RESUMO
GLI1, a key transcription factor of the Hedgehog (Hh) signaling pathway, plays an important role in the development of cancer. However, the function and mechanisms by which GLI1 regulates gene transcription are not fully understood in gastric cancer (GC). Here, we found that GLI1 induced the proliferation and metastasis of GC cells, accompanied by transcriptional upregulation of INHBA. This increased INHBA expression exerted a promoting activity on Smads signaling and then transcriptionally activated GLI1 expression. Notably, our results demonstrate that disrupting the interaction between GLI1 and INHBA could inhibit GC tumorigenesis in vivo. More intriguingly, we confirmed the N6-methyladenosine (m6A) activation mechanism of the Helicobacter pylori/FTO/YTHDF2/GLI1 pathway in GC cells. In conclusion, our study confirmed that the GLI1/INHBA positive feedback loop influences GC progression and revealed the mechanism by which H. pylori upregulates GLI1 expression through m6A modification. This positive GLI1/INHBA feedback loop suggests a novel noncanonical mechanism of GLI1 activity in GC and provides potential therapeutic targets for GC treatment.
Assuntos
Proliferação de Células , Progressão da Doença , Retroalimentação Fisiológica , Regulação Neoplásica da Expressão Gênica , Helicobacter pylori , Neoplasias Gástricas , Proteína GLI1 em Dedos de Zinco , Neoplasias Gástricas/patologia , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/genética , Proteína GLI1 em Dedos de Zinco/metabolismo , Proteína GLI1 em Dedos de Zinco/genética , Humanos , Animais , Linhagem Celular Tumoral , Camundongos , Transdução de Sinais , Infecções por Helicobacter/metabolismo , Infecções por Helicobacter/complicações , Infecções por Helicobacter/microbiologia , Infecções por Helicobacter/patologia , Regulação para Cima , Masculino , Carcinogênese/genéticaRESUMO
Gastrointestinal cancer is a significant global health burden, necessitating the development of novel therapeutic strategies. Emerging evidence has highlighted the potential of targeting ferritinophagy as a promising approach for the treatment of gastrointestinal cancer. Ferritinophagy is a form of selective autophagy that is mediated by the nuclear receptor coactivator 4 (NCOA4). This process plays a crucial role in regulating cellular iron homeostasis and has been implicated in various pathological conditions, including cancer. This review discusses the molecular mechanisms underlying ferritinophagy and its relevance to gastrointestinal cancer. Furthermore, we highlight the potential therapeutic implications of targeting ferritinophagy in gastrointestinal cancer. Several approaches have been proposed to modulate ferritinophagy, including small molecule inhibitors and immunotherapeutic strategies. We discuss the advantages and challenges associated with these therapeutic interventions and provide insights into their potential clinical applications.
Assuntos
Autofagia , Ferritinas , Neoplasias Gastrointestinais , Coativadores de Receptor Nuclear , Humanos , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/metabolismo , Ferritinas/metabolismo , Autofagia/efeitos dos fármacos , Animais , Coativadores de Receptor Nuclear/metabolismo , Ferro/metabolismo , HomeostaseRESUMO
Gastrointestinal (GI) cancer is one of the most severe types of cancer, with a significant impact on human health worldwide. Due to the urgent demand for more effective therapeutic strategies against GI cancers, novel research on metal ions for treating GI cancers has attracted increasing attention. Currently, with accumulating research on the relationship between metal ions and cancer therapy, several metal ions have been discovered to induce cell death. In particular, the three novel modes of cell death, including ferroptosis, cuproptosis, and calcicoptosis, have become focal points of research in the field of cancer. Meanwhile, other metal ions have also been found to trigger cell death through various mechanisms. Accordingly, this review focuses on the mechanisms of metal ion-induced cell death in GI cancers, hoping to provide theoretical support for further GI cancer therapies.
