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CircLIFR synergizes with MSH2 to attenuate chemoresistance via MutSα/ATM-p73 axis in bladder cancer
- Source :
- Molecular Cancer, Molecular Cancer, Vol 20, Iss 1, Pp 1-20 (2021)
- Publication Year :
- 2021
- Publisher :
- Springer Science and Business Media LLC, 2021.
-
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.
- Subjects :
- Male
0301 basic medicine
Cancer Research
CDDP
Ataxia Telangiectasia Mutated Proteins
0302 clinical medicine
RC254-282
In Situ Hybridization, Fluorescence
medicine.diagnostic_test
Bladder cancer
Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Middle Aged
Immunohistochemistry
female genital diseases and pregnancy complications
DNA-Binding Proteins
MutS Homolog 2 Protein
Oncology
030220 oncology & carcinogenesis
Molecular Medicine
Female
medicine.drug
Adult
Antineoplastic Agents
Biology
Flow cytometry
03 medical and health sciences
Mediator
Western blot
In vivo
Cell Line, Tumor
Biomarkers, Tumor
medicine
Animals
Humans
neoplasms
Aged
Cell Proliferation
Cisplatin
CircLIFR
Research
nutritional and metabolic diseases
RNA, Circular
medicine.disease
Xenograft Model Antitumor Assays
MSH2
Disease Models, Animal
030104 developmental biology
Gene Expression Regulation
Urinary Bladder Neoplasms
Drug Resistance, Neoplasm
Apoptosis
Cancer research
Subjects
Details
- ISSN :
- 14764598
- Volume :
- 20
- Database :
- OpenAIRE
- Journal :
- Molecular Cancer
- Accession number :
- edsair.doi.dedup.....d78bf95f76cabc02a3a0d1c49e99ef77