ERα36 is associated with SLC7A5/LAT1 expression, cervical cancer progression, and BNCT response: a translational...

To elucidate the role and molecular mechanism of the ERα36-SLC7A5/LAT1 signaling axis in the malignant progression of cervical cancer and its sensitivity to boron neutron capture therapy (BNCT).

Transcriptomic data from TCGA (n=296) and GTEx (n=10) were integrated to analyze SLC7A5 expression and its clinicopathological associations. Multiplex immunofluorescence staining was performed on a tissue microarray containing 99 cervical cancer specimens for spatial phenotyping. SiHa cell lines with stable ERα36 knockdown or overexpression were established using lentiviral transduction. CCK-8, flow cytometry, wound healing, Transwell, and colony formation assays were used to assess the effects of ERα36 on malignant phenotypes. Co-immunoprecipitation, Western blot, and qRT-PCR were employed to explore the interaction between ERα36 and LAT1 as well as downstream signaling changes. The impact of ERα36 on BNCT sensitivity was evaluated in both cellular and subcutaneous xenograft nude mouse models.

SLC7A5 was significantly upregulated in cervical cancer tissues and correlated with M stage and poor prognosis. ERα36 and SLC7A5 exhibited robust spatial co-expression in the tumor microenvironment, and the double-positive phenotype was associated with shorter overall survival (P<0.05). ERα36 interacted with LAT1 and was associated with elevated CD98hc and EGFR expression. Knockdown of ERα36 suppressed proliferation, migration, and colony formation while promoting apoptosis; overexpression produced opposite effects. In BNCT simulation experiments, ERα36 knockdown markedly attenuated BNCT-induced cytotoxicity, as evidenced by increased colony formation, reduced apoptosis, and altered S-phase distribution. Both cellular and animal models consistently showed downregulation of ERα36 and LAT1 protein expression after BNCT.

The ERα36-SLC7A5/LAT1 axis associated with malignant phenotypes and BNCT sensitivity in cervical cancer. The ERα36+/SLC7A5+ spatial double-positive phenotype may represent a prognostic biomarker, and ERα36 may serve as a predictive marker for BNCT response.