Altered composition of fatty acids exacerbates hepatotumorigenesis during activation of the phosphatidylinositol 3-kinase pathway

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• 作者：Yotaro Kudo¹ ; Yasuo Tanaka¹ ; Keisuke Tateishi¹ ;   ; ^{ktate-tky@umin.ac.jp} ; Keisuke Yamamoto¹ ; Shinzo Yamamoto¹ ; Dai Mohri¹ ; Yoshihiro Isomura¹ ; Motoko Seto¹ ; Hayato Nakagawa¹ ; Yoshinari Asaoka¹ ; Motohisa Tada² ; Miki Ohta¹ ; Hideaki Ijichi¹ ; Yoshihiro Hirata¹ ; Motoyuki Otsuka¹ ; Tsuneo Ikenoue¹ ; Shin Maeda³ ; Shuichiro Shiina¹ ; Haruhiko Yoshida¹ ; Osamu Nakajima⁴ ; Fumihiko Kanai² ; Masao Omata⁵ ; Kazuhiko Koike¹
• 关键词：Hepatocellular carcinoma ; Fatty acids ; NAFLD ; Tumor suppressor genes
• 刊名：Journal of Hepatology
• 出版年：2011
• 出版时间：December 2011
• 年：2011
• 卷：55
• 期：6
• 页码：1400-1408
• 全文大小：1371 K

文摘

Background & Aims

Some clinical findings have suggested that systemic metabolic disorders accelerate in vivo tumor progression. Deregulation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway is implicated in both metabolic dysfunction and carcinogenesis in humans; however, it remains unknown whether the altered metabolic status caused by abnormal activation of the pathway is linked to the protumorigenic effect.

Methods

We established hepatocyte-specific Pik3ca transgenic (Tg) mice harboring N1068fs*4 mutation.

Results

The Tg mice exhibited hepatic steatosis and tumor development. PPAR¦Ã-dependent lipogenesis was accelerated in the Tg liver, and the abnormal profile of accumulated fatty acid (FA) composition was observed in the tumors of Tg livers. In addition, the Akt/mTOR pathway was highly activated in the tumors, and in turn, the expression of tumor suppressor genes including Pten, Xpo4, and Dlc1 decreased. Interestingly, we found that the suppression of those genes and the enhanced in vitro colony formation were induced in the immortalized hepatocytes by the treatment with oleic acid (OA), which is one of the FAs that accumulated in tumors.

Conclusions

Our data suggest that the unusual FA accumulation has a possible role in promoting in vivo hepato-tumorigenesis under constitutive activation of the PI3K pathway. The Pik3ca Tg mice might help to elucidate molecular mechanisms by which metabolic dysfunction contributes to in vivo tumor progression.