July 24 2018
Tsugio Eto#, Keisuke Miyake#, Katsuhiko Nosho, Masaki Ohmuraya, Yu Imamura, Kota Arima, Shinichi Kanno, Lingfeng Fu, Yuki Kiyozumi, Daisuke Izumi, Hidetaka Sugihara, Yukiharu Hiyoshi, Yuji Miyamoto, Hiroshi Sawayama, Masaaki Iwatsuki, Yoshifumi Baba, Naoya Yoshida, Toru Furukawa, Kimi Araki, Hideo Baba* and Takatsugu Ishimoto*
(#These authors contributed equally to this work, *corresponding authors)
Impact of loss-of-function mutations at the RNF43 locus on colorectal cancer development and progression.
Journal of Pathology. 2018 Aug;245(4):445-455.
RNF43 mutations are frequently detected in colorectal cancer cells and lead to a loss of function of the ubiquitin E3 ligase. Here, we investigated the clinical significance of RNF43 mutations in a large Japanese cohort and the role of RNF43 at various stages of colorectal cancer development and progression. Mutation analysis of the RNF43 gene locus using pyrosequencing technology detected RNF43 hotspot mutations in 1 (0.88%) of 113 colorectal polyp cases and 30 (6.45%) of 465 colorectal cancer cases. Moreover, patients with colorectal cancer harboring mutated RNF43 experienced a higher recurrence rate than those harboring non-mutated RNF43. In addition, the growth of RNF43 wild-type colorectal cancer cell lines was significantly increased by RNF43 silencing. We generated Rnf43 knock-out mice in a C57BL/6N background using the CRISPR-Cas9 system. Although intestinal organoids from the Rnf43 knock-out mice did not show continuous growth compared with those from the wild-type mice in the absence of R-spondin, an azoxymethane (AOM)/dextran sodium sulfate (DSS) mouse model demonstrated that the tumors were markedly larger in the Rnf43 knock-out mice than in the wild-type mice. These findings provide evidence that Wnt signaling activation by RNF43 mutations during the tumorigenic stage enhances tumor growth and promotes a high recurrence rate in colorectal cancer patients.