Macroautophagy/autophagy inhibition is a novel anticancer therapeutic strategy, especially for tumors driven by mutant RAS. Here, we demonstrate that autophagy inhibition in RAS-mutated cells induces epithelial-mesenchymal transition (EMT), which is associated with enhanced tumor invasion. This is at least partially achieved by triggering the NFKB/NF-κB pathway via SQSTM1/p62. Knockdown of ATG3 or ATG5 increases oncogenic RAS-induced expression of ZEB1 and SNAI2/Snail2, and activates NFKB activity. Depletion of SQSTM1 abolishes the activation of the NFKB pathway induced by autophagy inhibition in RAS-mutated cells. NFKB pathway inhibition by depletion of RELA/p65 blocks this EMT induction. Finally, accumulation of SQSTM1 protein correlates with loss of CDH1/E-cadherin expression in pancreatic adenocarcinoma. Together, we suggest that combining autophagy inhibition with NFKB inhibitors may therefore be necessary to treat RAS-mutated cancer.
Although multidisciplinary treatment is widely applied in colorectal cancer (CRC), the prognosis of patients with advanced CRC remains poor. Immunotherapy blocking of programmed cell death ligand 1 (PD-L1) is a promising approach. Binding of the transmembrane protein PD-L1 expressed by tumor cells or tumor microenvironment cells to its receptor programmed cell death 1 (PD-1) induces immunosuppressive signals and reduces the proliferation of T cells, which is an important mechanism of tumor immune escape and a key issue in immunotherapy. However, the regulation of PD-L1 expression is poorly understood in CRC. Fibroblast growth factor (FGF) receptor (FGFR) 2 causes the tyrosine kinase domains to initiate a cascade of intracellular signals by binding to FGFs and dimerization (pairing of receptors), which is involved in tumorigenesis and progression. In this study, we showed that PD-L1 and FGFR2 were frequently overexpressed in CRC, and FGFR2 expression was significantly associated with lymph node metastasis, clinical stage, and poor survival. In the current study, PD-L1 expression was positively correlated with FGFR2 expression in CRC. Tumor-derived–activated FGFR2 induced PD-L1 expression via the JAK/STAT3 signaling pathway in human CRC cells (SW480 and NCI-H716), which induced the apoptosis of Jurkat T cells. FGFR2 also promoted the expression of PD-L1 in a xenograft mouse model of CRC. The results of our study reveal a novel mechanism of PD-L1 expression in CRC, thus providing a theoretical basis for reversing the immune tolerance of FGFR2 overexpression in CRC.
LncRNA OIP5-AS1 suppressed cell viability, promoted radio-induced apoptosis, and enhanced the radiosensitivity of CRC cells by regulating DYRK1A expression through miR-369-3p.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.