Xia T, Ji Y, Lu Y N, Xie H J, You Y W, You B
Department of Otorhinolaryngology Head and Neck Surgery, the Affiliated Hospital of Nantong University, Institute of Otorhinolaryngology Head and Neck Surgery, the Affiliated Hospital of Nantong University, Nantong 226001, China.
Clinical College, Medical School of Nantong University, Nantong 226001, China.
Zhonghua Er Bi Yan Hou Tou Jing Wai Ke Za Zhi. 2022 Sep 7;57(9):1102-1109. doi: 10.3760/cma.j.cn115330-20220119-00034.
To explore the effect of dormant polyploid giant cancer cells (PGCC) on nasopharyngeal carcinoma (NPC) recurrence and to clarify the role of inhibition of autophagy in inhibiting NPC-PGCC formation and preventing NPC recurrence. NPC cells-derived PGCC (NPC-PGCC) were induced by paclitaxel (PTX), and the morphology, polyploid characteristics and cell activity of PGCC were identified by light microscopy, immunofluorescence and Live/Dead cell double staining assays. RNA-seq was used to analyze the differentially expressed genes between NPC-PGCC and diploid nasopharyngeal carcinoma cells CNE2. Functional enrichment and pathway annotation analysis of differentially expressed genes were performed using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG). The level of autophagy in NPC-PGCC cells was assessed by Western Blot and transmission electron microscopy analysis. The role of autophagy in the formation of NPC-PGCC and the effect of NPC-PGCC on the recurrence of nasopharyngeal carcinoma were studied using a highly clinically relevant mouse nasopharyngeal carcinoma recurrence model. Statistical analysis was performed using GraphPad Prism 6 and -values<0.05 were considered statistically significant. NPC-PGCC induced by paclitaxel had the characteristics of burst-like division after dormancy. GO enrichment and KEGG pathway analyses identified the significant biological processes and pathways mainly concentrated in autophagy and related pathways involving the differentially expressed genes between NPC-PGCC and diploid nasopharyngeal carcinoma cells CNE2. The autophagy level was significantly enhanced in NPC-PGCC cells. In a highly clinically relevant mouse nasopharyngeal carcinoma recurrence model, the number of PGCC in the primary tumor of the nude mice treated with cisplatin were higher than those of the other groups. In nude mice pretreated with autophagy inhibitor and then co-treatment with autophagy inhibitor and cisplatin, the number of PGCC in primary tumors was less and the recurrence rate was significantly lower than in other groups. The mechanism of dormant polyploid giant cancer cells formation is related to autophagy. Inhibition of autophagy can inhibit the formation of PGCC and thus prevent the recurrence of nasopharyngeal carcinoma.
探讨休眠多倍体巨癌细胞（PGCC）对鼻咽癌（NPC）复发的影响，并阐明抑制自噬在抑制NPC-PGCC形成及预防NPC复发中的作用。用紫杉醇（PTX）诱导NPC细胞来源的PGCC（NPC-PGCC），通过光学显微镜、免疫荧光和活/死细胞双重染色试验鉴定PGCC的形态、多倍体特征及细胞活性。采用RNA测序分析NPC-PGCC与二倍体鼻咽癌细胞系CNE2之间的差异表达基因。利用基因本体论（GO）、京都基因与基因组百科全书（KEGG）对差异表达基因进行功能富集和通路注释分析。通过蛋白质免疫印迹法和透射电子显微镜分析评估NPC-PGCC细胞中的自噬水平。利用高度临床相关的小鼠鼻咽癌复发模型研究自噬在NPC-PGCC形成中的作用以及NPC-PGCC对鼻咽癌复发的影响。使用GraphPad Prism 6进行统计分析，P值<0.05被认为具有统计学意义。紫杉醇诱导的NPC-PGCC具有休眠后爆式分裂的特征。GO富集和KEGG通路分析确定，主要的生物学过程和通路集中在自噬以及涉及NPC-PGCC与二倍体鼻咽癌细胞系CNE2之间差异表达基因的相关通路。NPC-PGCC细胞中的自噬水平显著增强。在高度临床相关的小鼠鼻咽癌复发模型中，顺铂处理的裸鼠原发肿瘤中PGCC的数量高于其他组。在用自噬抑制剂预处理后再联合自噬抑制剂和顺铂处理的裸鼠中，原发肿瘤中PGCC的数量较少，复发率显著低于其他组。休眠多倍体巨癌细胞形成的机制与自噬有关。抑制自噬可抑制PGCC的形成，从而预防鼻咽癌的复发。
Zhonghua Er Bi Yan Hou Tou Jing Wai Ke Za Zhi. 2022-9-7
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