BackgroundThe Ste-20 family kinase Hippo restricts cell proliferation and promotes apoptosis for proper organ development in Drosophila. In C. elegans, Hippo homolog also regulates longevity. The mammalian Ste20-like protein kinase, Mst1, plays a role in apoptosis induced by various types of apoptotic stress. Mst1 also regulates peripheral naïve T cell trafficking and proliferation in mice. However, its functions in mammals are not fully understood.Methodology/Principal FindingsHere, we report that the Mst1-FoxO signaling pathway plays a crucial role in survival, but not apoptosis, of naïve T cells. In Mst1−/− mice, peripheral T cells showed impaired FoxO1/3 activation and decreased FoxO protein levels. Consistently, the FoxO targets, Sod2 and catalase, were significantly down-regulated in Mst1−/− T cells, thereby resulting in elevated levels of intracellular reactive oxygen species (ROS) and induction of apoptosis. Expression of constitutively active FoxO3a restored Mst1−/− T cell survival. Crossing Mst1 transgenic mice (Mst1 Tg) with Mst1−/− mice reduced ROS levels and restored normal numbers of peripheral naïve T cells in Mst1 Tg;Mst1−/− progeny. Interestingly, peripheral T cells from Mst1−/− mice were hypersensitive to γ-irradiation and paraquat-induced oxidative stresses, whereas those from Mst1 Tg mice were resistant.Conclusions/SignificanceThese data support the hypothesis that tolerance to increased levels of intracellular ROS provided by the Mst1-FoxOs signaling pathway is crucial for the maintenance of naïve T cell homeostasis in the periphery.

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RASSF2 belongs to the Ras-association domain family (RASSF) of proteins, which may be involved in the Hippo signalling pathway. However, the role of RASSF2 in vivo is unknown. Here, we show that Rassf2 knockout mice manifest a multisystemic phenotype including haematopoietic anomalies and defects in bone remodelling. Bone marrow (BM) transplantation showed that Rassf2 À/À BM cells had a normal haematopoietic reconstitution activity, indicating no intrinsic haematopoietic defects. Notably, in vitro differentiation studies revealed that ablation of Rassf2 suppressed osteoblastogenesis but promoted osteoclastogenesis. Co-culture experiments showed that an intrinsic defect in osteoblast differentiation from Rassf2 À/À osteoblast precursors likely leads to both haematopoiesis and osteoclast defects in Rassf2 À/À mice.Moreover, Rassf2 deficiency resulted in hyperactivation of nuclear factor (NF)-jB during both osteoclast and osteoblast differentiation. RASSF2 associated with IjB kinase (IKK) a and b forms, and suppressed IKK activity. Introduction of either RASSF2 or a dominant-negative form of IKK into Rassf2 À/À osteoclast or osteoblast precursors inhibited NF-jB hyperactivation and normalized osteoclast and osteoblast differentiation. These observations indicate that RASSF2 regulates osteoblast and osteoclast differentiation by inhibiting NF-jB signalling.

Background/AimsPulmonary sarcomatoid carcinoma (PSC) is a poorly differentiated non-small cell lung cancer (NSCLC) that contains components of spindle or giant cells. Owing to its low prevalence, there are insufficient data regarding its clinical features, therapeutic strategies and prognosis.MethodsThe medical records of 26 patients diagnosed with PSC from January 2009 to June 2015 were reviewed and analyzed for clinicopathological characteristics, treatment modality, and outcomes.ResultsThe median age was 69.5 years. Twenty-three patients (88%) were male. Twenty-four patients (92%) were smokers. The median time from symptom onset to diagnosis was one month. Eighteen patients (69%) were diagnosed at an advanced stage. Pleomorphic carcinoma was the most common subtype, and epidermal growth factor receptor (EGFR) mutation was positive in two of 11 patients. Among 13 patients tested for programmed death ligand 1 (PD-L1) immunohistochemistry assay, eight showed high expression of PD-L1. The median overall survival (OS) of all patients was 9.5 months. In total, 12 patients were treated with chemotherapy: nine with platinum-based doublet therapy, two with tyrosine kinase inhibitor, and one with docetaxel. Seven patients showed partial response or stable disease. The median OS and progression-free survival of patients who received chemotherapy were 8.7 and 2.8 months, respectively.ConclusionsPSC was more common in males, smokers, and the elderly, with worse prognosis than ordinary NSCLC; chemotherapy response was favorable, and EGFR mutation status and PD-L1 expression may offer more therapeutic options.

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Expression of the protease inhibitor elafin is deregulated in several human cancers. However, functions of the protein in cancer are yet to be established. Here, we show that elafin elicits pro-apoptotic effects in melanoma cells but not in normal melanocytes. Elafin triggered the intrinsic apoptotic pathway as evidenced by the increased caspase 9 activity and unaltered caspase 8 activity. Caspase 9-specific siRNA, but not caspase 8-specific siRNA, dramatically abrogated elafin-induced apoptosis. Elevated level of p53 was observed, resulting in increased transcriptional activation and consequent expression of downstream effector molecules (Bax, Puma, Noxa, p21). Moreover, the apoptotic effect of elafin was inhibited by p53-specific siRNA and the p53 inhibitor pifithrin-a. Elafin treatment of xenograft mice of melanoma cells led to significantly smaller tumor sizes compared with those of untreated control mice. Immunohistochemical analysis revealed decreased elafin expression in melanoma tissue specimens. Western blot and reverse transcription analyses indicated transcriptional repression of the elafin gene in melanoma cells. Our results collectively indicate that elafin induces apoptosis in melanoma cells through a p53-dependent intrinsic apoptotic pathway, and that repression of elafin expression in melanoma may contribute to disease progression.

Background/AimsPrevious data suggest that vitamin D has a significant role in inflammatory bowel disease (IBD). We investigated the incidence of vitamin D deficiency in Korean patients with IBD and the correlation between serum vitamin D level and disease activity.MethodsWe retrospectively analyzed the medical records of patients with IBD whose serum vitamin D levels were checked. Deficiency of 25-hydroxyvitamin D was defined as <20 ng/mL. Disease activity was evaluated using the partial Mayo score for ulcerative colitis (≥2 defined as active disease) and Harvey-Bradshaw index for Crohn’s disease (≥4 defined as active disease).ResultsWe enrolled 87 patients with IBD (ulcerative colitis [UC], 45; Crohn’s disease [CD], 42). Among them, 65.5% (57/87) were men, with a mean age of 44.9±15.1 years (range, 18–75 years). The mean duration of disease was 4.7±4.8 years (range, 0.1–17.1 years). Vitamin D deficiency was found in 73.6% (64/87) of patients with IBD. Patients with IBD (mean vitamin D level, 16.3±9.0 ng/mL) showed lower vitamin D level than the healthy control group (mean vitamin D level, 20.4±7.0 ng/mL), with no statistically significant difference (P=0.136). Disease activity was inversely correlated with vitamin D deficiency in patients with CD (P=0.007). However, no correlation was observed in patients with UC (P=0.134).ConclusionsApproximately 75% of Korean patients with IBD showed vitamin D deficiency state. Vitamin D deficiency is associated with disease activity, particularly in patients with CD.