MiR-378a-5p exerts a radiosensitizing effect on CRC through LRP8/β-catenin axis.

IF 4.4 4区医学 Q2 ONCOLOGY

Cancer Biology & Therapy Pub Date : 2024-12-31 Epub Date: 2024-02-22 DOI:10.1080/15384047.2024.2308165

Guolin Hu, Pengbiao Che, Ling Deng, Lei Liu, Jia Liao, Qi Liu

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引用次数: 0

Abstract

Background: MiRNAs are closely related to tumor radiosensitivity. MiR-378a-5p level is down-regulated in colorectal cancer (CRC). Therefore, this study intends to explore the role of miR-378a-5p in CRC, especially radiosensitivity.

Methods: The expression of miR-378a-5p was analyzed in CRC samples. CRC cell lines were treated with different doses of X-rays. Bioinformatics analysis, dual-luciferase reporter assay and RT-qPCR were used to detect the expressions and binding relationship of miR-378a-5p and low-density lipoprotein receptor-related protein 8 (LRP8). MiR-378a-5p inhibitor or/and siLRP8 were transfected into CRC cells with or without irradiation. Subsequently, clonogenic assay, flow cytometry and in vivo experiments including tumorigenesis assay, immunohistochemistry, RT-qPCR and Western blot were performed to clarify the role of miR-378a-5p/LRP8 axis in the radiosensitivity of CRC.

Results: The down-regulated expression of miR-378a-5p in CRC is related to histological differentiation and tumor-node-metastasis (TNM) stage. After irradiation, the survival fraction of CRC cells was decreased, while the apoptotic rate and the level of miR-378a-5p were increased. Restrained miR-378a-5p repressed apoptosis and apoptosis-related protein expressions, yet promoted the proliferation and the radioresistance of cells by regulating β-catenin in CRC cells. LRP8 was highly expressed in CRC, and targeted by miR-378a-5p. SiLRP8 improved radiosensitivity and reversed the effect of miR-378a-5p down-regulation on CRC cells. Overexpressed miR-378a-5p and irradiation enhanced the level of miR-378a-5p, yet suppressed the expressions of Ki67 and LRP8 as well as tumorigenesis.

Conclusion: MiR-378a-5p may exert a radiosensitizing effect on CRC through the LRP8/β-catenin axis, which may be a new therapeutic target for CRC radioresistance.

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MiR-378a-5p通过LRP8/β-catenin轴对CRC产生放射增敏作用。

背景MiRNA与肿瘤放射敏感性密切相关。MiR-378a-5p水平在结直肠癌（CRC）中下调。因此，本研究旨在探讨 miR-378a-5p 在 CRC 中的作用，尤其是放射敏感性：方法：分析 CRC 样本中 miR-378a-5p 的表达。方法：分析 miR-378a-5p 在 CRC 样本中的表达。生物信息学分析、双荧光素酶报告分析和 RT-qPCR 检测了 miR-378a-5p 和低密度脂蛋白受体相关蛋白 8（LRP8）的表达及结合关系。将 MiR-378a-5p 抑制剂或/和 siLRP8 转染至接受或不接受辐照的 CRC 细胞。随后，进行了克隆生成试验、流式细胞术和体内实验，包括肿瘤发生试验、免疫组化、RT-qPCR和Western印迹，以明确miR-378a-5p/LRP8轴在CRC放射敏感性中的作用：结果：miR-378a-5p在CRC中的下调表达与组织学分化和肿瘤-结节-转移（TNM）分期有关。辐照后，CRC 细胞的存活率下降，而凋亡率和 miR-378a-5p 水平上升。受抑制的miR-378a-5p抑制了CRC细胞的凋亡和凋亡相关蛋白的表达，但通过调节β-catenin促进了细胞的增殖和放射抗性。LRP8在CRC中高表达，并被miR-378a-5p靶向。SiLRP8能改善CRC细胞的放射敏感性，并逆转miR-378a-5p下调对CRC细胞的影响。过表达的miR-378a-5p和辐照提高了miR-378a-5p的水平，但却抑制了Ki67和LRP8的表达以及肿瘤的发生：MiR-378a-5p可能通过LRP8/β-catenin轴对CRC产生放射增敏作用，这可能是治疗CRC放射耐药的新靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cancer Biology & Therapy 医学-肿瘤学

CiteScore

7.00

自引率

0.00%

发文量

审稿时长

2.3 months

期刊介绍： Cancer, the second leading cause of death, is a heterogenous group of over 100 diseases. Cancer is characterized by disordered and deregulated cellular and stromal proliferation accompanied by reduced cell death with the ability to survive under stresses of nutrient and growth factor deprivation, hypoxia, and loss of cell-to-cell contacts. At the molecular level, cancer is a genetic disease that develops due to the accumulation of mutations over time in somatic cells. The phenotype includes genomic instability and chromosomal aneuploidy that allows for acceleration of genetic change. Malignant transformation and tumor progression of any cell requires immortalization, loss of checkpoint control, deregulation of growth, and survival. A tremendous amount has been learned about the numerous cellular and molecular genetic changes and the host-tumor interactions that accompany tumor development and progression. It is the goal of the field of Molecular Oncology to use this knowledge to understand cancer pathogenesis and drug action, as well as to develop more effective diagnostic and therapeutic strategies for cancer. This includes preventative strategies as well as approaches to treat metastases. With the availability of the human genome sequence and genomic and proteomic approaches, a wealth of tools and resources are generating even more information. The challenge will be to make biological sense out of the information, to develop appropriate models and hypotheses and to translate information for the clinicians and the benefit of their patients. Cancer Biology & Therapy aims to publish original research on the molecular basis of cancer, including articles with translational relevance to diagnosis or therapy. We will include timely reviews covering the broad scope of the journal. The journal will also publish op-ed pieces and meeting reports of interest. The goal is to foster communication and rapid exchange of information through timely publication of important results using traditional as well as electronic formats. The journal and the outstanding Editorial Board will strive to maintain the highest standards for excellence in all activities to generate a valuable resource.