Clinical Significance of SERPINA1 Gene and Its Encoded Alpha1-antitrypsin Protein in NSCLC

Abstract

High expression of SERPINA1 gene encoding acute phase protein, alpha1-antitrypsin (AAT), is associated with various tumors. We sought to examine the significance of SERPINA1 and AAT protein in non-small-cell lung cancer (NSCLC) patients and NSCLC cell lines. Tumor and adjacent non-tumor lung tissues and serum samples from 351 NSCLC patients were analyzed for SERPINA1 expression and AAT protein levels. We also studied the impact of SERPINA1 expression and AAT protein on H1975 and H661 cell behavior, in vitro. Lower SERPINA1 expression in tumor but higher in adjacent non-tumor lung tissues (n = 351, p = 0.016) as well as higher serum levels of AAT protein (n = 170, p = 0.033) were associated with worse survival rates. Specifically, in NSCLC stage III patients, higher blood AAT levels (>2.66 mg/mL) correlated with a poor survival (p = 0.002). Intriguingly, levels of serum AAT do not correlate with levels of C-reactive protein, neutrophils-to-leukocyte ratio, and do not correlate with SERPINA1 expression or AAT staining in the tumor tissue. Additional experiments in vitro revealed that external AAT and/or overexpressed SERPINA1 gene significantly improve cancer cell migration, colony formation and resistance to apoptosis. SERPINA1 gene and AAT protein play an active role in the pathogenesis of lung cancer and not just reflect inflammatory reaction related to cancer development.

Alpha1-antitrypsin protects lung cancer cells from staurosporine-induced apoptosis: the role of bacterial lipopolysaccharide

“…treatment 16,17 . In line, our current data imply that SERPINA1 gene encoding AAT and levels of AAT protein have a high influence on lung cancer patient's survival prognoses 18 .…”

“…The increased levels of AAT, one of the most abundant serpins in human circulation (1-2 g/L), have also been associated with worse overall patient survival and with more advanced tumor stages. In accordance, in a cohort of 351 NSCLC patients, we recently reported that higher circulating levels of AAT are prognostic for the patient's worse outcome 18 .…”

“…Supplementation of medium with AAT exaggerates H1975 and H661 cell proliferation. Based on our previous finding that higher plasma AAT levels correlate with a poor survival of NSCLC patients 18 , we investigated whether higher levels of AAT in the microenvironment of cancer cells influence them. We cultured H1975 and H661 cells for 3 weeks in a regular medium without and with AAT (2 mg/ml) supplementation.…”

Screening and identification of key genes and pathways in metastatic uveal melanoma based on gene expression using bioinformatic analysis

“…[ 45 ] APOB is a major protein constituent of chylomicrons, low-density lipoprotein and very-low density lipoprotein, lung cancer and colorectal cancer risk were increased with high APOB levels, [ 46 ] whereas the role of APOB in UM remains unclear. SERPINA1 and SERPINC1 are members of the serpin family, SERPINA1 was found to improve nonsmall cell lung cancer cell migration, colony formation, and resistance to apoptosis, [ 47 ] while knockdown of SERPINC1 was reported to inhibit neural progenitor cell proliferation via suppression of the PI3K/Akt/mTOR signaling pathway. [ 48 ] ITIH2, also known as serum-derived HA-associated protein (SHAP), forms complexes with hyaluronan (HA) to regulate the localization, synthesis, and degradation of HA in serum.…”

The Delivery of α1-Antitrypsin Therapy Through Transepidermal Route: Worthwhile to Explore

“…According to previous studies, AAT enters the tissues from the circulation by passive diffusion via cell membranes ( Stockley, 1984 ). For example, neutrophils, peripheral blood mononuclear cells, cancer cells, and endothelial cells cultured in the medium supplemented with AAT all show cytoplasmic immunostaining for AAT ( Sohrab et al., 2009 ; Janciauskiene et al., 2011 ; Jonigk et al., 2013 ; Ercetin et al., 2019 ). In line with this, experimental studies revealed that AAT added to the apical or the basolateral side of the endothelium appears intracellularly and secreted across the trans-well membrane, suggesting bidirectional transport of AAT across the endothelium ( Ferkol et al., 2000 ; Vogel and Larsen, 2000 ; Lockett, 2017 ).…”