The prognostic significance of fibroblast activation protein-α in human lung adenocarcinoma.

BACKGROUND: Fibroblast activation protein (FAP) is a type II cell surface-bound integral serine protease, which is an important biomarker of cancer-associated fibroblasts. FAP-α performs several biological activities, including remolding extracellular matrix and acting as an immunosuppressor in the tumor microenvironment. However, the proliferation role of FAP-α in human lung adenocarcinoma has not been fully elucidated. METHODS: The expression of FAP-α in 94-paired human lung adenocarcinoma tissues was identified by immunohistochemistry test. The effect of FAP on cell proliferation was examined by CCK-8 assay. RNA-sequencing and bioinformatics analysis were utilized to investigate the underlying mechanism. Western blot analysis, quantitative polymerase chain reaction (qPCR), and nude mice experiments, were also conducted for further validation. RESULTS: The proliferation rates of human fibroblast strains FAP-HFF and FAP-BJ, and human lung adenocarcinoma cell line FAP-SPC-A-1 were higher than those of controls. The nude mice experiment also showed that FAP could promote the proliferation of SPC-A-1 cell line in vivo. qPCR and Western blot analysis indicated that CCNB1 was upregulated by the overexpression of FAP in the lung adenocarcinoma cell line. The expression of FAP-α was higher in both the cytoplasm and stroma of lung adenocarcinoma than in adjacent normal tissues. Survival analysis indicated that patients with higher expression of FAP-α in tumor stroma had a poor prognosis (P=0.019). The Cancer Genome Atlas Program (TCGA) data also showed that the expression of FAP within tumor tissues was higher (in both cytoplasm and stroma) compared with that in normal tissues (P<0.05). CONCLUSIONS: Our study indicates that FAP-α could facilitate the proliferation of lung adenocarcinoma cells and can be a prognostic marker in human lung adenocarcinoma.

The glucose-6-phosphate dehydrogenase Mahidol variant protects against uncomplicated Plasmodium vivax infection and reduces disease severity in a Kachin population from northeast Myanmar.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is one of the most common red cell disorders in the world. The aim of this study was to investigate whether the G6PD Mahidol variant and haplotype 1311 T/93C, which are prevalent in the Kachin ethnic population along the China-Myanmar border area, offer protection against Plasmodium vivax infection. Malaria was monitored in nine villages near the Laiza township, Kachin State, Myanmar, where 258 cases of uncomplicated P. vivax were identified in 2013-2017. From the same villages, 250 unrelated, malaria-free participants were recruited to serve as the control cohort. Quantitative enzyme activity analysis in 100 healthy individuals identified that both male hemizygotes and female heterozygotes of the G6PD Mahidol variant had on average ~40% lower enzyme activity relative to the wild-type individuals. Compared with the overall prevalence of 25.2% in the control cohort, the G6PD Mahidol variant had a significantly lower prevalence (7.0%) among the 258 vivax patients (P <  .0001, χ2 test). Logistic regression analysis of G6PD genotypes stratified by sex showed that the individuals with the Mahidol 487A allele had dramatically reduced odds of having acute vivax malaria (adjusted odds ratio = 0.213 for male 487A hemizygotes, P < .0001, and 0.248 for female 487GA heterozygotes, P < .001). Furthermore, both 487A hemizygous male and 487GA heterozygous female patients had significantly lower asexual parasitemias than the wild-type patients, suggesting a potential effect on alleviating disease severity. In contrast, the silent mutation haplotype 1311 T/93C was highly prevalent (49.6%) in the study population, but it was not associated with altered G6PD enzymatic activities nor did it seem to provide protection against vivax infection or disease severity. Taken together, this study provided evidence that the Mahidol G > A mutation offers protection against P. vivax infection and potentially reduces disease severity in a Kachin population.

NUP58 facilitates metastasis and epithelial-mesenchymal transition of lung adenocarcinoma via the GSK-3ß/Snail signaling pathway.

The NUP58 gene encodes a nucleus-pore protein that is a component of nuclear pore complex (NPC). NPC facilitates the transportation of macromolecules (ions and other substances) into the nuclei of eukaryotic cells. However, there are no relevant reports about the NUP58 gene in human lung cancer. In this study, we demonstrated that NUP58 was highly expressed in the primary and metastatic foci of lung adenocarcinoma, with low expression in adjacent tissues and normal lung tissue. In patients with lung adenocarcinoma, the NUP58 gene was highly expressed in patients with stage IV disease (P < 0.05); NUP58 knockdown using a lentiviral vector-mediated shRNA inhibited metastasis and invasion of lung adenocarcinoma cell lines A549 and H1299 in vivo and in vitro. Furthermore, silencing of NUP58 resulted in altered expression of EMT markers, associated GSK-3ß/Snail pathways, tumor metastasis and invasion factors. In conclusion, these findings demonstrated that NUP58 can promote the metastasis and invasion of lung adenocarcinoma, which can be partially attributed to the GSK-3ß/Snail signaling pathway.