Extracellular matrix protein 1 promotes cell metastasis and glucose metabolism by inducing integrin β4/FAK/SOX2/HIF-1α signaling pathway in gastric cancer

Abstract

Extracellular matrix protein 1 (ECM1) is related to strong invasiveness and poor prognosis in major malignancies, but the underlying mechanism remains unknown. Here we aimed to elucidate the function of ECM1 on cell metastasis and glucose metabolism in gastric cancer (GC). The level of ECM1 in sera and tissues of patient with GC were positively correlated with tumor invasion and recurrence. Genetic manipulation of ECM1 expression affected cell metastasis and glucose metabolism in GC cell lines. Enhanced ECM1 expression facilitated gene expression levels associated with epithelial-mesenchymal transition (EMT) and glucose metabolism. Interestingly, our results indicated that ECM1 directly interacted with integrin β4 (ITGB4) and activated ITGB4/focal adhesion kinase (FAK)/glycogen synthase kinase 3β signaling pathway, which further induced the expression of transcription factor SOX2. Aberrant expression of SOX2 altered gene expression of EMT factors and glucose metabolism enzymes. Furthermore, SOX2 enhanced hypoxia-inducible factor α (HIF-1α) promoter activity to regulate glucose metabolism. The micro-positron emission tomography/computed tomography imaging of xenograft model showed that ECM1 substantially increased F-fluorodeoxyglucose uptake in xenograft tumors. Using in vivo mouse tail vein injection experiments, ECM1 was also found to increase in lung surface metastasis. These findings provide evidence that ECM1 regulates GC cell metastasis and glucose metabolism by inducing ITGB4/FAK/SOX2/HIF-1α signal pathway and have important implications for the development of therapeutic target to prevent tumor metastasis and recurrence.

Transforming growth factor beta‐induced, an extracellular matrix interacting protein, enhances glycolysis and promotes pancreatic cancer cell migration

“…Recent reports pointed at FAK phosphorylation as an important regulator of glucose uptake and consumption . In a previous publication Gan et al ., demonstrated that integrin–FAK signaling pathway resulted into the stabilization of hypoxia‐inducible factor alpha (HIF‐1α) that in turn favored increased glycolysis . In light of our previous results, where TGFBI silencing impaired FAK phosphorylation and downstream AKT, we sought to investigate if this could have an impact on HIF‐1α.…”

HIF-1α and HIF-2α Mediated PARVB Expression Promotes Tumor Growth and Metastasis in Malignantmelanoma

“…For example, HIF-1α and HIF-2α could promote melanoma metastasis through activating SRC independently [7]. PDGFRA and FAK were also identi ed to be the targets of HIF-1α or HIF-2α and participate in melanomagenesis [27,28]. Besides, HIF1-mediated suppression of melanoma growth could be rescued by MITF overexpression [29].…”

Peer Review #1 of "Expression and prognostic analyses of ITGA11, ITGB4 and ITGB8 in human non-small cell lung cancer (v0.1)"

“…Manuscript to be reviewed migration, epithelial-mesenchymal transition, invasion, and metastasis in different cancers (Gan et al 2018;Huang et al 2017;Kitajiri et al 2002;Li et al 2017). The aberrant expression of ITGA11, ITGB4, and ITGB8 have been reported in many cancers (Grossman et al 2000;Mertens-Walker et al 2015;Parajuli et al 2017;Tagliabue et al 1998).…”