Liu Kuijie, Lei Sanlin, Kuang Yong, Jin Qianqian, Long Dongju, Liu Chao, Jiang Yuhong, Zhao Hua, Yao Hongliang
Department of Gastroenterology, The Second Xiangya Hospital, Central South University, Changsha, China.
Front Oncol. 2021 Jul 28;11:652831. doi: 10.3389/fonc.2021.652831. eCollection 2021.
Photodynamic therapy (PDT) is considered a potential treatment regimen for colorectal cancer cases (CRC). p53 signaling and the miR-124/iASPP axis play an essential role in the PDT resistance of CRC cells. PDT treatment downregulated NEAT1 expression in p53 HCT116 and RKO cells. In these two cell lines, NEAT1 silencing enhanced the suppressive effects of PDT on cell viability and apoptosis. Within the subcutaneously implanted tumor model, NEAT1 silencing enhanced PDT-induced suppression on tumor growth. Regarding p53-deleted HCT116 cells, PDT only moderately affected cell proliferation but induced downregulation of NEAT1. NEAT1 directly targeted miR-124, acting as a ceRNA, competing with iASPP for miR-124 binding, and counteracting miR-124-mediated repression on iASPP under PDT treatment. NEAT1 silencing was enhanced, whereas miR-124 inhibition attenuated PDT effects on CRC cells; miR-124 inhibition significantly reversed the roles of NEAT1 silencing in PDT-treated CRC cells. miR-124 negatively correlated with NEAT1 and iASPP, respectively, whereas NEAT1 and iASPP positively correlated with each other. PDT downregulated c-Myc in CRC cells, and c-Myc activated the transcription of NEAT1 through the targeting of its promoter region. Within p53 SW480 cells, PDT failed to alter cell viability and apoptosis but still downregulated c-Myc, NEAT1, and iASPP and upregulated miR-124. In p53 mutant high-abundant CRC tissues, c-Myc and NEAT1 were up-regulated, and miR-124 was downregulated. In c-Myc high-abundant CRC tissues, NEAT1 and iASPP were up-regulated, and miR-124 was downregulated. The critical role of the c-Myc/NEAT1 axis in mediating CRC response to PDT treatment the miR-124/iASPP/p53 feedback loop was conclusively demonstrated.
光动力疗法（PDT）被认为是结直肠癌（CRC）病例的一种潜在治疗方案。p53信号通路和miR-124/iASPP轴在CRC细胞的PDT耐药性中起重要作用。PDT处理下调了p53野生型的HCT116和RKO细胞中NEAT1的表达。在这两种细胞系中，NEAT1沉默增强了PDT对细胞活力和凋亡的抑制作用。在皮下植入肿瘤模型中，NEAT1沉默增强了PDT诱导的对肿瘤生长的抑制作用。对于p53缺失的HCT116细胞，PDT仅适度影响细胞增殖，但诱导NEAT1下调。NEAT1直接靶向miR-124，作为一种竞争性内源性RNA（ceRNA），在PDT处理下与iASPP竞争miR-124结合位点，并抵消miR-124介导的对iASPP的抑制作用。NEAT1沉默增强，而miR-124抑制减弱了PDT对CRC细胞的作用；miR-124抑制显著逆转了NEAT1沉默在PDT处理的CRC细胞中的作用。miR-124分别与NEAT1和iASPP呈负相关，而NEAT1和iASPP彼此呈正相关。PDT下调CRC细胞中的c-Myc，并且c-Myc通过靶向其启动子区域激活NEAT1的转录。在p53野生型的SW480细胞中，PDT未能改变细胞活力和凋亡，但仍下调了c-Myc、NEAT1和iASPP并上调了miR-124。在p53突变高丰度的CRC组织中，c-Myc和NEAT1上调，而miR-124下调。在c-Myc高丰度的CRC组织中，NEAT1和iASPP上调，而miR-124下调。c-Myc/NEAT1轴在介导CRC对PDT治疗反应中的关键作用以及miR-124/iASPP/p53反馈环得到了确凿证明。
