Dying tumor cell-derived exosomal miR-194-5p potentiates survival and repopulation of tumor repopulating cells upon radiotherapy in pancreatic cancer

Autor: Furao Liu, Dian-na Gu, Ming-jie Jiang, Qian Huang, Ling Tian, Zhu Mei, Juan-juan Dai, Yi-yun Chen
Jazyk: angličtina
Rok vydání: 2020
Předmět:
0301 basic medicine
Cancer Research
DNA damage
medicine.medical_treatment
Apoptosis
Biology
DNA damage response
Exosomes
Exosome
lcsh:RC254-282
03 medical and health sciences
Mice
0302 clinical medicine
HMGA2
Cell Movement
Pancreatic cancer
microRNA
medicine
Biomarkers
Tumor
Tumor Cells
Cultured
Animals
Humans
Mitotic catastrophe
Cell Proliferation
Aspirin
Radiotherapy
Research
HMGA2 Protein
medicine.disease
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Tumor repopulation
Xenograft Model Antitumor Assays
Microvesicles
Radiation therapy
Tumor repopulating cell
Gene Expression Regulation
Neoplastic
Pancreatic Neoplasms
MicroRNAs
030104 developmental biology
Oncology
E2F3 Transcription Factor
030220 oncology & carcinogenesis
Cancer research
biology.protein
Disease Progression
Molecular Medicine
Zdroj: Molecular Cancer
Molecular Cancer, Vol 19, Iss 1, Pp 1-15 (2020)
ISSN: 1476-4598
Popis: Background Tumor repopulation is a major cause of radiotherapy failure. Previous investigations highlighted that dying tumor cells played vital roles in tumor repopulation through promoting proliferation of the residual tumor repopulating cells (TRCs). However, TRCs also suffer DNA damage after radiotherapy, and might undergo mitotic catastrophe under the stimulation of proliferative factors released by dying cells. Hence, we intend to find out how these paradoxical biological processes coordinated to potentiate tumor repopulation after radiotherapy. Methods Tumor repopulation models in vitro and in vivo were used for evaluating the therapy response and dissecting underlying mechanisms. RNA-seq was performed to find out the signaling changes and identify the significantly changed miRNAs. qPCR, western blot, IHC, FACS, colony formation assay, etc. were carried out to analyze the molecules and cells. Results Exosomes derived from dying tumor cells induced G1/S arrest and promoted DNA damage response to potentiate survival of TRCs through delivering miR-194-5p, which further modulated E2F3 expression. Moreover, exosomal miR-194-5p alleviated the harmful effects of oncogenic HMGA2 under radiotherapy. After a latent time, dying tumor cells further released a large amount of PGE2 to boost proliferation of the recovered TRCs, and orchestrated the repopulation cascades. Of note, low-dose aspirin was found to suppress pancreatic cancer repopulation upon radiation via inhibiting secretion of exosomes and PGE2. Conclusion Exosomal miR-194-5p enhanced DNA damage response in TRCs to potentiate tumor repopulation. Combined use of aspirin and radiotherapy might benefit pancreatic cancer patients.
Databáze: OpenAIRE
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