Kim Kyungmin, Jung Kyung Oh, Oh Sera, Kim Young-Hwa, Lee Seok-Yong, Hong Seongje, Cho Su Han, Kim Hyejin, Rhee Siyeon, Cheon Gi Jeong, Kang Keon Wook, Chung June-Key, Youn Hyewon
Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, Korea.
Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.
Exp Hematol Oncol. 2024 Dec 18;13(1):120. doi: 10.1186/s40164-024-00585-5.
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.
放射疗法作为一种有效的非手术策略被广泛用于控制恶性肿瘤。然而，复发是即使在有效的放射治疗后治疗失败的常见原因之一。在本研究中，我们聚焦于辐射诱导的外泌体miR-21对肿瘤微环境的影响，以探究复发的原因。对TCGA数据库的分析显示，与未接受放疗的乳腺癌患者相比，miR-21水平高的乳腺癌患者在接受放疗时总生存期显著缩短，这表明miR-21在接受该治疗的患者中具有较高的风险比。此外，发现外泌体miR-21在乳腺腺癌患者血清中高表达。为了探究miR-21如何导致受照射乳腺癌预后不良，我们用低剂量或高剂量辐射照射4T1细胞系，并检测分泌的外泌体miR-21对乳腺癌细胞和肿瘤微环境的影响。在10 Gy照射后，4T1细胞分泌的外泌体增加2.20±0.10倍，外泌体miR-21水平增加1.85±0.01倍。用来自10 Gy照射癌细胞的外泌体处理导致肿瘤细胞增殖、伤口愈合和迁移增强。与用0 Gy外泌体处理的肿瘤细胞（n = 10）相比，用10 Gy照射的肿瘤细胞与10 Gy来源的外泌体共孵育后的存活率提高了2.83倍。此外，与用0 Gy外泌体处理的肿瘤（n = 10）相比，用10 Gy外泌体处理的皮下肿瘤（n = 13）生长明显更快（P < 0.05）。总之，我们的研究表明，高剂量辐射诱导的外泌体通过外泌体miR-21的转移增强肿瘤增殖和侵袭性。基于这些发现，我们认为辐射诱导的外泌体miR-21可能导致接受放疗的乳腺癌患者预后更差。
