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Involvement of JNK pathway in the promotion of the early stage of colorectal carcinogenesis under high-fat dietary condition
  1. Hiroki Endo (t066011b{at}yokohama-cu.ac.jp)
  1. Yokohama City University School of Medicine, Japan
    1. Kunihiro Hosono
    1. Yokohama City University School of Medicine, Japan
      1. Toshio Fujisawa
      1. Yokohama City University School of Medicine, Japan
        1. Hirokazu Takahashi
        1. Yokohama City University School of Medicine, Japan
          1. Michiko Sugiyama
          1. Yokohama City University School of Medicine, Japan
            1. Kyoko Yoneda
            1. Yokohama City University School of Medicine, Japan
              1. Yuichi Nozaki
              1. Yokohama City University School of Medicine, Japan
                1. Koji Fujita
                1. Yokohama City University School of Medicine, Japan
                  1. Masato Yoneda
                  1. Yokohama City University School of Medicine, Japan
                    1. Masahiko Inamori
                    1. Yokohama City University School of Medicine, Japan
                      1. Koichiro Wada
                      1. Osaka University, Japan
                        1. Hitoshi Nakagama
                        1. National Cancer Center Research Institute, Japan
                          1. Atsushi Nakajima (nakajima-tky{at}umin.ac.jp)
                          1. Yokohama City University School of Medicine, Japan

                            Abstract

                            Background and aims: The molecular mechanisms underlying the promotion of colorectal carcinogenesis by a high-fat diet (HFD) remain unclear. We investigated the role of the insulin-signal pathway and the c-Jun N-terminal kinase (JNK) pathway, which reportedly play crucial roles in insulin resistance, during colorectal carcinogenesis in the presence of hyperinsulinemia induced by a HFD.

                            Methods: Azoxymethane-induced aberrant crypt foci formation and cell proliferation in the colonic epithelium were compared between mice fed a normal diet (ND) and mice fed a HFD. A western blot analysis was performed to elucidate the mechanism affecting colorectal carcinogenesis by a HFD.

                            Results: The number of aberrant crypt foci and the colonic epithelial cell proliferative activity were significantly higher in the HFD group than in the ND group. While the plasma insulin level was significantly higher in the HFD group than in the ND group, a western blot analysis revealed the inactivation of Akt, which is located downstream of the insulin receptor, in the colonic epithelia of the HFD group. On the other hand, JNK activity was significantly higher in the HFD group than in the ND group. A JNK specific inhibitor significantly suppressed the increase in epithelial cell proliferation only under a HFD, but not under a ND.

                            Conclusions: Colonic cell proliferation was promoted via the JNK pathway in the presence of a HFD but not in the presence of a ND. This novel mechanism may explain the involvement of the JNK pathway in the effect of dietary fat intake on colon carcinogenesis.

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