Importin-7 Facilitates Cervical Cancer Progression Through MSI2 Nuclear Import and Is Associated With MSI2-MYC-Linked Glycolytic Reprogramming.

BACKGROUND: Cervical cancer (CC) remains a major cause of cancer-related mortality in women. This study aimed to clarify the oncogenic role and underlying mechanism of Importin-7 (IPO7), a nuclear transport protein, in CC progression. METHODS: TCGA and GEO datasets were analyzed, with experimental validation in CC cell lines and xenograft mouse models. IPO7 function was assessed through RNA interference, followed by evaluations of cell proliferation, apoptosis, migration, invasion, and tumor growth. Mass spectrometry identified IPO7 cargo. Molecular interactions were investigated by co-immunoprecipitation, nuclear/cytoplasmic fractionation, ubiquitination assays, and nuclear localization signal (NLS) mutagenesis. RNA sequencing, Seahorse flux analysis, and Western blotting were used to assess downstream transcriptomic and metabolic changes. RESULTS: IPO7 was significantly upregulated in CC and correlated with advanced disease stage and poor prognosis. IPO7 knockdown impaired tumor growth in vitro and in vivo. MSI2 was identified as a direct nuclear cargo of IPO7, with binding dependent on its NLS. IPO7 promoted nuclear translocation of MSI2 and prevented its ubiquitin-mediated cytoplasmic degradation. MSI2 silencing abrogated the oncogenic effects of IPO7. High co-expression of IPO7 and MSI2 was associated with the worst patient outcomes. Mechanistically, IPO7, MSI2, and c-MYC formed a ternary complex that promoted MSI2-dependent nuclear accumulation of c-MYC and enhanced c-MYC mRNA stability. Disruption of this axis suppressed MYC-linked metabolic programs, including reduced glycolytic activity in CC cells. CONCLUSIONS: IPO7 facilitates CC progression by mediating MSI2 nuclear import and enhancing c-MYC-dependent transcriptional programs. This axis is associated with metabolic reprogramming, including a glycolysis-related signature in CC. The IPO7-MSI2-MYC axis represents a novel prognostic marker and therapeutic target in CC.