Department of Gastroenterology, Dazhou Hospital of Integrated Traditional Chinese and Western Medicine, Dazhou, China.
Department of Oncology, Linyi Third People's Hospital, Linyi, China.
Biomol Biomed. 2024 Oct 17;24(6):1669-1681. doi: 10.17305/bb.2024.10313.
Colorectal cancer (CRC) is one of the most common non-cutaneous malignancies, causing significant mortality and a substantial burden. This study aims to explore the role of KIAA1429 (also known as vir-like m6A methyltransferase associated [VIRMA]) protein in the radioresistance of CRC. CRC cells and a radioresistant cell line were cultured, and KIAA1429 expression was detected. After the down-regulation of KIAA1429, its effect on the radioresistance and ferroptosis of cancer cells was analyzed. The role of ferroptosis in radioresistance was verified. The binding relationship among long non-coding RNA endogenous Bornavirus-like nucleoprotein 3, pseudogene (lncRNA EBLN3P), microRNA (miR)-153-3p, and KIAA1429 was analyzed. KIAA1429 and lncRNA EBLN3P were highly expressed in CRC, while miR-153-3p was poorly expressed. KIAA1429 and lncRNA EBLN3P were further increased/decreased in the radioresistant cells. KIAA1429 knockdown decreased the survival rate of the radioresistant cell line after X-ray irradiation and increased gamma H2A histone family member X (γ-H2AX), ferroptosis, and oxidative stress. A ferroptosis inhibitor alleviated the inhibitory effect of KIAA1429 knockdown on radioresistance. KIAA1429-mediated m6A modification up-regulated lncRNA EBLN3P, and lncRNA EBLN3P increased KIAA1429 by competitively binding to miR-153-3p. miR-153-3p silencing or lncRNA EBLN3P overexpression attenuated the promotion of ferroptosis and the inhibition of radioresistance induced by KIAA1429 knockdown. Overall, KIAA1429-mediated m6A modification up-regulated lncRNA EBLN3P expression, and lncRNA EBLN3P increased KIAA1429 expression by competitively binding to miR-153-3p, thus reducing ferroptosis and increasing the radioresistance of CRC.
结直肠癌（CRC）是最常见的非皮肤恶性肿瘤之一，导致高死亡率和沉重负担。本研究旨在探索 KIAA1429（也称为病毒样 m6A 甲基转移酶相关 [VIRMA]）蛋白在 CRC 放射抵抗中的作用。培养 CRC 细胞和放射抵抗细胞系，并检测 KIAA1429 表达。下调 KIAA1429 后，分析其对癌细胞放射抵抗和铁死亡的影响。验证铁死亡在放射抵抗中的作用。分析长链非编码 RNA 内源性 Bornavirus 样核蛋白 3、假基因（lncRNA EBLN3P）、微小 RNA（miR）-153-3p 和 KIAA1429 之间的结合关系。CRC 中 KIAA1429 和 lncRNA EBLN3P 高表达，而 miR-153-3p 低表达。放射抵抗细胞中进一步增加/减少 KIAA1429 和 lncRNA EBLN3P。X 射线照射后，下调 KIAA1429 降低放射抵抗细胞系的存活率，并增加γ H2A 组蛋白家族成员 X（γ-H2AX）、铁死亡和氧化应激。铁死亡抑制剂缓解了 KIAA1429 下调对放射抵抗的抑制作用。KIAA1429 介导的 m6A 修饰上调 lncRNA EBLN3P，lncRNA EBLN3P 通过竞争性结合 miR-153-3p 增加 KIAA1429。沉默 miR-153-3p 或过表达 lncRNA EBLN3P 可减弱 KIAA1429 下调诱导的铁死亡促进和放射抵抗抑制。总之，KIAA1429 介导的 m6A 修饰上调 lncRNA EBLN3P 表达，lncRNA EBLN3P 通过竞争性结合 miR-153-3p 增加 KIAA1429 表达，从而减少铁死亡并增加 CRC 的放射抵抗性。
