Hui Zhang1, Xingyuan Xiao1, Wenjie Wei1, Chao Huang1, Miao Wang1, Liang Wang1, Yuanqiao He2, Jiayin Sun1, Yangkai Jiang1, Guosong Jiang3, Xiaoping Zhang4. 1. Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. 2. Department of Laboratory Animal Science, Nanchang University, Nanchang, 330006, China. 3. Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. jiangguosongdoc@hotmail.com. 4. Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. 1994xh0526@hust.edu.cn.
Abstract
BACKGROUND: Cisplatin (CDDP) has become a standard-of-care treatment for muscle-invasive bladder cancer (MIBC), while chemoresistance remains a major challenge. Accumulating evidence indicates that circular RNAs (circRNAs) are discrete functional entities. However, the regulatory functions as well as complexities of circRNAs in modulating CDDP-based chemotherapy in bladder cancer are yet to be well revealed. METHODS: Through analyzing the expression profile of circRNAs in bladder cancer tissues, RNA FISH, circRNA pull-down assay, mass spectrometry analysis and RIP, circLIFR was identified and its interaction with MSH2 was confirmed. The effects of circLIFR and MSH2 on CDDP-based chemotherapy were explored by flow cytometry and rescue experiments. Co-IP and Western blot were used to investigate the molecular mechanisms underlying the functions of circLIFR and MSH2. Biological implications of circLIFR and MSH2 in bladder cancer were implemented in tumor xenograft models and PDX models. RESULTS: CircLIFR was downregulated in bladder cancer and expression was positively correlated with favorable prognosis. Moreover, circLIFR synergizing with MSH2, which was a mediator of CDDP sensitivity in bladder cancer cells, positively modulated sensitivity to CDDP in vitro and in vivo. Mechanistically, circLIFR augmented the interaction between MutSα and ATM, ultimately contributing to stabilize p73, which triggered to apoptosis. Importantly, MIBC with high expression of circLIFR and MSH2 was more sensitive to CDDP-based chemotherapy in tumor xenograft models and PDX models. CONCLUSIONS: CircLIFR could interact with MSH2 to positively modulate CDDP-sensitivity through MutSα/ATM-p73 axis in bladder cancer. CircLIFR and MSH2 might be act as promising therapeutic targets for CDDP-resistant bladder cancer.
BACKGROUND:Cisplatin (CDDP) has become a standard-of-care treatment for muscle-invasive bladder cancer (MIBC), while chemoresistance remains a major challenge. Accumulating evidence indicates that circular RNAs (circRNAs) are discrete functional entities. However, the regulatory functions as well as complexities of circRNAs in modulating CDDP-based chemotherapy in bladder cancer are yet to be well revealed. METHODS: Through analyzing the expression profile of circRNAs in bladder cancer tissues, RNA FISH, circRNA pull-down assay, mass spectrometry analysis and RIP, circLIFR was identified and its interaction with MSH2 was confirmed. The effects of circLIFR and MSH2 on CDDP-based chemotherapy were explored by flow cytometry and rescue experiments. Co-IP and Western blot were used to investigate the molecular mechanisms underlying the functions of circLIFR and MSH2. Biological implications of circLIFR and MSH2 in bladder cancer were implemented in tumor xenograft models and PDX models. RESULTS:CircLIFR was downregulated in bladder cancer and expression was positively correlated with favorable prognosis. Moreover, circLIFR synergizing with MSH2, which was a mediator of CDDP sensitivity in bladder cancer cells, positively modulated sensitivity to CDDP in vitro and in vivo. Mechanistically, circLIFR augmented the interaction between MutSα and ATM, ultimately contributing to stabilize p73, which triggered to apoptosis. Importantly, MIBC with high expression of circLIFR and MSH2 was more sensitive to CDDP-based chemotherapy in tumor xenograft models and PDX models. CONCLUSIONS:CircLIFR could interact with MSH2 to positively modulate CDDP-sensitivity through MutSα/ATM-p73 axis in bladder cancer. CircLIFR and MSH2 might be act as promising therapeutic targets for CDDP-resistant bladder cancer.
Authors: Emily Feld; Joanna Harton; Neal J Meropol; Blythe J S Adamson; Aaron Cohen; Ravi B Parikh; Matthew D Galsky; Vivek Narayan; John Christodouleas; David J Vaughn; Rebecca A Hubbard; Ronac Mamtani Journal: Eur Urol Date: 2019-07-28 Impact factor: 20.096
Authors: S Aebi; B Kurdi-Haidar; R Gordon; B Cenni; H Zheng; D Fink; R D Christen; C R Boland; M Koi; R Fishel; S B Howell Journal: Cancer Res Date: 1996-07-01 Impact factor: 12.701
Authors: Robert S Svatek; Brent K Hollenbeck; Sten Holmäng; Richard Lee; Simon P Kim; Arnulf Stenzl; Yair Lotan Journal: Eur Urol Date: 2014-01-21 Impact factor: 20.096
Authors: H von der Maase; S W Hansen; J T Roberts; L Dogliotti; T Oliver; M J Moore; I Bodrogi; P Albers; A Knuth; C M Lippert; P Kerbrat; P Sanchez Rovira; P Wersall; S P Cleall; D F Roychowdhury; I Tomlin; C M Visseren-Grul; P F Conte Journal: J Clin Oncol Date: 2000-09 Impact factor: 44.544
Authors: Bishoy M Faltas; Davide Prandi; Scott T Tagawa; Ana M Molina; David M Nanus; Cora Sternberg; Jonathan Rosenberg; Juan Miguel Mosquera; Brian Robinson; Olivier Elemento; Andrea Sboner; Himisha Beltran; Francesca Demichelis; Mark A Rubin Journal: Nat Genet Date: 2016-10-17 Impact factor: 38.330