Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Sciences, 75 Nowon-Ro, Nowon-Gu, Seoul, 01812, Republic of Korea.
Department of Life Science, Hanyang University, Seoul, Republic of Korea.
J Transl Med. 2024 Oct 29;22(1):980. doi: 10.1186/s12967-024-05797-1.
BACKGROUND: Although the representative treatment for colorectal cancer (CRC) is radiotherapy, cancer cells survive due to inherent radioresistance or resistance acquired after radiation treatment, accelerating tumor malignancy and causing local recurrence and metastasis. However, the detailed mechanisms of malignancy induced after radiotherapy are not well understood. To develop more effective and improved radiotherapy and diagnostic methods, it is necessary to clearly identify the mechanisms of radioresistance and discover related biomarkers. METHODS: To analyze the expression pattern of miRNAs in radioresistant CRC, sequence analysis was performed in radioresistant HCT116 cells using Gene Expression Omnibus, and then miR-1226-5p, which had the highest expression in resistant cells compared to parental cells, was selected. To confirm the effect of miR-1226-5 on tumorigenicity, Western blot, qRT-PCR, transwell migration, and invasion assays were performed to confirm the expression of EMT factors, cell mobility and invasiveness. Additionally, the tumorigenic ability of miR-1226-5p was confirmed in organoids derived from colorectal cancer patients. In CRC cells, IRF1, a target gene of miR-1226-5p, and circSLC43A1, which acts as a sponge for miR-1226-5p, were discovered and the mechanism was analyzed by confirming the tumorigenic phenotype. To analyze the effect of tumor-derived miR-1226-5p on macrophages, the expression of M2 marker in co-cultured cells and CRC patient tissues were confirmed by qRT-PCR and immunohistochemical (IHC) staining analyses. RESULTS: This study found that overexpressed miR-1226-5p in radioresistant CRC dramatically promoted epithelial-mesenchymal transition (EMT), migration, invasion, and tumor growth by suppressing the expression of its target gene, IRF1. Additionally, we discovered circSLC43A1, a factor that acts as a sponge for miR-1226-5p and suppresses its expression, and verified that EMT, migration, invasion, and tumor growth are suppressed by circSLC43A1 in radioresistant CRC cells. Resistant CRC cells-derived miR-1226-5p was transferred to macrophages and contributed to tumorigenicity by inducing M2 polarization and secretion of TGF-β. CONCLUSIONS: This study showed that the circSLC43A1/miR-1226-5p/IRF1 axis is involved in radioresistance and cancer aggressiveness in CRC. It was suggested that the discovered signaling factors could be used as potential biomarkers for diagnosis and treatment of radioresistant CRC.
背景：虽然放疗是结直肠癌（CRC）的代表性治疗方法，但由于固有放射抗性或放疗后获得的抗性，癌细胞存活下来，加速了肿瘤的恶性程度，并导致局部复发和转移。然而，放疗后恶性程度增加的详细机制尚不清楚。为了开发更有效和改进的放疗和诊断方法，有必要明确识别放射抗性的机制，并发现相关的生物标志物。
方法：为了分析放射抗性 CRC 中 miRNA 的表达模式，使用基因表达综合数据库（Gene Expression Omnibus）对放射抗性 HCT116 细胞中的 miRNA 进行序列分析，然后选择与亲本细胞相比在抗性细胞中表达最高的 miR-1226-5p。为了确认 miR-1226-5 对肿瘤发生的影响，通过 Western blot、qRT-PCR、transwell 迁移和侵袭实验，证实 EMT 因子、细胞迁移和侵袭的表达。此外，在源自结直肠癌患者的类器官中证实了 miR-1226-5p 的致瘤能力。在 CRC 细胞中，IRF1 是 miR-1226-5p 的靶基因，circSLC43A1 作为 miR-1226-5p 的海绵，通过证实致瘤表型来分析其机制。为了分析肿瘤衍生的 miR-1226-5p 对巨噬细胞的影响，通过 qRT-PCR 和免疫组织化学（IHC）染色分析，在共培养细胞和 CRC 患者组织中证实了 M2 标志物的表达。
结果：本研究发现，在放射抗性 CRC 中过表达 miR-1226-5p 通过抑制其靶基因 IRF1 的表达，显著促进上皮-间充质转化（EMT）、迁移、侵袭和肿瘤生长。此外，我们发现 circSLC43A1 是一种作为 miR-1226-5p 海绵并抑制其表达的因子，并证实 circSLC43A1 在放射抗性 CRC 细胞中抑制 EMT、迁移、侵袭和肿瘤生长。耐药 CRC 细胞衍生的 miR-1226-5p 被转移到巨噬细胞中，并通过诱导 M2 极化和 TGF-β 的分泌促进肿瘤发生。
结论：本研究表明，circSLC43A1/miR-1226-5p/IRF1 轴参与了 CRC 中的放射抗性和癌症侵袭性。研究结果提示，所发现的信号因子可作为放射抗性 CRC 诊断和治疗的潜在生物标志物。
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