Most lung adenocarcinomas harbor mutations in KRAS gene (32%) and epidermal growth factor receptor (EGFR) (11%), resulting in overactivation of the RAS-RAF-MEK-ERK pathway. Therefore, ERK signaling appears important or critical in at least 30–50% of NSCLC.
ERK1/2 is activate by dual threonine and tyrosine phosphorylation of a TxY (threonine-x-tyrosine, TEY) motif by the mitogen activate protein kinases (MAPKs), mitogen-activate protein kinase kinase 1 (MEK1) and mitogen-activate protein kinase kinase 2 (MEK2), which in turn are activate by oncogenic drivers RAF-RAS.
The MAPK family members
ERK5 is a relatively recently identify MAPK and displays different functions from MAPK family members. ERK5 activation mediate by RAS has been associate with a diverse range of cellular processes including cell proliferation, migration, survival and angiogenesis. Besides, activation of ERK5 in fibroblasts can lead to changes in the organization of actin cytoskeleton, including a loss of stress fibers and formation of invasive adhesion structures term podosomes.
The intensity and long-lasting effect of ERK1/2 signaling is regulate by a family of dual-specific mitogen activate protein (MAP) kinase phosphatases (DUSPs); hence including both cytoplasmic (DUSP6, 7 and 9) and nuclear DUSPs (DUSP5). DUSPs act differently and may even play opposing roles in various cancers depending on tumor types and progression state of the disease.
MAP kinase phosphatase 6/DUSP6 in particular; which show to act as a negative feedback regulator for ERK1/2 and ERK5; so inhibiting the mitogenic response mediate by those kinases. DUSP6 is functionally involve in suppressing tumor progression in pancreatic, ovarian and lung cancers.
Primary ovarian cancer
Down-regulation of its expression is observe in primary ovarian cancer. In lung cancer, DUSP6 is progressively lost; so as tumor grade increases. In addition, the tumor suppressive effects of DUSP6 have demonstrate; hence both in in vivo and in vitro assays, in ESCC and NPC. Moreover, it is suggest to modulate epithelial-mesenchymal transition (EMT) properties; so being associate with loss of invasiveness.
DUSP6 is a dual specific phosphatase localize at the cytoplasm; hence that is usually involve in the inactivation of ERK kinase, and with lower specificity, JNK and p38 kinases. The role of DUSP6 in cancer is mostly relate with the type of tumor; so being pro-oncogenic or tumor suppressive. Previous work in the literature describe it as an ERK-mediate inhibitor in lung cancer cells, or to be require for tumor associate angiogenesis.
Low expression levels of DUSP6 in NSCLC would affect these pathways; hence by increasing tumorigenicity, cell motility, EMT transition and consequently tumor progression associate; so with poor prognosis in NSCLC patients. Our manuscript sheds light on the unclear mechanism of downregulation of DUSP6 expression in NSCLC and other types of tumors and strongly indicates that re-establishment of DUSP6 expression seems to be a good strategy to revert the malignant phenotype