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Loss of beta‐catenin Accelerates N‐nitrosodiethylamine–Induced Hepatocarcinogenesis by Activating Phosphoinositide 3‐Kinase (PI3K)/Akt Signaling Pathway
Author(s) -
Zhang Xufeng,
Tan Xinping,
Monga Satdarshan S
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.359.4
Subject(s) - protein kinase b , carcinogenesis , pi3k/akt/mtor pathway , wnt signaling pathway , downregulation and upregulation , gsk 3 , cancer research , endocrinology , chemistry , knockout mouse , medicine , signal transduction , biology , microbiology and biotechnology , receptor , cancer , biochemistry , gene
β‐catenin, the pivotal component of canonical Wnt pathway, plays an important role in liver regeneration, growth and cancers. To further address the role of β‐catenin in liver carcinogenesis, we used a hepatocyte specific β‐catenin knockout (Ko) mouse model. 5 μg/g body weight of N‐nitrosodiethylamine (DEN), a well‐known hepatocarcinogenic agent, was injected i.p., at the age of 14 days to induce tumors in both Ko and wild type (WT) mice. Intriguingly, rather than being protected from carcinogenesis, β‐catenin Ko mice were more susceptible to DEN. In the Ko, liver tumors appeared more rapidly and were also larger and more in numbers. The Ko livers after DEN also showed a considerable increase in the number of proliferating cells by PCNA staining. We identified upregulation of platelet‐derived growth factor receptor‐α (PDGFRα), glycogen synthase kinase 3β (GSK3β), GSK3β (Ser 9) and phospho‐Akt (Thr 308) in Ko livers. Also phospho‐Akt (Thr 308) was exclusively upregulated in tumors in Ko livers as seen by immunohistochemistry. In conclusion, β‐catenin Ko livers were more prone to carcinogenesis, secondary to PI3K/Akt activation, thus accounting for earlier onset of tumor and an overall robust disease.