Oocyte development requires coordinated metabolic and signaling support from granulosa and theca cells. By performing integrated single-cell RNA sequencing and spatial transcriptomic analyses of murine and human ovaries, we discovered a functionally specialized stromal subtype essential for folliculogenesis. These stromal cells (SCs) with glutamyl aminopeptidase (ENPEP) function, designated perifollicular SCs based on their circumferential follicle localization, exhibit two hallmark features: (1) dynamic proliferation synchronized with follicular maturation from primary to secondary to antral stages, and (2) secretion of midkine (MDK), which activates nucleolin (NCL) receptor signaling to drive granulosa cell (GC) expansion. Furthermore, analyses of ovarian aging revealed the concurrent depletion of perifollicular SCs and the attenuation of MDK–NCL signaling between perifollicular SCs and GCs. The unique spatial confinement and regulatory capacity of perifollicular SCs endow them with the potential to become important components of the follicular functional unit, providing new theoretical support for understanding the molecular regulatory mechanisms of ovarian aging from the perspective of the follicular microenvironment.
Zhe Zhang, Na Kong, J. Mei et al.· Cell Discovery· 0 citations
Eukaryotic translation initiation factors (eIFs) play a crucial role in tumor progression; however, which eIFs are most significant in cervical cancer (CC) remains unclear. In this study, eIF3A and eIF4E were found to be highly expressed in CC and associated with poor prognosis. Silencing either factor inhibited CC cell proliferation, induced apoptosis, and reduced glycolytic activity. Quantitative proteomic analysis and subsequent functional validation identified α-enolase (ENO1) as a common downstream effector of eIF3A and eIF4E, through which they promoted aerobic glycolysis and CC progression. Notably, eIF3A consistently exhibited a more pronounced functional effect than eIF4E. Further analyses demonstrated that eIF3A associated with N6-methyladenosine (m6A)-modified ENO1 mRNA and promoted its translation. eIF3A depletion reduced the abundance of ENO1 mRNA in actively translating polysomes and decreased the ENO1 protein-to-mRNA ratio without affecting total ENO1 mRNA abundance. Mutation of a key m6A site A359 in ENO1 mRNA similarly weakened its association with eIF3A and reduced ENO1 translation. Moreover, pharmacological inhibition of m6A-related regulation partially attenuated eIF3A-induced ENO1 expression, glycolytic activation, and tumor growth. Collectively, our results identify eIF3A as a key regulator of CC progression in an m6A-dependent ENO1 translation and suggest that targeting the eIF3A-m6A-ENO1 may have therapeutic potential for CC.
Linjuan Cai, Yu Jiang, Lingfeng Gu et al.· Cancer Genetics· 0 citations