Hypoxic Microenvironment-Induced Reduction in PTEN-L Secretion Promotes Non-Small Cell Lung Cancer Metastasis through PI3K/AKT Pathway

Abstract

Objective. Lung cancer is the leading cause of cancer-related deaths worldwide. The aim of this study was to investigate the effects of hypoxic microenvironment on PTEN-L secretion and the effects of PTEN-L on the metastasis of non-small cell lung cancer (NSCLC) and the potential mechanisms. Methods. The expression levels of PTEN-L in NSCLC tissues, cells, and cell culture media were detected. The transfection of PTEN-L overexpression construct or HIF-1α-siRNAs was conducted to manipulate the expression of PTEN-L or HIF-1α. NSCLC cells were introduced into 200 μM CoCl2 medium for 72 hours under 37°C to simulate hypoxia. The proliferation and apoptosis of the A549 cells were determined by the Cell Counting Kit-8 assay and Annexin V-FITC/PI-stained flow cytometry assay, respectively. Wound healing assay and transwell invasion assay were used to measure the migration and invasion of A549 cells. The protein expression of PTEN, PTEN-L, PI3K/AKT pathway-related proteins, and HIF-1α was detected by Western blot. Results. PTEN and PTEN-L are downregulated in lung cancer tissues and cells. The protein expression of PTEN-L in the culture medium of lung cancer cell lines is decreased. The hypoxic microenvironment inhibits PTEN-L secretion. The low level of PTEN-L promotes cell proliferation, migration, and invasion, as well as inhibits apoptosis of A549 cells. The overexpression of PTEN-L attenuated the activation of the PI3K/AKT pathway by the hypoxic microenvironment. The knockdown of HIF-1α upregulates PTEN-L secretion under hypoxia. Conclusions. The hypoxic microenvironment inhibits PTEN-L secretion and thus activates PI3K/AKT pathway to induce proliferation, migration, and invasion promotion, and apoptosis inhibition in NSCLC cells.

Pro-inflammatory activity of long noncoding RNA FOXD2-AS1 in Achilles tendinopathy

“…In addition, this study also confirmed that PTEN expression was elevated in rats with Achilles tendinopathy. PTEN is a prominent tumor suppressor gene [ 47 ] that inhibits the PI3K/AKT pathway through lipid phosphatase activity [ 48 , 49 ]. Recently, PTEN has been revealed to be involved in tendon healing and regeneration [ 50 ].…”

Hypoxic Effects on Matrix Metalloproteinases’ Expression in the Tumor Microenvironment and Therapeutic Perspectives

“…Likewise, HIF-1α expression can be regulated by the PI3K/AKT/mTOR signaling pathway, fumarate hydratase (FH), succinate dehydrogenase (SDH), phosphatase and tensin homolog (PTEN), protein kinase A (PKA), and Ra4/MAPK pathway under hypoxic conditions or independently of oxygen concentrations due to mutations of any of these components, [67][68][69][70].…”