adenomas, although the staining was sometimes weaker than in the surrounding normal hepatic tissues, ß-catenin was localized mostly to the cell membrane (Fig. 1BCitation and Table 1Citation ). Most HCCs showed elevated ß-catenin expression (Fig. 1, C and D)Citation , although areas of intense and weak immunoreactivity were frequently admixtured in the same tumor. Eighteen percent of the HCCs mainly showed membranous staining, 30% showed both membranous and cytoplasmic staining, and 52% showed nuclear staining in 1–20% of the cells, in addition to membranous and cytoplasmic staining (Table 1)Citation .



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  		Fig. 1. Immunohistochemistry of ß-catenin in normal liver and hepatic lesions. A, in normal hepatocytes, the staining is mainly positive on the membrane facing sinusoids and the recesses between adjacent hepatocytes. Sinusoidal lining cells are also positively stained (arrows; x400). B, hepatic adenoma (Ad) shows membranous staining like normal hepatocytes (N; x100). C, this HCC (H) is located within an adenoma (Ad; x100). Cytoplasmic staining is dominant in HCC, whereas membranous staining is retained in adenoma. D, higher magnification of HCC (x200). Nuclear staining (arrows) is seen to various degrees in addition to cytoplasmic and membranous staining.

 

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  		Table 1 Immunohistochemistry of ß-catenin in hepatic lesions

 
ß-Catenin Mutations.
The sequence of ß-catenin exon 3 for the five normal DNA samples was identical to the published sequence for mouse ß-catenin cDNA (24) . Electrophoresis of PCR products from DNA of dissected adenomas and HCC tissues showed the same-sized band. DNA sequencing identified no mutations in any of 14 adenomas. On the other hand, 7 of 13 HCCs had mutations in codon 41. All were transitions; five from ACC (threonine) to ATC (isoleucine) change, and two from ACC to GCC (alanine; Fig. 2Citation and Table 2Citation ).



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  		Fig. 2. Sequencing data for DNA from normal liver (A) and HCC samples (B and C). C to T transition at the second base of codon 41 (B). A to G change at the first base of codon 41(C).

 

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  		Table 2 ß-Catenin mutations in HCCs

 
Because deletion and splicing abnormalities involving ß-catenin exon 3 can occur, as well as point mutations, in cancer (2 , 7 , 9) , we also examined ß-catenin exon 3 in mRNA of HCCs by RT-PCR and sequencing. RT-PCR of ß-catenin mRNA spanning the sequence from the end of exon 2 to the beginning of exon 4 generated a 275-bp fragment from normal hepatic tissues. No abnormal bands were seen in seven HCC samples tested. Sequencing of the fragments detected no deletion, insertion, or point mutations in these samples.


   Discussion
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 ABSTRACT
 Introduction
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REFERENCES
 
Activation of the Wnt-Tcf signal pathway can play a critical role in oncogenesis (1, 2, 3, 4, 5, 6, 7, 8, 9) . Either ß-catenin mutations involving the GSK-3ß phosphorylation sites or inactivation of APC are related to activation of the pathway in colon cancer and melanomas (1 , 2 , 16) . Although no information has been available up to this time about APC mutations in mouse HCC, to our knowledge, incidences of HCCs are not elevated in APC gene homozygously deleted Min mice, with a high frequency of spontaneous intestinal and mammary tumors (25) . Loss of heterozygosity at the APC locus on chromosome 5 has been detected only at low frequency in human HCCs (26) , indicating that inactivation of APC may be infrequent. In the present study, immunohistochemistry revealed ß-catenin staining to be frequently increased in the cytoplasm and occasionally in nuclei of HCCs, suggesting stabilization of the protein. The staining was found not only in association with ß-catenin mutations, but also the lesions without any mutations in exon 3. Although contamination of the tumor DNA samples with normal DNA from stromal components might have caused the mutations to be undetected, other possibilities such as mutations outside of the exon and alterations in other components of the Wnt-Tcf pathway or regulators of this system (27 , 28) also require investigation.

The fact that ß-catenin mutations were limited to HCCs and not found in hepatic adenomas indicates that they are late events during multistep hepatic carcinogenesis in mice. In contrast, activating mutations of the H-ras gene have been detected in 15% of small early adenomas induced by DEN (29) . Whether ß-catenin and H-ras mutations may have cooperative or independent roles in mouse hepatic carcinogenesis remains to be clarified.

We could not detect any mutations in seven RNA samples from HCCs by RT-PCR and sequencing analysis, although the mutations were positive in the DNAs isolated from other HCCs. This is probably because RNAs were isolated from the whole mass of HCCs, whereas the DNA samples were isolated from the dissected focal areas within HCCs that showed cytoplasmic and nuclear staining, as well as membranous staining. This suggests that ß-catenin mutations may occur focally in HCCs, and normal ß-catenin mRNA may much exceed the mutated one in the whole mass of HCCs.

Recent evidence has shown that the ß-catenin-Tcf complex targets the c-myc gene (19) . Elevation of c-myc expression at protein and mRNA levels is frequently observed in human (20) and rodent HCCs (30) . Although some HCC cases with high c-myc expression are due to insertion of the hepatitis viral genome close to or within the c-myc gene or amplification of the c-myc gene (31) , the cause of the high c-myc expression is not clear for other cases. The possibility that activation of ß-catenin is involved clearly warrants attention.

All of the ß-catenin mutations were detected in codon 41 in the present investigation. This is in contrast to other studies in which the point mutations were rather found to be distributed throughout all of the GSK-3ß phosphorylation sites (codons 33, 35, 37, 41, and 45) and/or next to these sites (codons 32, 34, and 40; Refs. 1, 2, 3, 4, 5, 6, 7, 8, 9 ). Furthermore, in contrast to findings for human HCCs (7) and tumors in H-ras or c-myc transgenic mice (9) , deletions involving exon 3 were not detected in our samples. Although the underlying reasons are not known, one possibility is that molecular changes may differ between chemical carcinogen and transgenic mouse cases.

The base changes detected in this study were all transitions rather than transversions. Because the mutations were not found in adenomas, putative precursors for HCCs, the mutations were presumably not due to the direct action of the initiating carcinogen. The C to T change found in five cases is known to be specifically induced by nitric oxide through oxidative deamination of cytosine residues (32) . About half of H-ras mutations in DEN-induced HCCs in B6C3F1 mice have been reported to be transversions (CAA to AAA or CTA) with other half transitions (CAA to CGA) at codon 61 (22) , suggesting that the mechanisms leading to H-ras and ß-catenin mutations may be different.

The present study showed that ß-catenin mutations may have a critical role in malignant progression of mouse hepatic carcinogenesis. However, because not all HCCs with cytoplasmic and nuclear staining showed ß-catenin exon 3 mutations, the other mechanism(s) for stabilization and activation of ß-catenin should be investigated.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 Supported by a grant from the Japanese Ministry of Education, Science, Sports and Culture, Japan. Back

2 To whom requests for reprints should be addressed, at Department of Pathology, Asahikawa Medical College, 4-5-3-11 Nishikagura, Asahikawa 078-8510, Japan. Phone: 81-166-68-2370; Fax: 81-166-68-2379. Back

3 The abbreviations used are: GSK-3ß, glycogen synthetase kinase-3ß; HCC, hepatocellular carcinoma; APC, adenomatous polyposis coli; DEN, diethylnitrosamine; RT-PCR, reverse transcription-PCR. Back

Received 11/30/98. Accepted 3/ 2/99.


   REFERENCES
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 

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