Lung fibrosis is a major medical problem for the aging population worldwide. Fibroblast migration plays an important role in fibrosis. Focal Adhesion Kinase (FAK) senses the extracellular stimuli and initiates signaling cascades that promote cell migration. This study first examined the dose and time responses of FAK activation in human lung fibroblasts treated with platelet derived growth factor BB (PDGF-BB). The data indicate that FAK is directly recruited by integrin β1 and the subsequent FAK activation is required for fibroblast migration on fibronectin. In addition, the study has identified that α5β1 and α4β1 are the major integrins for FAK-mediated fibroblast migration on fibronect. In contrast, integrins αvβ3, αvβ6, and αvβ8 play a minor but distinct role in fibroblast migration on fibronectin. FAK inhibitor significantly reduces PDGF-BB stimulated fibroblast migration. Importantly, FAK inhibitor protects bleomycin-induced lung fibrosis in mice. FAK inhibitor blocks FAK activation and significantly reduces signaling cascade of fibroblast migration in bleomycin-challenged mice. Furthermore, FAK inhibitor decreases lung fibrotic score, collagen accumulation, fibronectin production, and myofibroblast differentiation in in bleomycin-challenged mice. These data demonstrate that FAK mediates fibroblast migration mainly via integrin β1. Furthermore, the findings suggest that targeting FAK signaling is an effective therapeutic strategy against fibrosis.

INTRODUCTION: Prostate-specific membrane antigen (PSMA) was originally found to be specifically expressed in normal prostate, and its expression was upregulated in almost all stages of prostate cancer. In recent years, PSMA was also found to be expressed in tumor-associated vasculature in many nonprostatic solid tumors. However, the expression pattern of PSMA in hepatocellular carcinoma (HCC) is not well studied. METHODS: In this study, we examined PSMA expression in 103 HCC tissues using immunohistochemical staining and analyzed the association between PSMA expression and other clinicopathological features and prognosis. RESULTS: Among the 103 cases, 27 cases (26%) showed PSMA expression in more than 50% of tumor-associated vasculature, 49 cases (48%) showed PSMA expression in less than 50% of vasculature, and 27 cases (26%) did not have detectable PSMA expression. Vascular PSMA expression was associated with several clinicopathological features, such as tumor stage, tumor differentiation, lymph node metastasis, and Ki-67 index. Furthermore, high vascular PSMA expression was also associated with poor prognosis in patients with HCC. Univariate and multivariate analyses showed that high vascular PSMA expression can be used as an independent prognostic marker for HCC. DISCUSSION: Our study provides the evidence that PSMA is specifically expressed in tumor-associated vasculature of HCC, and vascular PSMA expression may be used as a novel prognostic marker and a vascular therapeutic target for HCC.

Understanding the underlying molecular mechanisms of liver fibrosis is important to develop effective therapy. Herein, we show that focal-adhesion-kinse (FAK) plays a key role in promoting hepatic stellate cells (HSCs) activation in vitro and liver fibrosis progression in vivo. FAK activation is associated with increased expression of α-smooth muscle actin (α-SMA) and collagen in fibrotic live tissues. Transforming growth factor beta-1 (TGF-β1) induces FAK activation in a time and dose dependent manner. FAK activation precedes the α-SMA expression in HSCs. Inhibition of FAK activation blocks the α-SMA and collagen expression, and inhibits the formation of stress fibers in TGF-β1 treated HSCs. Furthermore, inhibition of FAK activation significantly reduces HSC migration and small GTPase activation, and induces apoptotic signaling in TGF-β1 treated HSCs. Importantly, FAK inhibitor attenuates liver fibrosis in vivo and significantly reduces collagen and α-SMA expression in an animal model of liver fibrosis. These data demonstrate that FAK plays an essential role in HSC activation and liver fibrosis progression, and FAK signaling pathway could be a potential target for liver fibrosis.

In a Chinese Han population in Shandong, idiopathic bronchiectasis is the most common form of bronchiectasis followed by post-tuberculosis bronchiectasis. Patients with different causes differ in distribution and pattern of bronchiectasis on computed tomography.

To evaluate the impact of hypoxia on the angiogenic capability of endothelial cells (ECs), and further investigate whether the cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) signalling is involved in the angiogenic response of ECs to hypoxia. We explored the impact of various periods (1, 3, 6, 12, 24 hrs) of hypoxia (2% O2) on human umbilical vein endothelial cells (HUVECs) in vitro. We observed cell viability, migration, tube formation, analysed COX-2, vascular endothelial growth factor (VEGF), AQP1 mRNA transcription, protein expression and measured PGE2, VEGF protein concentration in cell supernatants. Then we treated HUVECs with COX-2 selective inhibitor NS398, EP1/2 combined antagonist AH6809 and exogenous PGE2 to investigate the role of COX-2/PGE2 signalling in the angiogenic response of ECs to hypoxia. The results demonstrated that short-term hypoxic treatment enhanced HUVECs proliferation, migration, tube formation, significantly up-regulated COX-2, VEGF, AQP1 mRNA level, protein expression and promoted PGE2, VEGF release. The pharmacological inhibition study revealed that exposure of HUVEC to NS398 and AH6809 under hypoxia impaired the biological responses of ECs to hypoxia. Exogenous PGE2 augments the effects of hypoxia on HUVECs, and partially reversed the inhibitory effects of NS398 on HUVECs proliferation and angiogenic capability. Short-term hypoxic treatment enhanced angiogenic capability of ECs, and COX-2/PGE2 signalling may play a critical role in the biological response of ECs to hypoxia.

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Diabetic retinopathy (DR) is one of the severest complications in the development of diabetes with a characteristic of intraretinal new vessel formation. Our present study attempts to probe into the involvement of Yes-associated protein 1 (YAP1) in retinal microvascular endothelial cells (RMECs) and the underlying mechanism. The DR mouse model was induced by streptozotocin injection and a high-glucose/ high-fat diet. After that, with the utilization of the Pearsonʼs correlation analysis, the correlation between YAP1 and metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) was analyzed. The relationship between microRNA-200b-3p (miR-200b-3p) and MALAT1 or vascular endothelial growth factor A (VEGFA) was then validated. Finally, the cellular processes including the abilities of proliferation, migration, as well as tube formation, were evaluated after the alteration of YAP1, MALAT1, and miR-200b-3p expression. YAP1 was observed to be highly expressed in retinas from DR mice, which promoted the cellular processes of RMECs through upregulating the MALAT1 expression. It was further confirmed that MALAT1 could sponge miR-200b-3p, and miR-200b-3p directly targeted VEGFA. When YAP1 was silenced, the RMEC proliferation, migration, and angiogenesis in the retina of DR mice were reduced. From these data, we conclude that YAP1 may exert some promotive effects on the development of DR through its regulation of the MALAT1/ miR-200b-3p/VEGFA axis, highlighting that YAP1 silencing may be instrumental for the therapeutic targeting of DR. K E Y W O R D S angiogenesis, diabetic retinopathy, MALAT1, microRNA-200b-3p, VEGFA, YAP1