Liu Hao, Zhang Zhe, Han Yanan, Fan Ahui, Liu Haiming, Zhang Xiangyuan, Liu Yanhong, Zhang Rugang, Liu Wanning, Lu Yuanyuan, Fan Daiming, Zhao Xiaodi, Nie Yongzhan
State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China.
Department of Gastroenterology and Hepatology, Hainan Branch of Chinese PLA General Hospital, Sanya, China.
Front Oncol. 2021 Mar 22;11:634579. doi: 10.3389/fonc.2021.634579. eCollection 2021.
The dysregulation of long non-coding RNAs (lncRNAs) and transcription factors (TFs) is closely related to the development and progression of drug resistance in cancer chemotherapy. However, their regulatory interactions in the multidrug resistance (MDR) of gastric cancer (GC) has largely remained unknown. In this study, we report a novel oncogenic role of lncRNA FENDRR in conferring MDR in GC by coordinated regulation of FOXC2 expression at the transcriptional and posttranscriptional levels. and experiments demonstrated that downregulation of FENDRR expression remarkably decreased drug resistant ability of GC MDR cells while upregulation of FENDRR expression produced the opposite effect. FENDRR overexpression was observed in MDR GC cell lines, patient-derived xenografts, and clinical samples. And the high levels of FENDRR expression were correlated with poor prognosis in GC patients. Regarding the mechanism, FENDRR was revealed to increase proto-oncogene FOXC2 transcription by performing an enhancer-like role in the nucleus and by sponging miR-4700-3p in the cytoplasm. Both FOXC2 and miR-4700-3p were shown to be functionally involved in the FENDRR-induced chemoresistance. In addition, there is a positive correlation between FENDRR and FOXC2 expression in clinic and the overexpressed FOXC2 indicated a poor prognosis in GC patients. Collectively, our findings provide a new perspective for the lncRNA-TF regulatory interaction involved in MDR, suggesting that targeting the FENDRR/FOXC2 axis may be an effective approach to circumvent GC chemoresistance.
长链非编码RNA（lncRNAs）和转录因子（TFs）的失调与癌症化疗中耐药性的发生和发展密切相关。然而，它们在胃癌（GC）多药耐药（MDR）中的调控相互作用在很大程度上仍不清楚。在本研究中，我们报道了lncRNA FENDRR通过在转录和转录后水平协调调控FOXC2表达，在赋予GC多药耐药性方面具有新的致癌作用。实验表明，FENDRR表达下调显著降低了GC多药耐药细胞的耐药能力，而FENDRR表达上调则产生相反的效果。在多药耐药GC细胞系、患者来源的异种移植瘤和临床样本中观察到FENDRR过表达。并且FENDRR的高表达水平与GC患者的不良预后相关。关于其机制，研究发现FENDRR通过在细胞核中发挥类似增强子的作用以及在细胞质中吸附miR-4700-3p来增加原癌基因FOXC2的转录。FOXC2和miR-4700-3p在功能上均参与了FENDRR诱导的化学抗性。此外，临床中FENDRR与FOXC2表达之间存在正相关，且FOXC2过表达表明GC患者预后不良。总体而言，我们的研究结果为lncRNA-TF调控相互作用参与多药耐药提供了新的视角，表明靶向FENDRR/FOXC2轴可能是规避GC化学抗性的有效方法。
