CircLIFR synergizes with MSH2 to attenuate chemoresistance via MutS\u03b1/ATM-p73 axis in bladder cancer

Hui Zhang,Xiaoping Zhang,Yangkai Jiang,Liang Wang,Yuanqiao He,Guosong Jiang,Miao Wang,Wenjie Wei,Xingyuan Xiao,Jiayin Sun,Chao Huang

doi:10.1186/s12943-021-01360-4

Hui Zhang, Xiaoping Zhang + Show 9 more

Open Access

https://doi.org/10.1186/s12943-021-01360-4

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Abstract

BackgroundCisplatin (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.MethodsThrough 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.ResultsCircLIFR 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.ConclusionsCircLIFR 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.

Highlights

Cisplatin (CDDP) has become a standard-of-care treatment for muscle-invasive bladder cancer (MIBC), while chemoresistance remains a major challenge
Our findings provided a systematic elucidation into the regulation of circLIFR on the function of MutS homolog 2 (MSH2), and indicated that circLIFR and MSH2 might be act as promising therapeutic targets for CDDP-resistant bladder cancer
Consistent with the RNA-seq results [22], circLIFR was significantly downregulated in bladder cancer tissues (Fig. 1b), while the expression of LIFR pre-mRNA and mRNA showed no significant difference between bladder cancer and paired normal tissues (Fig. S1, A and B)

Summary

Introduction

Cisplatin (CDDP) has become a standard-of-care treatment for muscle-invasive bladder cancer (MIBC), while chemoresistance remains a major challenge. The regulatory functions as well as complexities of circRNAs in modulating CDDP-based chemotherapy in bladder cancer are yet to be well revealed. Cisplatin (CDDP)-based gemcitabine and cisplatin (GC) regimen has become a standard-of-care treatment for muscle-invasive bladder cancer (MIBC) [2, 3]. 60% of patients with metastatic MIBC demonstrate an objective response to CDDP-based chemotherapy, this response is rarely durable, and chemoresistance remains a major challenge in this disease setting [2, 4]. A retrospective cohort study shows decreased survival in patients treated with immunotherapy monotherapy relative to the chemotherapy arms [6]. A better comprehension of the mechanisms underlying the development of CDDP resistance in patients with bladder cancer will represent a major step forward in optimizing patients’ outcomes

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