TRIP13 impairs mitotic checkpoint surveillance and is associated with poor prognosis in multiple myeloma
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Yi Tao1,*, Guang Yang1,*, Hongxing Yang2,3,*, Dongliang Song1, Liangning Hu1, Bingqian Xie1, Houcai Wang1, Lu Gao1, Minjie Gao1, Hongwei Xu4, Zhijian Xu5, Xiaosong Wu1, Yiwen Zhang1, Weiliang Zhu5, Fenghuang Zhan4, Jumei Shi1
1Department of Hematology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, China
2Shanghai Key Laboratory of Plant Functional Genomics and Resources, Shanghai Chenshan Botanical Garden, Shanghai 201602, China
3Shanghai Chenshan Plant Science Research Center, Chienes Academy of Sciences, Shanghai 201602, China
4Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA
5CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
*These authors have contributed equally to this work
Jumei Shi, email: email@example.com
Fenghuang Zhan, email: firstname.lastname@example.org
Keywords: TRIP13, multiple myeloma, prognosis, drug resistance, MAD2
Received: April 16, 2016 Accepted: January 10, 2017 Published: February 01, 2017
AAA-ATPase TRIP13 is one of the chromosome instability gene recently established in multiple myeloma (MM), the second most common and incurable hematological malignancy. However, the specific function of TRIP13 in MM is largely unknown. Using sequential gene expression profiling, we demonstrated that high TRIP13 expression levels were positively correlated with progression, disease relapse, and poor prognosis in MM patients. Overexpressing human TRIP13 in myeloma cells prompted cell growth and drug resistance, and overexpressing murine TRIP13, which shares 93% sequence identity with human TRIP13, led to colony formation of NIH/3T3 fibroblasts in vitro and tumor formation in vivo. Meanwhile, the knockdown of TRIP13 inhibited myeloma cell growth, induced cell apoptosis, and reduced tumor burden in xenograft MM mice. Mechanistically, we observed that the overexpression of TRIP13 abrogated the spindle checkpoint and induced proteasome-mediated degradation of MAD2 primarily through the Akt pathway. Thus, our results demonstrate that TRIP13 may serve as a biomarker for MM disease development and prognosis, making it a potential target for future therapies.
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