Abstract
Autophagy has emerged as a critical pathway in tumor development. S100A4 plays important roles in tumor metastasis, but its role in regulating autophagy has not been well characterized. In this study, we found that S100A4 was significantly upregulated in lung adenocarcinoma tissues. Clinical investigation demonstrated that high expression level of S100A4 was associated with tumor size and advanced tumor grades of lung adenocarcinoma patients. Moreover, our results revealed that extracellular S100A4 or overexpression of S100A4 inhibited starvation-induced autophagy and promoted cell proliferation in lung cancer cells in vitro; whereas small interfering RNA (siRNA)-mediated suppression of S100A4 increased autophagy and reduced cell viability in both A549 and LLC cells. Additionally, S100A4 inhibited starvation-induced autophagy to promote tumor cell viability via the Wnt pathway. Increased expression of β-catenin consistently led to a decreased LC3-II protein abundance. Further, the inhibitory effect of S100A4 on autophagy and its promotion role in cell proliferation was abolished in A549 and LLC cells using the receptor for advanced glycation end products (RAGE)-specific inhibitor (FPS-ZM1). S100A4-deficient mice showed retarded tumor development. This effect was well correlated with increased expression of autophagy markers. Our findings demonstrate that S100A4 promotes lung tumor development through inhibiting autophagy in a β-catenin signaling and S100A4 receptor RAGE-dependent manner, which provides a novel mechanism of S100A4-associated promotion of tumor development.
Highlights
Lung cancer is a common cancer and has become the leading cause of deaths from cancer in many developed and developing countries[1]
To identify the relationship between S100A4 expression and lung cancer progression, the expression of S100A4 in lung adenocarcinoma tissues was performed in a Tissue microarrays (TMAs) by immunohistochemistry
We found that only a few S100A4+ cells were detected in paracarcinoma tissues, various ranges of immunostaining intensities were observed in lung adenocarcinoma tissues (Fig. 1a)
Summary
Lung cancer is a common cancer and has become the leading cause of deaths from cancer in many developed and developing countries[1]. The majority (approximately 80%) of lung cancer cases are non-small-cell lung cancer (NSCLC) cases, of which 30–50% are adenocarcinoma, the most common histological type[2]. 1) inactivation, play important roles in lung cancer development[4,5,6]. The precise regulatory mechanisms of lung cancer development need to be studied further. S100A4 ( known as fibroblast-specific protein 1), a member of the S100 calcium-binding protein family, was first cloned in metastatic cells and fibroblasts[8,9]. It is a Official journal of the Cell Death Differentiation Association
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