Jian Wang1, Zhan-Guo Zhang1, Ze-Yang Ding1, Wei Dong1, Hui-Fang Liang1, Liang Chu1, Bi-Xiang Zhang1, Xiao-Ping Chen2. 1. Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology; Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery; Key Laboratory of Organ Transplantation, Ministry of Education and Ministry of Public Health; Wuhan, China. 2. Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology; Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery; Key Laboratory of Organ Transplantation, Ministry of Education and Ministry of Public Health; Wuhan, China. Electronic address: xpchen@tjh.tjmu.edu.cn.
Abstract
BACKGROUND: Isocitrate dehydrogenase 1/2 (IDH1/2) mutations have been reported in intrahepatic cholangiocarcinoma (IHCC). However, the prognosis of a single IDH1 mutation and impact of mutant IDH1 on IHCC tumor growth remain unclear. METHODS: A total of 85 IHCC tumor samples were sequenced. Prognosis and clinicopathological correlation were analyzed. The role of mutant IDH1 in IHCC tumor growth was measured by cell proliferation assay, colony formation assay in soft agar, and xenograft tumor models. Akt, ERK, p38 MAPK, and JNK signaling, which commonly affect tumor growth, were examined by Western blotting to explore the potential mechanism. RESULTS: IDH1 mutations correlated with a beneficial prognosis and smaller tumor size. Mutant IDH1 exhibited a growth-inhibitory effect on IHCC cell lines in vitro and in vivo. Akt signaling was suppressed in IHCC cell lines expressing a mutant IDH1. The reactivation of Akt signaling by SC79 restored the inhibited growth of cell lines expressing a mutant IDH1 in IHCC. CONCLUSIONS: Collectively, we demonstrated that mutant IDH1 correlates with a beneficial prognosis and inhibits tumor growth by suppressing Akt signaling in IHCC. We suggest that patients with IDH1 mutations could be considered for both less-aggressive therapy and therapy tailored to the presence of their mutant enzyme in the future.
BACKGROUND: Isocitrate dehydrogenase 1/2 (IDH1/2) mutations have been reported in intrahepatic cholangiocarcinoma (IHCC). However, the prognosis of a single IDH1 mutation and impact of mutant IDH1 on IHCC tumor growth remain unclear. METHODS: A total of 85 IHCC tumor samples were sequenced. Prognosis and clinicopathological correlation were analyzed. The role of mutant IDH1 in IHCC tumor growth was measured by cell proliferation assay, colony formation assay in soft agar, and xenograft tumor models. Akt, ERK, p38 MAPK, and JNK signaling, which commonly affect tumor growth, were examined by Western blotting to explore the potential mechanism. RESULTS:IDH1 mutations correlated with a beneficial prognosis and smaller tumor size. Mutant IDH1 exhibited a growth-inhibitory effect on IHCC cell lines in vitro and in vivo. Akt signaling was suppressed in IHCC cell lines expressing a mutant IDH1. The reactivation of Akt signaling by SC79 restored the inhibited growth of cell lines expressing a mutant IDH1 in IHCC. CONCLUSIONS: Collectively, we demonstrated that mutant IDH1 correlates with a beneficial prognosis and inhibits tumor growth by suppressing Akt signaling in IHCC. We suggest that patients with IDH1 mutations could be considered for both less-aggressive therapy and therapy tailored to the presence of their mutant enzyme in the future.
Authors: Rohit Chandwani; William R Jarnagin; Thomas Boerner; Esther Drill; Linda M Pak; Bastien Nguyen; Carlie S Sigel; Alexandre Doussot; Paul Shin; Debra A Goldman; Mithat Gonen; Peter J Allen; Vinod P Balachandran; Andrea Cercek; James Harding; David B Solit; Nikolaus Schultz; Ritika Kundra; Henry Walch; Michael I D'Angelica; Ronald P DeMatteo; Jeffrey Drebin; Nancy E Kemeny; T Peter Kingham; Amber L Simpson; Jaclyn F Hechtman; Efsevia Vakiani; Maeve A Lowery; J N M Ijzermans; S Buettner; B Groot Koerkamp; M Doukas Journal: Hepatology Date: 2021-09 Impact factor: 17.298