Fig. 3

Roles of nonsense-mediated mRNA decay (NMD) in cancer. a Disabling mutations or changes in the gene expression level of the key NMD factors (UPF1 as an example) occur in different cancer types [for example, lung inflammatory myofibroblastic tumor (IMT), pancreatic adenosquamous carcinoma (ASC), lung adenocarcinoma (ADC), and hepatocellular carcinoma (HCC)]. The case on the left represents mutated (Mut) UPF1, which leads to a decreased NMD activity resulting in the upregulation of an NMD target encoding the mitogen activated protein kinase kinase kinase 14 (MAP 3 K14) and stimulating NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) activity, thus inducing chemokine production and immune infiltrations. The example in the middle illustrates lower NMD activity due to the downregulation of UPF1, which causes the upregulation of several factors of the transforming growth factor beta (TGF-β) pathway. This favors the epithelial-mesenchymal transition (EMT) and consequently, the number of metastatic events. The example on the right shows the interaction between three oncoproteins, STAT3, GLI1 and tGL1, to induce higher protein levels of UPF3A, which inhibits NMD activity, increasing malignant progression of the tumor. b Tumor suppressor genes can completely loss their function by PTC acquisition and subsequent NMD degradation, combined with either deletion of the wild-type allele, or haploinsufficiency of the remaining allele. On the other hand, a tumor suppressor gene can experience an NMD-resistant mutation, leading to a dominant-negative protein that hampers the wild-type function. c The tumor microenvironment modulates NMD in order to overcome different types of cellular stresses associated with the unconstrained growth of the tumor. Stresses such as hypoxia, production of reactive oxygen species (ROS), or nutrient deprivation promote, eIF2α phosphorylation, which inhibits NMD and therefore, several mRNAs encoding stress-responsive factors are stabilized, allowing tumor progression and adaptation. WT: wild type; PTC: premature termination codon; aa: amino acid