Adenylate Kinase-4 Is a Marker of Poor Clinical Outcomes That Promotes Metastasis of Lung Cancer by Downregulating the Transcription Factor ATF3

Abstract

Biomarkers predicting metastatic capacity might assist the development of better therapeutic strategies for aggressive cancers such as lung cancer. In this study, we show that adenylate kinase-4 (AK4) is a progressionassociated gene in human lung cancer that promotes metastasis. Analysis of published microarray data showed that AK4 was upregulated in lung adenocarcinoma compared with normal cells. High AK4 expression was associated with advanced stage, disease recurrence and poor prognosis. Loss of AK4 expression suppressed the invasive potential of lung cancer cell lines, whereas AK4 overexpression promoted invasion in vitro and in vivo. Mechanistically, the transcription factor ATF3 was identified as a pivotal regulatory target of AK4. Simultaneous reduction in AK4 and ATF3 expression abolished the inhibitory effects of ATF3 on invasion. ATF3 overexpression in AK4-overexpressing cells limits invasion activity. Furthermore, patients with high AK4 and low ATF3 expression showed unfavorable outcomes compared with patients with low AK4 and high ATF3 expression. Taken together, our findings indicated that AK4 promotes malignant progression and recurrence by promoting metastasis in an ATF3-dependent manner.

ASBEL –TCF3 complex is required for the tumorigenicity of colorectal cancer cells

“…We also found that ATF3 expression is down-regulated in colon cancer cells compared with noncancerous tissues. These results appear to be consistent with a previous report showing that ATF3 suppresses tumor growth in colon cancer and many other types of cancer, including glioblastoma and bladder and lung cancer (32)(33)(34)(35). Our ChIP analysis with anti-TCF3 antibody showed that TCF3 is associated with the TBS at the ATF locus in an ASBEL-dependent manner.…”

“…ATF3 has been shown to suppress tumor growth and metastasis in many cancer types, including glioblastoma, colon, bladder, and lung cancer (32)(33)(34)(35). We examined the expression of ATF3 in human colorectal tumor tissues and found that ATF3 was localized to the nucleus (Fig.…”

The Activating Transcription Factor 3 Protein Suppresses the Oncogenic Function of Mutant p53 Proteins

“…Whereas we and others demonstrated that ATF3 represses proinvasive matrix metalloproteinase 2 expression (21,43,44), ATF3 has been shown to suppress migration, invasion, and hepatic metastasis in colon cancer (19,45). A recent report demonstrated that ATF3 suppresses the invasion of lung cancer cells and that ATF3 expression correlates with a better survival of lung cancer patients (20). More recently, ATF3 was found to suppress invasion and metastasis in bladder cancer by regulating cytoskeleton remodeling (18).…”

“…Further analysis by scoring ATF3 staining intensity (Fig. 7D) (20) revealed that high ATF3 staining scores were often found in p53-positive tumors lacking lymph node metastasis (Fig. 7E).…”

Bioinformatics Analyses of m-RNA Profiling Following Ezrin Knockdown in Esophageal Squamous Cell Carcinoma

“…Several #: the first number refers to the annotated DEGs in the pathway; the second number is total number of pathways. [20]. Though Ezrin is a membrane-actin cross-linking protein, its translocation to cytosol has been found in multiple cancers, which is considered to be involved in cell motility, invasion, and carcinoma metastasis [21][22][23].…”