Yang Xian-Zi, Ma Lei, Fang Shu-Xian, Song Ye, Zhu Si-Yu, Jin Chuan, Liu Wei, Lu Qin, Zeng Li-Si, Cui Shu-Zhong
Department of Medical Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou 510095, China.
Department of Gastrointestinal Surgery II, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou 510095, China.
Pathol Res Pract. 2022 Jun;234:153904. doi: 10.1016/j.prp.2022.153904. Epub 2022 Apr 19.
Emerging evidence highlights the multifunctional role of noncoding RNAs (ncRNAs) in gastric cancer (GC) chemoresistance. However, the comprehensive expression profile and competing endogenous RNAs (ceRNAs) regulatory network of GC chemoresistance remain unanswered.
The whole-transcriptome sequencing (RNA sequencing) was performed to comprehensively analyze the differentially expressed (DE) lncRNAs, miRNAs and mRNAs in cisplatin-resistant cells MGC-803/DDP and GC cells MGC-803. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted to investigate the biological functions implicated with the DEncRNAs. Then, the cisplatin-resistant-related ceRNA network and potential regulatory axes were constructed by bioinformatic analysis.
We successfully generated cisplatin-resistant GC cell line MGC-803/DDP. Differential expression analysis showed that a total of 1936 DElncRNAs, 2194 DEmRNAs and 174 DEmiRNAs were identified. Functional enrichment analysis indicated that those DEncRNAs were mainly involved in neuroactive ligand-receptor interaction, drug metabolism and Hippo signaling pathway. Subsequently, the cisplatin-resistant-related ceRNA network was constructed with the widely accepted vital chemo-resistant-related genes and signaling pathways. In addition, two constructed regulatory axes (include FAM66C/miR-129-5p/7 mRNAs and SFTA1P/miR-206/FN1 or NRP1) were successfully validated by the Genomic Data Commons (GDC) GC data.
The novel ceRNA network and the potential regulatory axes may provide the most comprehensive view of GC chemoresistance to date. Our findings uncovered potential biomarkers for prognostic prediction and novel therapeutic targets for reversing cisplatin resistance in GC.
新出现的证据凸显了非编码RNA（ncRNAs）在胃癌（GC）化疗耐药中的多功能作用。然而，GC化疗耐药的综合表达谱和竞争性内源性RNA（ceRNAs）调控网络仍未得到解答。
进行全转录组测序（RNA测序），以全面分析顺铂耐药细胞MGC-803/DDP和GC细胞MGC-803中差异表达的（DE）lncRNAs、miRNAs和mRNAs。进行基因本体论（GO）和京都基因与基因组百科全书（KEGG）通路富集分析，以研究与DElncRNAs相关的生物学功能。然后，通过生物信息学分析构建顺铂耐药相关的ceRNA网络和潜在调控轴。
我们成功构建了顺铂耐药的GC细胞系MGC-803/DDP。差异表达分析显示，共鉴定出1936个DElncRNAs、2194个DEmRNAs和174个DEmiRNAs。功能富集分析表明，这些DElncRNAs主要参与神经活性配体-受体相互作用、药物代谢和Hippo信号通路。随后，利用广泛认可的重要化疗耐药相关基因和信号通路构建了顺铂耐药相关的ceRNA网络。此外，通过基因组数据共享库（GDC）的GC数据成功验证了两个构建的调控轴（包括FAM66C/miR-129-5p/7个mRNA和SFTA1P/miR-206/FN1或NRP1）。
新的ceRNA网络和潜在调控轴可能提供了迄今为止对GC化疗耐药最全面的认识。我们的研究结果揭示了用于预后预测的潜在生物标志物以及逆转GC顺铂耐药的新治疗靶点。
