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Autophagy related RHEB-CSF1R complex promotes tumor metastasis via advancing phosphorylation levels of PI3K, AKT, mTOR in pancreatic cancer
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DOI：10.3748/wjg.v32.i12.112725.png)
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Abstract
En 中文
BACKGROUND Pancreatic cancer (PC) is a prevalent and highly malignant tumor. Reports indicate that autophagy exerts a dual role, potentially promoting or suppressing tumor progression at different stages of PC. Ras homolog enriched in brain (RHEB) is also recognized as a key gene regulating cellular autophagy through two distinct pathways. AIM To investigate RHEB's role in PC metastasis and the underlying mechanisms. METHODS RHEB functions were validated using in vitro, cell counting kit-8 colony formation, and Transwell assays. RNA-seq and co-immunoprecipitation were then used to find proteins interacting with the gene before using transmission electron microscopy and immunofluorescence to validate the relationship between RHEB and autophagy. Western blot further validated the results at the protein level. Rescue experiments were subsequently performed to validate the detailed mechanism, with a distance liver metastasis model even established to explore RHEB's effects in vivo. Multiple bioinformatic analysis tools were eventually utilized to elucidate RHEB's mechanism and construct a prognostic signature. RESULTS RHEB promoted PC proliferation and metastasis in vitro. Higher RHEB expression was negatively correlated with longer survival times, with the gene also interacting directly with colony stimulating factor 1 receptor (CSF1R) to inhibit autophagy. The RHEB-CSF1R complex further advanced phosphorylation levels of phosphatidylinositol 3-kinase (PI3K), AKT serine/threonine kinase 1, and the mammalian target of rapamycin, as well as autophagy markers. The use of autophagy inhibitors confirmed that the RHEB-CSF1R complex could promote epithelial-mesenchymal transition markers expression levels. Finally, Transwell assays with CSF1R-overexpression/silencing, PI3K activator/inhibitor, and autophagy inhibitor revealed that these factors could affect PC metastasis phenotype. CONCLUSION This study found that RHEB lowered PC patients' survival. RHEB expression promoted PC proliferation, migration, and invasive ability, but it also inhibited autophagy by upregulating and interacting with CSF1R, leading to PI3K, AKT serine/threonine kinase 1, and mammalian target of rapamycin phosphorylation. This, in turn, promoted PC metastasis by promoting epithelial-mesenchymal transition marker expression. The above results indicated that RHEB can be a promising biomarker for predicting prognosis and developing new treatment strategies in PC.
Keywords:
Ras homolog enriched in brain
Colony stimulating factor 1 receptor
Autophagy
Phosphorylation of phosphatidylinositol 3-kinase
AKT serine/threonine kinase 1
Mammalian target of rapamycin
Pancreatic cancer
Metastasis
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