LPAR5 confers cancer cells radioresistance associated with EMT activation via ERK/ Snail pathway

Abstract

Epithelial-to-mesenchymal transition (EMT) is a critical event contributing cancer cells more aggressive phenotypes. EMT programs are frequently activated in radiation-targeted cells during the course of radiotherapy, and which often endows cancers the acquired radioresistance. Through RNA-seq based transcriptome analysis, here we found that LPAR5 is downregulated in the early response of HeLa cells to γ-rays irradiation. Radiation-induced alterations of LPAR5 expression were further revealed to be a bidirectional dynamic process in HeLa and A549 cells, i.e., early downregulating phase at 2 ~ 4h and late upregulating phase at 24h post-irradiation. Overexpression of LPAR5 prompts EMT programing and migration of cancer cells. Moreover, increased expression of LPAR5 is significantly associated with IR-induced EMT and confers cancer cells radioresistance. Knockdown of LPAR5 suppressed IR-induced EMT by attenuating the activation of ERK signaling and downstream Snail, MMP1, and MMP9 expressions. In conclusion, LPAR5 is an important upstream regulator of IR-induced EMT through modulating ERK/Snail pathway. This study provides further insights into understanding the mechanism of radiation-induced EMT and promising target for improving the effectiveness of cancer radiation therapy.

RNA N6-Methyladenosine Modification in DNA Damage Response and Cancer Radiotherapy

“…Although a remarkablly increased M 6 A level in RNAs was induced in U2OS cells by UV irradiation, no induction of M 6 A was observed by 10 Gy of γ-ray IR [52]. Our team's latest research indicated that the overall M 6 A level of RNAs was decreased at 2 h and until 12 h after 4Gy γ-ray irradiation in both HeLa and HepG2 cells [57], that is due to the depressed expression of METTL3 by IR. Transcriptome-wide m 6 Aseq and RNA-seq assays also indicate that the ratio of manscripts with decreased M 6 A level is higher than that of increased level.…”