Hypoxia induces chemoresistance of esophageal cancer cells to cisplatin through regulating the lncRNA-EMS/miR-758-3p/WTAP axis

Abstract

Hypoxia contributes significantly to the development of chemoresistance of many malignancies including esophageal cancer (EC). Accumulating studies have indicated that long non-coding RNAs play important roles in chemotherapy resistance. Here, we identified a novel lncRNA-EMS/miR-758-3p/WTAP axis that was involved in hypoxia-mediated chemoresistance to cisplatin in human EC. Hypoxia induced the expressions of lncRNA EMS and WTAP, and reduced the expression of miR-758-3p in EC cell line ECA-109. In addition, the expressions of EMS and WTAP were required for the hypoxia-induced drug resistance to cisplatin in EC cells, while overexpression of miR-758-3p reversed such chemoresistance. The targeting relationships between EMS and miR-758-3p, as well as miR-758-3p and WTAP, were verified by luciferase-based reporter assays and multiple quantitative assays after gene overexpression/knockdown. Moreover, we found significant correlations between tumor expressions of these molecules. Notably, higher levels of EMS/WTAP, or lower levels of miR-758-3p in tumors predicted worse survivals of EC patients. Furthermore, in a xenograft mouse model, targeted knockdown of EMS and WTAP in ECA-109 cells markedly attenuated the resistance of tumors to cisplatin treatments. Our study uncovers a critical lncRNA-EMS/miR-758-3p/WTAP axis in regulating hypoxia-mediated drug resistance to cisplatin in EC.

The Role of lncRNA PCAT6 in Cancers

“…In past decades, cytotoxic chemotherapy has been developed, but has no significant advantages for overcoming drug resistance (62). However, accumulating studies have demonstrated that lncRNAs play important roles in chemotherapy resistance (63,64). PCAT6 facilitated chemoresistance of CC cells to cisplatin via the PCAT6/miR-543/ZEB1 axis (46).…”

Hypoxia-Induced Intracellular and Extracellular Heat Shock Protein gp96 Increases Paclitaxel-Resistance and Facilitates Immune Evasion in Breast Cancer

“…report that hypoxia induces chemoresistance in non-small cell lung cancer (NSCLC) ( 55 ), and Zhu et al. find that cisplatin-resistance in esophageal cancer cells was also enhanced by hypoxic conditions ( 54 ). Of note, hypoxia also promotes paclitaxel-resistance in multiple cancers ( 52 , 53 ), which are supported by our results that hypoxia promoted paclitaxel-resistance in PS-BC cells.…”

Construction and Verification of a Hypoxia-Stemness-Based Gene Signature for Risk Stratification in Esophageal Cancer

“…A recent study showed that high expression levels of the long noncoding RNA (lncRNA) E2F1 messenger RNA (mRNA) stabilizing factor (EMS), Wilms’ tumor 1-associating protein (WTAP), and low expression levels of miR-758-3p were associated with poorer survival in patients with esophageal cancer. In addition, they demonstrated that the interaction between lncRNA-EMS/miR-758-3p/WTAP might be a potential mechanism for hypoxia-mediated cisplatin resistance in patients with esophageal cancer[ 25 ].…”