Serous IFNA3 predicts unfavorable prognosis in lung cancer via abnormal activation of AKT signaling

Abstract

This study addresses the demand through datamining The Cancer Genome Atlas (TCGA) database and elucidates mechanistic involvements of interferon alpha 8 (IFNA8) in lung cancer. The overall survival and disease-free survival of lung cancer patients in respect to IFNA8 expression level were analyzed. IFNA8 expression levels in both serum and tumor tissue were determined by real-time polymerase chain reaction. The diagnostic value of serous IFNA8 in lung cancer was assessed by receiver operating characteristic (ROC) curve analysis. Cell viability and proliferation were measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and Cell Counting Kit-8 assays. in vivo pro-tumor effect of IFNA8 was evaluated using xenograft tumor model. The metastasis-prone behaviors were determined by Transwell chamber assay and tail vein-injection in mice. Protein levels of p-AKT, total AKT, and endogenous reference actin were analyzed by western blot. We uncovered high IFNA8 associated with unfavorable overall survival and disease-free survival in lung cancer patients from TCGA. We further characterized the aberrant over-expression of IFNA8 in both peripheral blood and solid tumor from our clinical patient panel, and ROC analysis suggested its potential diagnostic value. Ectopic over-expression of IFNA8 promoted viability and proliferation in both A549 and H1299 cells in vitro and accelerated xenograft tumor growth in vivo. Furthermore, IFNA8 facilitated migration, invasion, and metastasis of A549 cells in vivo. Mechanistically, we disclosed the over-activation of AKT signaling in IFNA8-proficient A549 cells, inhibition of which completely abolished the pro-tumor effects of IFNA8. We have identified IFNA8 as a novel biomarker for either diagnostic or prognostic purpose in lung cancer, which is mechanistically associated with abnormal activation of AKT signaling. K E Y W O R D SAKT signaling, biomarker, IFNA8, lung cancer

Nilotinib Exerts a Therapeutic Approach via JAK/STAT Pathway and Cytokine Network in Chronic Myeloid Leukemia Cells

“…This controversy might be related to the molecular pathogenesis of CML in case of gain of resistance to TKI or nilotinib not perfectly targeting all leukemic cells. As another possibility, in a current study by Ge Q, IFNA8 has been reported to be aberrantly activated in the AKT pathway (32); thus an AKT inhibitor cotreatment might be an alternative approach in nilotinibbased CML treatment since IFNA8 is a positive regulator of peptidyl-serine phosphorylation of STAT proteins (33). The expression of genes associated with immune system regulation, especially IFNA17 was significantly related to prognostic markers for disease-specific survival, and IFNA17 was down-regulated in many types of cancer (34).…”

“…Especially IFNA7 is upregulated in leukemia as regulating interferon signaling and also JAK/STAT signaling thus should be downregulated (31). Among those that we analyzed, only IFNA8 expression was increased, whereas its immunogenomic structure was reported to have an association with survival (32). This controversy might be related to the molecular pathogenesis of CML in case of gain of resistance to TKI or nilotinib not perfectly targeting all leukemic cells.…”