Zhongguo aizheng zazhi (Mar 2023)

Mechanism of METTL14-mediated ERα m6A regulation of endometrial cancer metastasis

  • ZHAO Manying, WU Dongyue, DU Ruiting, YIN Lu, LUO Yulu

DOI
https://doi.org/10.19401/j.cnki.1007-3639.2023.03.008
Journal volume & issue
Vol. 33, no. 3
pp. 250 – 259

Abstract

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Background and purpose: Aberrant N6-methyladenosine (m6A) modification caused by dysregulation of methyltransferase-like factor 14 (METTL14) plays an important role in the progression of various cancers, and it is unclear whether it is involved in the endometrial cancer (EC) progression. This study aimed to investigate the role of aberrant m6A modification caused by dysregulation of METTL14 in EC invasion and metastasis. Methods: Ninety-six EC patients who underwent curative surgery in Qinghai Provincial People’s Hospital from 2017 to 2021 were enrolled. RNA (70 pairs) or proteins (10 pairs) were isolated from frozen tissues for real-time fluorescence quantitative polymerase chain reaction (RTFQ-PCR) or immunoblot analysis to assess METTL14 expression in EC. The expression of METTL14 and its correlation with clinicopathological features of EC were assessed. The biological effects of METTL14 in EC were determined in vitro and in vivo. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) combined with RNA sequencing (RNA-seq), and following m6A dot blot, MeRIP-RTFQ-PCR, RIP-RTFQ-PCR or dual luciferase reporter assays were employed to screen and validate the candidate targets of METTL14. Results: The mRNA expression and protein levels of METTL14 were significantly downregulated in EC compared with matched adjacent tissues. Compared with the METTL14 high expression group, the METTL14 low expression group had a significant increase in International Federation of Gynecology and Obstetrics (FIGO) stage, infiltration depth, lymphovascular invasion, lymph node metastasis and the number of cases of tumor metastasis (P<0.05). Functionally, METTL14 inhibited the proliferation and invasive capacity of EC cells in vitro and in vivo. Mechanistically, METTL14-mediated demethylation of m6A resulted in post-transcriptional repression of estrogen receptor alpha (ERα). Furthermore, compared with METTL14, ERα induced oncogenic behavior of tumors. Conclusion: METTL14 attenuates ERα expression in EC cells in a m6A-dependent manner, thereby inhibiting tumor metastasis and invasion.

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