瘢痕疙瘩对电离辐射的分子反应:靶向FOXO1放射致敏瘢痕疙瘩。

IF 2.1 4区 医学 Q2 BIOLOGY International Journal of Radiation Biology Pub Date : 2023-01-01 DOI:10.1080/09553002.2022.2121871
Min Hong, Xiaoqian Li, Yulan Liu, Wei Mo, Bin Shi, Shigao Chen, Tao Yan, Yuhong Shi, Daojiang Yu, Shuyu Zhang
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引用次数: 1

摘要

目的:瘢痕疙瘩是由皮肤病变后伤口愈合过程异常引起的良性真皮肿瘤。手术切除加放疗在瘢痕疙瘩的治疗中起着重要作用。然而,放射耐药仍然是影响治疗效果的一个严重障碍。研究瘢痕疙瘩对辐射的分子反应可能有助于制定放射增敏策略。材料和方法:分离人瘢痕疙瘩原代成纤维细胞,x线照射。采用mRNA测序法测定未辐照和辐照原代瘢痕疙瘩成纤维细胞mRNA的表达谱。然后,我们通过对近端启动子的生物信息学分析,确定了失调mrna的共同基序和相应的转录因子。然后用GO和KEGG分析差异表达基因的功能富集情况。结果:辐射不仅抑制瘢痕疙瘩成纤维细胞的增殖,而且增加细胞衰老。在4 Gy和8 Gy辐照的原代瘢痕疙瘩成纤维细胞中,分别有184个mrna和204个mrna表现出显著变化。其中,8个上调mrna和30个下调mrna在4 Gy和8 Gy辐照的原代瘢痕疙瘩成纤维细胞中表现出一致的改变。更重要的是,xForkhead box O1 (FOXO1)信号通路参与了辐照响应。FOXO1信号抑制剂AS1842856预处理可显著促进辐照后原代瘢痕疙瘩成纤维细胞LDH释放、细胞凋亡和衰老。结论:我们的研究结果说明了人类瘢痕疙瘩成纤维细胞在辐射反应中的分子变化,FOXO1通路抑制有望为瘢痕疙瘩的放射增敏提供一种新的策略。
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Molecular response of keloids to ionizing radiation: targeting FOXO1 radiosensitizes keloids.

Purpose: Keloids are benign dermal tumors that arise from abnormal wound healing processes following skin lesions. Surgical excision followed by radiotherapy plays an important role in the treatment of keloids. Nevertheless, radioresistance remains a serious impediment to treatment efficacy. Investigation of the molecular response of keloids to radiation may contribute to radiosensitizing strategies.

Materials and methods: Primary keloid fibroblasts from human keloids were isolated and irradiated with X-ray. The expression profiles of messenger RNA (mRNA) in nonradiated and irradiated primary keloid fibroblasts were measured by mRNA sequencing analysis. Then, we identified common motifs and corresponding transcription factors of dysregulated mRNAs by using bioinformatic analysis of the proximal promoters. Whereafter, GO and KEGG were used to analyze the functional enrichment of the differentially expressed genes.

Results: We found that radiation not only suppressed proliferation but also increased cell senescence of primary keloid fibroblasts. There were 184 mRNAs and 204 mRNAs that showed significant changes in 4 and 8 Gy irradiated primary keloid fibroblasts, respectively. Among them, 8 upregulated and 30 downregulated mRNAs showed consistent alterations in 4 and 8 Gy irradiated primary keloid fibroblasts. More importantly, the xForkhead box O1 (FOXO1) signaling pathway was involved in the irradiation response. Pretreatment with the FOXO1 signaling inhibitor AS1842856 significantly promoted LDH release, apoptosis and senescence of primary keloid fibroblasts following irradiation.

Conclusion: Our findings illustrated the molecular changes in human keloid fibroblasts in response to radiation, and FOXO1 pathway inhibition is expected to provide a novel strategy for the radiosensitization of keloids.

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来源期刊
CiteScore
5.00
自引率
11.50%
发文量
142
审稿时长
3 months
期刊介绍: The International Journal of Radiation Biology publishes original papers, reviews, current topic articles, technical notes/reports, and meeting reports on the effects of ionizing, UV and visible radiation, accelerated particles, electromagnetic fields, ultrasound, heat and related modalities. The focus is on the biological effects of such radiations: from radiation chemistry to the spectrum of responses of living organisms and underlying mechanisms, including genetic abnormalities, repair phenomena, cell death, dose modifying agents and tissue responses. Application of basic studies to medical uses of radiation extends the coverage to practical problems such as physical and chemical adjuvants which improve the effectiveness of radiation in cancer therapy. Assessment of the hazards of low doses of radiation is also considered.
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