RESUMO
BACKGROUND: Anti-oestrogenic therapy has been used for breast cancer patients with oestrogen susceptibility cancer cells. However, little has been known about its potential role for immune cell biology within TME, particularly in cancer patients without oestrogen sensitivity of tumour cells. Therefore, we aimed to study the effect of oestrogen on immunity within TME. METHODS: Using a clinical dataset, immune cells of humans and mice, female mice with and without ovaries, and several murine ERα-negative cancer cell lines, we evaluated the effect of oestrogen on immunity in TME. RESULTS: Clinical data analysis suggested oestrogen's suppressive efficacy against CTLs. Additionally, in vitro and in vivo experiments revealed intra-tumoural CTLs' direct repressive action by oestrogen in both mice and humans; blockade of oestrogen signals cancelled its immunosuppression resulting in tumour growth reduction in vivo. Most notably, immunotherapy (immune checkpoint inhibitor; ICI) combined with anti-oestrogenic therapy exhibited a dramatic anti-tumour effect. CONCLUSIONS: This study provides novel insights into how oestrogen contributes to tumour progression and a therapeutic rationale for blocking oestrogen signalling to boost the anti-tumour effect of ICI, regardless of tumour cells' ERα expression.
Assuntos
Neoplasias da Mama , Receptor alfa de Estrogênio , Humanos , Feminino , Camundongos , Animais , Receptor alfa de Estrogênio/metabolismo , Estrogênios/farmacologia , Estrogênios/uso terapêutico , Neoplasias da Mama/patologia , Receptores de Estrogênio/metabolismo , Transdução de SinaisRESUMO
Cigarette smoke (CS) is a crucial factor in chronic obstructive pulmonary disease (COPD). Wnt/ß-catenin signaling deregulation may further contribute to COPD progression. The deregulation and dysfunction of miRNAs in COPD have been reported. Investigating the deregulated miRNAs and their potential role in COPD progression may provide novel strategies for COPD treatment. In the present study, we analyzed significantly differentially-expressed miRNAs in COPD according to GSE44531 and miR-130a was selected. We revealed the upregulation of miR-130a in COPD, both in cigarette smoke extract (CSE)-treated BEAS-2B cells and CS-exposed mice. MiR-130a negatively regulated three critical factors in Wnt/ß-catenin signaling, Wnt1, ß-Catenin, and LEF1. MiR-130a inhibition rescued CSE-blocked activation of Wnt/ß-catenin signaling in vitro. MiR-130a targets WNT1 3'UTR to inhibit its expression. Moreover, in CSE-stimulated BEAS-2B cells, miR-130a overexpression aggravated, while miR-130a inhibition partially attenuated CSE-caused suppression on cell migration and proliferation. MiR-130a aggravates CSE-induced cellular injury in BEAS-2B cells by targeting Wnt signaling. In summary, miR-130a has a pathogenetic role in CS-induced COPD and regulates Wnt/ß-catenin signaling via targeting Wnt1. Our findings indicate that miR-130a is a potential therapeutic target for the treatment of CS-induced COPD.