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miR-378a-5p 通过 LRP8/β-连环蛋白轴对 CRC 发挥放射增敏作用。

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

机构信息

Department of Oncology, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, China.

Department of Ultrasound, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, China.

出版信息

Cancer Biol Ther. 2024 Dec 31;25(1):2308165. doi: 10.1080/15384047.2024.2308165. Epub 2024 Feb 22.

DOI:10.1080/15384047.2024.2308165
PMID:38389136
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10896128/
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 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.

摘要

背景

miRNAs 与肿瘤放射敏感性密切相关。miR-378a-5p 在结直肠癌（CRC）中表达下调。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。用不同剂量 X 射线处理 CRC 细胞系。采用生物信息学分析、双荧光素酶报告基因检测和 RT-qPCR 检测 miR-378a-5p 与低密度脂蛋白受体相关蛋白 8（LRP8）的表达及结合关系。用 miR-378a-5p 抑制剂或/和 siLRP8 转染有无照射的 CRC 细胞。随后，进行集落形成实验、流式细胞术和肿瘤发生实验、免疫组织化学、RT-qPCR 和 Western blot 等实验，以阐明 miR-378a-5p/LRP8 轴在 CRC 放射敏感性中的作用。

结果

CRC 中 miR-378a-5p 的下调表达与组织学分化和肿瘤-淋巴结-转移（TNM）分期有关。照射后，CRC 细胞的存活分数降低，而凋亡率和 miR-378a-5p 水平增加。抑制 miR-378a-5p 抑制细胞凋亡和凋亡相关蛋白表达，但通过调节 CRC 细胞中的β-catenin 促进细胞增殖和放射抵抗。LRP8 在 CRC 中高表达，是 miR-378a-5p 的靶点。siLRP8 提高放射敏感性并逆转 miR-378a-5p 下调对 CRC 细胞的影响。过表达 miR-378a-5p 和照射增强了 miR-378a-5p 的水平，同时抑制了 Ki67 和 LRP8 的表达以及肿瘤发生。

结论

miR-378a-5p 可能通过 LRP8/β-catenin 轴对 CRC 发挥放射增敏作用，这可能是 CRC 放射抵抗的新治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe02/10896128/eaf020ac87fb/KCBT_A_2308165_F0009_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe02/10896128/c168007ff100/KCBT_A_2308165_F0001_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe02/10896128/3e10069c1fbf/KCBT_A_2308165_F0002_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe02/10896128/d4904175ed3f/KCBT_A_2308165_F0003_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe02/10896128/ff446635a11c/KCBT_A_2308165_F0004_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe02/10896128/a11ac1ce873b/KCBT_A_2308165_F0005_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe02/10896128/25dc083d1745/KCBT_A_2308165_F0006_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe02/10896128/69ebd72642dc/KCBT_A_2308165_F0007_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe02/10896128/8296f9dd1289/KCBT_A_2308165_F0008_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe02/10896128/eaf020ac87fb/KCBT_A_2308165_F0009_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe02/10896128/c168007ff100/KCBT_A_2308165_F0001_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe02/10896128/3e10069c1fbf/KCBT_A_2308165_F0002_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe02/10896128/d4904175ed3f/KCBT_A_2308165_F0003_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe02/10896128/ff446635a11c/KCBT_A_2308165_F0004_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe02/10896128/a11ac1ce873b/KCBT_A_2308165_F0005_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe02/10896128/25dc083d1745/KCBT_A_2308165_F0006_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe02/10896128/69ebd72642dc/KCBT_A_2308165_F0007_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe02/10896128/8296f9dd1289/KCBT_A_2308165_F0008_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe02/10896128/eaf020ac87fb/KCBT_A_2308165_F0009_OC.jpg

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