Jiang Ming-Jie, Lin Chen-Jing, Liu Fu-Rao, Mei Zhu, Gu Dian-Na, Tian Ling
Department of Head and Neck Surgery, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
Department of Central Laboratory, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China.
Heliyon. 2024 May 15;10(10):e31346. doi: 10.1016/j.heliyon.2024.e31346. eCollection 2024 May 30.
Pancreatic cancer is one of the most lethal cancers with significant radioresistance and tumor repopulation after radiotherapy. As a type of short non-coding RNA that regulate various biological and pathological processes, miRNAs might play vital role in radioresistance. We found by miRNA sequencing that microRNA-26a (miR-26a) was upregulated in pancreatic cancer cells after radiation, and returned to normal state after a certain time. miR-26a was defined as a tumor suppressive miRNA by conventional tumor biology experiments. However, transient upregulation of miR-26a after radiation significantly promoted radioresistance, while stable overexpression inhibited radioresistance, highlighting the importance of molecular dynamic changes after treatment. Mechanically, transient upregulation of miR-26a promoted cell cycle arrest and DNA damage repair to promote radioresistance. Further experiments confirmed HMGA2 as the direct functional target, which is an oncogene but enhances radiosensitivity. Moreover, PTGS2 was also the target of miR-26a, which might potentiate tumor repopulation via delaying the synthesis of PGE2. Overall, this study revealed that transient upregulation of miR-26a after radiation promoted radioresistance and potentiated tumor repopulation, highlighting the importance of dynamic changes of molecules upon radiotherapy.
胰腺癌是最致命的癌症之一，具有显著的放射抗性且放疗后肿瘤会再增殖。作为一类调控各种生物学和病理学过程的短链非编码RNA，微小RNA（miRNA）可能在放射抗性中发挥重要作用。我们通过miRNA测序发现，放射后胰腺癌细胞中的微小RNA-26a（miR-26a）上调，且在一定时间后恢复至正常状态。通过传统肿瘤生物学实验，miR-26a被定义为一种肿瘤抑制性miRNA。然而，放射后miR-26a的短暂上调显著促进了放射抗性，而稳定过表达则抑制了放射抗性，这突出了治疗后分子动态变化的重要性。从机制上讲，miR-26a的短暂上调促进细胞周期停滞和DNA损伤修复以促进放射抗性。进一步实验证实高迁移率族蛋白A2（HMGA2）是直接功能靶点，其虽为一种癌基因但可增强放射敏感性。此外，前列腺素内过氧化物合酶2（PTGS2）也是miR-26a的靶点，其可能通过延迟前列腺素E2（PGE2）的合成增强肿瘤再增殖。总体而言，本研究揭示了放射后miR-26a的短暂上调促进了放射抗性并增强了肿瘤再增殖，突出了放疗时分子动态变化的重要性。
