Abstract
XB130 is a novel oncoprotein that promotes cancer cell survival, proliferation and migration. Its physiological function in vivo is largely unknown. The objective of this study was to determine the role of XB130 in lipopolysaccharide (LPS)-induced septic responses and acute lung injury. LPS was intraperitoneally administrated to Xb130 knockout (KO) and wild type (WT) mice. There was a significant weight loss in KO mice at Day 2 and significantly higher disease scores during the 7 days of observation. The levels of tumor necrosis factor-alpha, monocyte chemoattractant protein-1, interleukin-6 and interleukin-10 in the serum were significantly higher in KO mice at Day 2. In KO mice there were a significantly higher lung injury score, higher wet/dry lung weight ratio, more apoptotic cells and less proliferative cells in the lung. Macrophage infiltration was significantly elevated in the lung of KO mice. There was significantly increased number of p-GSK-3β positive cells in KO mice, which were mainly neutrophils and macrophages. XB130 is expressed in alveolar type I and type II cells in the lung. The expression in these cells was significantly reduced after LPS challenge. XB130 deficiency delayed the recovery from systemic septic responses, and the presence of XB130 in the alveolar epithelial cells may provide protective mechanisms by reducing cell death and promoting cell proliferation, and reducing pulmonary permeability.
Highlights
XB130 is a novel adaptor protein for signal transduction [1, 2]
To examine the role of XB130 in LPS-induced systemic septic response, wild type (WT) and Xb130 KO mice were challenged with 25 mg/kg LPS
At Day 2 after LPS treatment, most of these cytokines returned to basal levels in WT mice, but the levels of monocyte chemoattractant protein-1 (MCP-1), TNF-α, IL-6 and IL-10 in Xb130 KO mice were significantly higher compared to those in WT mice (Figure 2A and 2B)
Summary
XB130 is a novel adaptor protein for signal transduction [1, 2]. Due to its high molecular similarity with actin filament associated protein (AFAP), XB130 is known as actin filament associated protein 1-like 2 (AFAP1L2) [3, 4]. XB130 was found in colorectal cancer cells as a Src family kinase target [10], and found as a target of RET/PTC oncogenic kinase in thyroid cancer cells [6]. XB130 protein expression was not associated with the postoperative prognosis of patients with hepatocellular carcinoma [11]. XB130 expression was an independent prognostic factor in human esophageal squamous cell carcinoma [12]. In gastric cancer, reduced XB130 protein expression is a prognostic biomarker for shorter survival and a higher recurrence rate [13]. In human ductal breast cancer, XB130 was present in the cytoplasm of malignant cells, but not in the normal breast cells, and positive XB130 expression was an independent risk factor for overall survival and recurrence free survival [14]. XB130, may play different role in tumorigenesis depending upon the types of cancers
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