Abstract
Recently, a growing number of ADP ribosylation factor (ARF) family members has been suggested to be critical in tumorigenesis. However, the effects of most ARF members on lung adenocarcinoma pathogenesis are still not well disclosed yet. In this study, ARF-like GTPase 14 (ARL14) was screened as an important prognostic factor of lung adenocarcinoma from The Cancer Genome Atlas (TCGA) database and validated by our in vitro experiments. It was found that silencing of ARL14 gene inhibited cell proliferation and the abilities of cell migration and invasion, and it also attenuated radiation damage of lung adenocarcinoma cells but had no effect on the proliferation of normal lung cells. Notably, ARL14 siRNA blocked the extracellular signal-regulated kinase (ERK)/p38 signaling pathway and induced cell cycle arrest in G0 phase, ultimately leading to cell dormancy. Moreover, ARL14 siRNA enhanced the expression of cell death activator DFFA-like effector (CIDEC) that had opposite roles in cell proliferation and migration to ALR14. Collectively, our results suggest that ARL14 has an important role in the pathogenesis of lung adenocarcinoma through CIDEC/ERK/p38 signaling pathway, and thus it could be applied as a new candidate of prognosis indicator and/or therapeutic target of lung adenocarcinoma.
Highlights
With the development of diagnostic techniques and treatment strategies, significant improvements have been made in the quality of life of patients with lung cancer; malignant lung tumors still show the highest morbidity and mortality rates among cancer types (Siegel et al, 2017), with only 16.8% of patients surviving for 5 years after diagnosis (Ridge et al, 2013)
Analyzing the data of lung adenocarcinoma samples and matched normal control tissues obtained from The Cancer Genome Atlas (TCGA) online resource, we found that the mRNA expression of ADP ribosylation factor-like GTPase 14 (ARL14) in lung adenocarcinoma samples was significantly higher than that in the matched normal tissues (Figure 1A, N = 57, fold change = 2.3, P = 1.23E-06), and the expression of ARL14 in adenocarcinoma had a very strong negative correlation with the overall survival of those lung cancer patients (Figure 1B, N = 482, P = 4.12E-04)
Our measurement further confirmed that the expression levels of ARL14 in lung adenocarcinoma cells (A549 and PC9) were higher than that in normal lung cells (BEAS-2B and MRC-5) (Figure 1C), which is consistent with the results obtained from TCGA cohort
Summary
With the development of diagnostic techniques and treatment strategies, significant improvements have been made in the quality of life of patients with lung cancer; malignant lung tumors still show the highest morbidity and mortality rates among cancer types (Siegel et al, 2017), with only 16.8% of patients surviving for 5 years after diagnosis (Ridge et al, 2013). 40% of all lung cancer cases are lung adenocarcinoma, which is the most common type of NSCLC (Xue et al, 2018). The prognosis of patients with lung adenocarcinoma is extremely poor because of the lack of effective treatment measures against metastatic lung cancer. The ARL11 polymorphisms Trp149Stop and Cys148Arg have been shown to be associated with a high risk of familial cancers, such as breast, SiRNA ARL14 Induces Cell Dormancy ovarian, colorectal, and hematological malignancies, among others (Calin et al, 2005; Frank et al, 2006; Masojc et al, 2006; Siltanen et al, 2008; Yang et al, 2009; Hamadou et al, 2017). ARL11 was reported as a novel tumor suppressor gene in lung and prostate cancer (Yendamuri et al, 2007, 2008; Siltanen et al, 2013). The function of ARL14 in the formation and progression of human cancer is unknown
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