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Abstract
Radiotherapy is widely used as an effective non-surgical strategy to control malignant tumors. However, recurrence is one of common causes of treatment failure even after the effective radiotherapy. In this study, we focused on the effects of radiation-induced exosomal miR-21 on the tumor microenvironment to investigate the causes of recurrence. Analysis of the TCGA database revealed that breast cancer patients with high levels of miR-21 have significantly reduced overall survival when treated with radiotherapy compared to those who did not receive radiotherapy, indicating a high hazard ratio for miR-21 in patients undergoing this treatment. Additionally, exosomal miR-21 is found to be highly expressed in the serum of breast adenocarcinoma patients. To explore how miR-21 induces poor prognosis in irradiated breast cancer, we irradiated 4T1 cell line with low or high doses of radiation, and examined the impact of secreted exosomal miR-21 on breast cancer cell and tumor microenvironment. After 10 Gy irradiation, 4T1 cells secreted 2.20 ± 0.10 times more exosomes and exhibited a 1.85 ± 0.01-fold increase in exosomal miR-21 levels. Treatment with exosomes from 10 Gy-irradiated cancer cells led to enhanced tumor cell proliferation, wound healing, and migration. The survival rate of 10 Gy-irradiated tumor cells incubated with 10 Gy-derived exosomes increased by 2.83-fold. Moreover, the growth of subcutaneous tumors treated with 10 Gy exosomes (n = 13) was significantly faster compared to tumors treated with 0 Gy exosomes (n = 10, P < 0.05). In summary, our study revealed high-dose irradiation-induced exosomes were found to enhance tumor proliferation and invasiveness via the transfer of exosomal miR-21. Based on these findings, we suggest that radiation-induced exosomal miR-21 may contribute to a poorer prognosis of breast cancer patients undergoing radiotherapy.

Affiliations

Kyungmin Kim # 1 2 3, Kyung Oh Jung # 4, Sera Oh 1 2 3, Young-Hwa Kim 1 3 5, Seok-Yong Lee 1 2 3, Seongje Hong 6, Su Han Cho 7 8, Hyejin Kim 9 8, Siyeon Rhee 8 10, Gi Jeong Cheon 1 3, Keon Wook Kang 1 2 3, June-Key Chung 1, Hyewon Youn 11 12 13
1Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, Korea.
2Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.
3Laboratory of Molecular Imaging and Therapy, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
4Department of Anatomy, College of Medicine, Chung-Ang University, Seoul, Korea. kojung@cau.ac.kr.
5Department of Pharmacy, School of Pharmacy, Jeonbuk National University, Jeonju, Korea.
6Department of Anatomy, College of Medicine, Chung-Ang University, Seoul, Korea.
7Department of Biology, Kyung Hee University, Seoul, Korea.
8K-BioX, Palo Alto, CA, USA.
9Woodang Network, Kangwondaehak-gil, Gangwon-do, Korea.
10Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford University, Stanford, CA, USA.
11Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, Korea. hwyoun@snu.ac.kr.
12Laboratory of Molecular Imaging and Therapy, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea. hwyoun@snu.ac.kr.
13Cancer Imaging Center, Seoul National University Hospital, #207-4, 103 Daehak-ro, Jongno-gu, Seoul, 110-799, Korea. hwyoun@snu.ac.kr.
#Contributed equally.