LncRNA CASC19 Enhances the Radioresistance of Nasopharyngeal Carcinoma by Regulating the miR-340-3p/FKBP5 Axis

Abstract

Radioresistance remains a serious obstacle encountered in the radiotherapy of nasopharyngeal carcinoma (NPC). Both mRNAs and non-coding RNAs (ncRNAs), including long ncRNA (lncRNA) and microRNA (miRNA), play essential roles in radiosensitivity. However, the comprehensive expression profiles and competing endogenous RNA (ceRNA) regulatory networks among lncRNAs, miRNAs, and mRNAs in NPC radioresistance are still bewildering. In this study, we performed an RNA-sequencing (RNA-seq) assay in the radioresistant NPC cells CNE2R and its parental cells CNE2 to identify the differentially expressed lncRNAs, miRNAs, and mRNAs. The ceRNA networks containing lncRNAs, miRNAs, and mRNAs were predicted on the basis of the Pearson correlation coefficients and authoritative miRanda databases. In accordance with bioinformatic analysis of the data of the tandem mass tag (TMT) assay of CNE2R and CNE2 cells and the gene chip assay of radioresistant NPC samples in pre- and post-radiotherapy, the radioresistance-related signaling network of lncRNA CASC19, miR-340-3p, and FKBP5 was screened and further verified using an RT-qPCR assay. CASC19 was positively associated with FKBP5 expression while negatively correlated with miR-340-3p, and the target binding sites of CASC19/miR-340-3p and miR-340-3p/FKBP5 were confirmed using a dual-luciferase reporter assay. Moreover, using an mRFP–GFP–LC3 maker, it was found that autophagy contributed to the radioresistance of NPC. MiR-340-3p inhibition or FKBP5 overexpression could rescue the suppression of autophagy and radioresistance induced by CASC19 knockdown in CNE2R cells. In conclusion, the CASC19/miR-340-3p/FKBP5 network may be instrumental in regulating NPC radioresistance by enhancing autophagy, which provides potential new therapeutic targets for NPC.

The promising role of miRNAs in radioresistance and chemoresistance of nasopharyngeal carcinoma

“…Research has shown a trend toward the expression of approximately fifty new miRNAs, such as miR-150, miR-483-5p and miR-454-3p, in radiation-resistant NPC ( 19 , 32 , 33 ). Furthermore, more than thirty miRNAs, including miR-31-5p, miR-613 and miR-340-3p, have been shown to modulate the radiosensitivity of NPC ( 34 – 36 ).…”

“…A mechanistic study revealed that miR-340-3p can suppress FKBP5 expression and alleviate cytophagy, thereby improving the radiation sensitivity of NPC cells. This might lead to the identification of a new target for optimizing the effectiveness of radiotherapy in treating NPC ( 34 ). Interestingly, exosomal miR-197-3p can suppress AKT/mTOR signaling by activating phosphorylation and blocking autophagy mediated by heat shock 70-kDa protein 5 (HSPA5) ( 71 ).…”

Role of long non-coding RNA in chemoradiotherapy resistance of nasopharyngeal carcinoma

“…CASC19 expression is closely related to the resistance of NPC cells to radiotherapy. It regulates NPC sensitivity to radiotherapy by modulating not only AMPK-mTOR and blocking autophagy ( 33 ) but also FKBP5 expression, acting as a molecular sponge for miR-340-3p, thereby influencing radiation resistance ( 34 ). Because of its inherent resistance to radiation, NPC tends to relapse and metastasize distantly, resulting in a poor prognosis for patients ( 72 ).…”