LncRNA TTN‐AS1/miR‐134‐5p/PAK3 axis regulates the radiosensitivity of human large intestine cancer cells through the P21 pathway and AKT/GSK‐3β/β‐catenin pathway

Abstract

Radiotherapy is an important adjuvant treatment for large intestine cancer even though it does not cause any response in many patients. The present study aimed to investigate the effects of the TTN antisense RNA 1 (TTN-AS1) long noncoding RNA (lncRNA) on radiotherapy dynamics of large intestine cancer cells and to explore the underlying molecular mechanisms. TTN-AS1 expression was evaluated by reversetranscription quantitative polymerase chain reaction, western blot, and cellular immunofluorescence, and flow cytometry analysis was used to measure apoptosis. Radiotherapy was simulated in vitro by exposing cancer cells to X-ray. TTN-AS1 was highly expressed in large intestine cancer cells after an X-ray exposition for 24 hr. TTN-AS1 knockdown improved the radiosensitivity of large intestine cancer cells and promoted apoptosis by increasing Bax/Bcl2 protein expression and the activecaspase 3/caspase 3 ratios following X-ray treatment. In addition, TTN-AS1 negatively regulated miR-134-5p expression, and miR-134-5p-mimic transfection decreased PAK3 protein expression in large intestine cancer cells. Importantly, TTN-AS1 promoted PAK3 and P21 protein expression in HT29 cells after X-ray treatment. Moreover, the knockdown of P21 protein expression improved radiosensitivity and promoted X-ray-induced apoptosis of HT29 cells. Finally, PAK3 knockdown expression decreased the p-AKT/AKT and p-GSK-3β/GSK-3β ratios and promoted the β-catenin transfer from the nucleus to the cytoplasm. These data suggest that the TTN-AS1 lncRNA promoted resistance to radiotherapy of large intestine cancer cells by increasing PAK3 expression via miR-134-5p inhibition, and this may be related to the P21 and AKT/GSK-3β/β-catenin pathway.

miRNAs derived from circulating small extracellular vesicles as diagnostic biomarkers for nasopharyngeal carcinoma

“…26 Decreasing the expression of miR-134-5p was also suggested to promote radioresistance by the P21 and AKT/ GSK-3β/β-catenin pathway. 27 In our study, the predicted genes targeted by miR-134-5p included ATM and JAK1, both of which have been associated with NPC. Several studies have revealed that ATM mediates DNA repair and activates the resistance of NPC cells to radiotherapy or chemotherapy by the ATM-associated signaling pathway.…”

“…miR‐134‐5p potentially acts as a tumor suppressor, repressing the proliferation of NPC cells by directly targeting E74‐like ETS transcription factor 2 (ELF2) 26 . Decreasing the expression of miR‐134‐5p was also suggested to promote radioresistance by the P21 and AKT/GSK‐3β/β‐catenin pathway 27 . In our study, the predicted genes targeted by miR‐134‐5p included ATM and JAK1 , both of which have been associated with NPC.…”

Oxymatrine inhibits the development of radioresistance in NSCLC cells by reversing EMT through the DcR3/AKT/GSK-3β pathway

“…Combined with our study, these results showed that Dcr3 may be an important molecule in the regulation of radioresistance of lung cancer cells. Numerous studies have suggested the involvement of AKT/GSK-3β pathway in radioresistance [35][36][37][38]. Using the AKT inhibitor MK-2206, we revealed that the inhibition of AKT/GSK-3β pathway was responsible for the effect of OMT on radiosensitivity.…”

Mechanisms of microRNA action in rectal cancer radiotherapy

“…Moreover, Chen et al [30] demonstrated that exosomal miR-590-3p derived from cancer-associated fibroblasts (CAFs) increases the radiation resistance of RC by positively regulating the chloride channel accessory 4-dependent PI3K/AKT signaling pathway in vivo and in vitro. Another study showed that, in vitro, the lncRNA, TTN antisense RNA 1, promotes the radiotherapy resistance of CRC cells by negatively regulating miR-134-5p and increasing the expression levels of p21-activated kinase 3, [31] which may be associated with the P21 and AKT/glycogen synthase kinase-3β/β-catenin pathways.…”