Abstract
Hypoxia contributes to the progression and metastasis of lung adenocarcinoma (LUAD). However, the specific underlying molecular mechanisms have not been fully elucidated. Here we report that Notch4 is upregulated in lung tissue from lung cancer patients. Functionally, Hypoxia activates the expressions of Delta-like 4 and Notch4, resulting in the excessive proliferation and migration of LUAD cells as well as apoptotic resistance. Notch4 silencing reduced ERK, JNK, and P38 activation. Meanwhile, Notch4 overexpression enhanced ERK, JNK, and P38 activation in LUAD cells. Furthermore, Notch4 exerted pro-proliferation, anti-apoptosis and pro-migration effects on LUAD cells that were partly reversed by the inhibitors of ERK, JNK, and p38. The binding interaction between Notch4 and ERK/JNK/P38 were confirmed by the co-immunoprecipitation assay. In vivo study revealed that Notch4 played a key role in the growth and metastasis of LUAD using two xenograft models. This study demonstrates that hypoxia activates Notch4-ERK/JNK/P38 MAPK signaling pathways to promote LUAD cell progression and metastasis.
Highlights
Lung cancer is the most common cancer and the leading cause of cancer death in both men and women worldwide (Siegel et al, 2018)
Hypoxia increases the expression of Notch4 in A549 and H1299 cells, which promotes cell proliferation and migration and inhibits cell apoptosis via the extracellular signal-regulated kinase (ERK)/c-Jun N-terminal kinase (JNK)/P38 mitogen-activated protein kinase (MAPK) pathway
Hypoxia-inducible factor-1α (HIF-1α) activates the transcription of genes involved in cell proliferation and metastasis in cancers (Krishnamachary et al, 2003; Pennacchietti et al, 2003)
Summary
Lung cancer is the most common cancer and the leading cause of cancer death in both men and women worldwide (Siegel et al, 2018). Lung adenocarcinoma (LUAD) accounts for 40% of all types of lung cancer (Imielinski et al, 2012). Lung cancer is characterized by sustained cell proliferation, resistance to cell death, invasion and metastasis (Hanahan and Weinberg, 2011). Intratumoral hypoxia is a critical microenvironmental factor driving cancer progression and is associated with poor clinical prognosis (Taiakina et al, 2014; Schito and Semenza, 2016; Li et al, 2021). Hypoxia upregulates a large number of oncogenes that contribute to the excessive proliferation, invasion, metastasis, and so on (Wigerup et al, 2016; Mennerich et al, 2019).
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