Previously we have reported that stratifin (SFN, 14-3-3 sigma) acts as a novel oncogene, accelerating the tumor initiation and progression of lung adenocarcinoma. Here, pull-down assay and LC-MS/MS analysis revealed that ubiquitin-specific protease 8 (USP8) specifically bound to SFN in lung adenocarcinoma cells. Both USP8 and SFN showed higher expression in human lung adenocarcinoma than in normal lung tissue, and USP8 expression was significantly correlated with SFN expression. Expression of SFN, but not of USP8, was associated with histological subtype, pathological stage, and poor prognosis. USP8 stabilizes receptor tyrosine kinases (RTKs) such as EGFR and MET by deubiquitination, contributing to the proliferative activity of many human cancers including non-small cell lung cancer. In vitro, USP8 binds to SFN and they co-localize at the early endosomes in lung adenocarcinoma cells. Moreover, USP8 or SFN knockdown leads to downregulation of tumor cellular proliferation and upregulation of apoptosis, p-EGFR or p-MET, which are related to the degradation pathway, and accumulation of ubiquitinated RTKs, leading to lysosomal degradation. Additionally, mutant USP8, which is unable to bind to SFN, reduces the expression of RTKs and p-STAT3. We also found that interaction with SFN is critical for USP8 to exert its autodeubiquitination function and avoid dephosphorylation by PP1. Our findings demonstrate that SFN enhances RTK stabilization through abnormal USP8 regulation in lung adenocarcinoma, suggesting that SFN could be a more suitable therapeutic target for lung adenocarcinoma than USP8.

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Although several non-alcoholic steatohepatitis (NASH) models have been reported to date, few of these models fully reflect the histopathology and pathophysiology of human NASH. The aim of this study was to establish a novel NASH model by feeding a high-fat (HF) diet and administering both carbon tetrachloride (CCl 4 ) and the Liver X receptor agonist T0901317. Male C57BL/6J mice were divided into four groups (each n ¼ 5): HF, HF þ CCl 4 , HF þ T0901317, and the novel NASH model (HF þ CCl 4 þ T0901317). CCl 4 (0.1 mL/kg) and T0901317 (2.5 mg/ kg) were intraperitoneally administered four times and five times, respectively. The livers of the novel NASH model group presented a whitish colour. The serum levels of TNF-a and IL-6 were significantly increased in the novel NASH model group, and mice in this group exhibited histopathological features and insulin resistance reflective of NASH, i.e., macrovesicular hepatic steatosis, ballooning hepatocytes, Mallory-Denk bodies, lobular inflammation and fibrosis. The novel NASH model group presented significantly upregulated expression levels of mRNAs related to lipogenesis, oxidative stress, fibrosis and steatosis and significantly downregulated expression levels of mRNAs related to triglyceride export. We successfully established a novel experimental NASH model that exhibits similar histopathology and pathophysiology to human NASH.Key words: insulin resistance, Liver X receptor, mouse model, NAFLD activity score, non-alcoholic steatohepatitis Metabolic syndrome has been increasing worldwide concomitant with the increased prevalence of obesity, diabetes mellitus, and hyperlipidemia. Non-alcoholic fatty liver disease (NAFLD) was recently recognized as a hepatic manifestation of metabolic syndrome. A high-fat (HF) diet model is also widely used for the basic study of NASH because it causes obesity and insulin resistance. 15 In the HF diet models, long-term feeding of a HF diet leads to steatohepatitis that resembles that observed in human NASH. 16 However, this model is not suitable for researching the pathogenesis of NASH because a long time is required for the development of NASH symptoms and because the hepatic fibrosis in the model animals is weaker than that found in human NASH. 16Therefore, the establishment of a novel animal model that exhibits features similar to those of human NASH is necessary for the basic study of NASH. We aimed to develop a novel NASH model by feeding an HF diet and administering both carbon tetrachloride (CCl 4 ) and T0901317, which resulted in a combination of multiple important factors, including overnutrition, oxidative stress and lipogenesis. The administration of CCl 4 is known to induce chronic oxidative stress and liver injury in mice, and CCl 4 has been used to create acute hepatitis animal models. 17 An analysis of histopathological findings has revealed that CCl 4 leads to inflammation and fibrosis but not steatosis or ballooning. The liver X receptor (LXR) is a nuclear receptor that plays a key role in regulating cholesterol, fatty ac...

The clinicopathological implications of ovarian cancer immunoreactive antigen domain containing 2 (OCIAD2) in lung adenocarcinoma were investigated. The expression of OCIAD2 in 191 surgically resected lung adenocarcinomas was examined using immunohistochemistry. OCIAD2 expression was quantified using the H‐score and dichotomized as high or low. High OCIAD2 protein expression was significantly correlated with vascular invasion (P = 0.0018), lymphatic permeation (P = 0.049), T factor (P = 0.0024), and pathological stage (P = 0.0003). High OCIAD2 expression was significantly associated with poorer overall survival (OS) (n = 191, P = 0.0325). In peripheral‐type lung adenocarcinomas (n = 161), high OCIAD2 expression was significantly associated with both poorer OS (P = 0.0214) and poorer disease‐free survival (P = 0.0496). Adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) showed weaker OCIAD2 expression than invasive adenocarcinoma. Among small adenocarcinomas measuring 2 cm or less in greatest dimension classified according to the Noguchi's classification (n = 79), invasive adenocarcinomas showed significantly higher OCIAD2 expression than non‐invasive adenocarcinomas (P = 0.0007). Interestingly, OCIAD2 was expressed heterogeneously even within a tumor, and its expression was higher in areas of invasion than in areas of in situ spread. Our results suggest that OCIAD2 could be a useful prognostic biomarker of lung adenocarcinoma.

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