Identification of MALT1 as both a prognostic factor and a potential therapeutic target of regorafenib in cholangiocarcinoma patients
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Chun-Nan Yeh1,*, Yu-Chan Chang2,*, Yeu Su3, Dennis Shin-Shian Hsu4, Chi-Tung Cheng1, Ren-Chin Wu5, Yi-Hsiu Chung6, Kun-Chun Chiang1, Ta-Sen Yeh1, Meng-Lun Lu7, Chun-Yu Liu7,8, Peter Mu-Hsin Chang7,8, Ming-Han Chen8, Chi-Ying F. Huang3, Michael Hsiao2,9,# and Ming-Huang Chen7,8,#
1Department of Surgery, Liver Research Center, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan
2Genomics Research Center, Academia Sinica, Taipei, Taiwan
3Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan
4Genome Research Center, National Yang-Ming University, Taipei, Taiwan
5Department of Pathology, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan
6Center for Advanced Molecular Imaging and Translation, Chang Gung Memorial Hospital, Taoyuan, Taiwan
7Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan
8School of Medicine, National Yang-Ming University, Taipei, Taiwan
9Department of Biochemistry, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
*These authors contributed equally to this work
#These are senior authors and contributed equally to this work
Michael Hsiao, email: [email protected]
Ming-Huang Chen, email: [email protected]
Keywords: cholangiocarcinoma; regorafenib; MALT1; MI-2; Elk-1
Received: June 22, 2017 Accepted: November 14, 2017 Published: December 08, 2017
Intrahepatic cholangiocarcinoma (CCA) is an aggressive cancer that lacks an effective targeted therapy. Here, we assessed the therapeutic efficacy of regorafenib in CCA, as well as elucidated its underlying mechanism. We first demonstrated that regorafenib not only inhibited growth but also induced apoptosis in human CCA cells. Subsequently, we used in silico approaches to identify MALT1 (Mucosa-associated lymphoid tissue protein 1), which plays an important role in activating NF-κB, as a potential target of regorafenib. Overexpression of Elk-1, but not Ets-1, in HuCCT1 cells markedly reduced their sensitivity to regorafenib, which might be attributed to a significant increase in MALT1 levels. Our results further demonstrated that this drug drastically inhibited MALT1 expression by suppressing the Raf/Erk/Elk-1 pathway. The efficacy of regorafenib in decreasing in vivo CCA growth was confirmed in animal models. Regorafenib efficacy was observed in two MALT1-positive CCA patients who failed to respond to several other lines of therapy. Finally, MALT1 was also identified as an independent poor prognostic factor for patients with intrahepatic CCA. In conclusion, our study identified MALT1 to be a downstream mediator of the Raf/Erk/Elk-1 pathway and suggested that MALT1 may be a new therapeutic target for successful treatment of CCA by regorafenib.
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