Transcriptomic analysis reveals Streptococcus agalactiae activation of oncogenic pathways in cervical adenocarcinoma

Cervical adenocarcinoma (AC), a subtype of uterine cervical cancer (CC), poses a challenge due to its resistance to therapy and poor prognosis compared with squamous cervical carcinoma. Streptococcus agalactiae [group B Streptococcus (GBS)], a Gram-positive coccus, has been associated with cervical intraepithelial neoplasia in CC. However, the underlying mechanism interaction between GBS and CC, particularly AC, remains elusive. Leveraging The Cancer Genome Atlas public data and time-series transcriptomic data, the present study investigated the interaction between GBS and AC, revealing activation of two pivotal pathways: 'MAPK signaling pathway' and 'mTORC1 signaling'. Western blotting, reverse transcription-quantitative PCR and cell viability assays were performed to validate the activation of these pathways and their role in promoting cancer cell proliferation. Subsequently, the present study evaluated the efficacy of two anticancer drugs targeting these pathways (binimetinib and ridaforolimus) in AC cell treatment. Binimetinib demonstrated a cytostatic effect, while ridaforolimus had a modest impact on HeLa cells after 48 h of treatment, as observed in both cell viability and cytotoxicity assays. The combination of binimetinib and ridaforolimus resulted in a significantly greater cytotoxic effect compared to monotherapy, even though the synergy score indicated an additive effect. Furthermore, this drug combination may enhance the effect on HeLa cells exposed to GBS compared to those without exposure. In general, the MAPK and mTORC1 signaling pathways were identified as the main pathways associated with GBS and AC cells. The combination of binimetinib and ridaforolimus could be a potential AC treatment. Overall design: To elucidate the underlying mechanism between host adenocarcinoma cells and GBS, we conducted a time-series experiment involving Hela cells infected with GBS for 0, 2, 6, and 24 hours, alongside corresponding control groups treated solely with a bacteria-free human medium. The experimental design included triplicate replicates. Subsequently, we performed transcriptomic time-series analysis across the four time points, comparing treatment and control groups to pinpoint clusters linked with the impact of GBS. Furthermore, pathway enrichment analysis was employed to delineate transcriptome profiles of pathways involved in the interaction between host cervical cancer cells and GBS.