RESUMEN
Cigarette smoking is one of the most impactful behavior-related risk factors for multiple cancers including hepatocellular carcinoma (HCC). Nicotine, as the principal component of tobacco, is not only responsible for smoking addiction but also a carcinogen; nevertheless, the underlying mechanisms remain unclear. Here we report that nicotine enhances HCC cancer stemness and malignant progression by upregulating the expression of GC-rich binding factor 2 (GCF2), a gene that was revealed to be upregulated in HCC and whose upregulation predicts poor prognosis, and subsequently activating the Wnt/êµ-catenin/SOX2 signaling pathway. We found that nicotine significantly increased GCF2 expression and that silencing of GCF2 reduced nicotine-induced cancer stemness and progression. Mechanistically, nicotine could stabilize the protein level of GCF2, and then GCF2 could robustly activate its downstream Wnt/ß-catenin signaling pathway. Taken together, our results thus suggest that GCF2 is a potential target for a therapeutic strategy against nicotine-promoted HCC.
Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/inducido químicamente , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/inducido químicamente , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Nicotina/toxicidad , Línea Celular Tumoral , Vía de Señalización Wnt/genética , Regulación Neoplásica de la Expresión Génica , Proliferación CelularRESUMEN
PURPOSE: Pancreatic cancer is a lethal malignancy with a grim prognosis. Previous studies have proven that Leucine Rich Repeat of Flightless-1 Interacting Protein 1 (LRRFIP1) plays a pivotal role in cell biological processes, while its clinical significance and function in pancreatic cancer remain to be elucidated. Hence, we aimed to explore the roles and mechanisms of LRRFIP1 in pancreatic cancer. METHODS: The expression of LRRFIP1 in pancreatic cancer tissues and its clinical significance for pancreatic cancer were analyzed by immunohistochemistry assay and bioinformatic analysis. The influences of LRRFIP1 on the proliferation and migration of pancreatic cancer cells were assessed in vitro. The underlying mechanisms of LRRFIP1 in pancreatic cancer progression were explored using gene set enrichment analysis (GSEA) and molecular experiments. RESULTS: The results showed that LRRFIP1 expression was significantly upregulated in pancreatic cancer tissues compared to the normal tissues, and such upregulation was associated with poor prognosis of patients with pancreatic cancer. GSEA revealed that LRRFIP1 upregulation was significantly associated with various cancer-associated signaling pathways, including PI3K/AKT signaling pathway and Wnt pathway. Furthermore, LRRFIP1 was found to be associated with the infiltration of various immune cells. Functionally, LRRFIP1 silencing suppressed cell proliferation somewhat and inhibited migration substantially. Further molecular experiments indicated that LRRFIP1 silencing inactivated the AKT/GSK-3ß/ß-catenin signaling axis. CONCLUSION: Taken together, LRRFIP1 is associated with tumorigenesis, immune cell infiltration, and prognosis in pancreatic cancer, which suggests that LRRFIP1 may be a potential biomarker and therapeutic target for pancreatic cancer.
RESUMEN
PURPOSE: Lipoyltransferase 1 (LIPT1) has been recently identified as a cuproptosisrelated gene. As a key enzyme of lipoic acid metabolism, LIPT1 has been revealed to play important roles in hereditary diseases involved with lipoic acid biosynthesis defects, while its roles in hepatocellular carcinoma (HCC) remain to be elucidated. Hence, we aimed to explore the roles and mechanisms of LIPT1 in HCC progression. METHODS: The expression of LIPT1 in HCC tissues and its clinical significance for HCC were evaluated by bioinformatic analysis and in our patient cohort. The influences of LIPT1 on the growth, migration, and lipid metabolism of HCC cells were assessed in vitro. The underlying mechanisms were explored using gene set enrichment analysis (GSEA) and molecular experiments. RESULTS: LIPT1 expression was significantly elevated in HCC tissues compared to the normal tissues, and such upregulation was associated with more malignant pathological features and poor prognosis of patients with HCC. LIPT1 silencing significantly inhibited cell proliferation, migration, and lipid content. GSEA revealed that LIPT1 upregulation was significantly associated with various cancer-associated signaling pathways, including the PI3K-AKT signaling pathway and the Wnt/ß-catenin pathway. Further molecular experiments indicated that LIPT1 silencing repressed the expression of peroxisome proliferator-activated receptor gamma (PPARγ) and inactivated the AKT/GSK-3ß/ß-catenin signaling axis. CONCLUSIONS: Upregulation of LIPT1 is involved in metabolic dysregulation of fatty acid and poor prognosis of HCC patients, which suggests that LIPT1 plays an important role in reprogramming lipid metabolism and could act as a potential prognostic marker and therapeutic target for HCC.