METTL14 promotes proliferation, migration, and invasion in endometriotic stromal cell growth by activating the ZEB1/MEK/ERK pathway.

OBJECTIVE:Endometriosis (EMs) commonly occurs in reproductive women. We explored the mechanism of methyltransferase-like 14 (METTL14) on human endometriotic stromal cell (ESC; HEM15A) proliferation, migration and invasion, to provide novel therapy for EMs. METHODS:HEM15A and human endometrial stromal cells (HESCs) were cultured in vitro. HEM15A cells were treated with oe-METTL14 and oe-zinc finger E-box-binding protein 1 (ZEB1) plasmids, N6-methyladenosine (m6A) inhibitor 3-deazaadenosine (3-DAA) and the mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway inhibitor isoprenaline (ISO). After identifying HEM15A and HESCs, METTL14, ZEB1, p-ERK1/2/ERK1/2 and p-MEK/MEK levels, and cell proliferation, migration and invasion were assessed. The modification sites of ZEB1 and m6A were predicted using SRAMP database, with m6A modification level assessed by MeRIP. The binding of YT521-B homology domain 2 (YTHDF2) to ZEB1 messenger RNA (mRNA), and ZEB1 stability and mRNA level were tested. RESULTS:Compared with HESCs, METTL14 level in HEM15A was significantly reduced. METTL14 overexpression in HEM15A prominently increased its proliferation, migration and invasion. METTL14 overexpression notably elecated m6A-methylated ZEB1 mRNA level and reduced the stability and expression of ZEB1 mRNA. Further m6A modification inhibition increased ZEB1 mRNA stability and mRNA and protein levels, and decreased ZEB1 m6A modification level. ZEB1 upregulation partially reversed METTL14 overexpression-inhibited HEM15A proliferation, migration and invasion. METTL14 inhibited the MEK/ERK signaling activation by regulating ZEB1, and the MEK/ERK signaling activation partly averted METTL14-suppressed proliferation, migration and invasion. CONCLUSION:METTL14 lowered ZEB1 expression by regulating ZEB1 m6A modification levels, thereby inhibiting the MEK/ERK pathway activation and ESC proliferation, migration and invasion.