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EpCAM (epithelial cell adhesion molecule) was discovered four decades ago as a tumor antigen on colorectal carcinomas. Owing to its frequent and high expression on carcinomas and their metastases, EpCAM serves as a prognostic marker, a therapeutic target, and an anchor molecule on circulating and disseminated tumor cells (CTCs/DTCs), which are considered the major source for metastatic cancer cells. Today, EpCAM is reckoned as a multi-functional transmembrane protein involved in the regulation of cell adhesion, proliferation, migration, stemness, and epithelial-to-mesenchymal transition (EMT) of carcinoma cells. To fulfill these functions, EpCAM is instrumental in intra- and intercellular signaling as a full-length molecule and following regulated intramembrane proteolysis, generating functionally active extra- and intracellular fragments. Intact EpCAM and its proteolytic fragments interact with claudins, CD44, E-cadherin, epidermal growth factor receptor (EGFR), and intracellular signaling components of the WNT and Ras/Raf pathways, respectively. This plethora of functions contributes to shaping intratumor heterogeneity and partial EMT, which are major determinants of the clinical outcome of carcinoma patients. EpCAM represents a marker for the epithelial status of primary and systemic tumor cells and emerges as a measure for the metastatic capacity of CTCs. Consequentially, EpCAM has reclaimed potential as a prognostic marker and target on primary and systemic tumor cells.

Background: Preoperative radiotherapy (RT) is widely used to downstage rectal tumours, but the rate of recurrence varies significantly. Therefore, new biomarkers are needed for better treatment and prognosis. It has been shown that astrocyte elevated gene-1 (AEG-1) is a key mediator of migration, invasion, and treatment resistance. Our aim was to analyse the AEG-1 expression in relation to RT in rectal cancer patients and to test its radiosensitising properties. Methods: The AEG-1 expression was examined by immunohistochemistry in 158 patients from the Swedish clinical trial of RT. Furthermore, we inhibited the AEG-1 expression by siRNA in five colon cancer cell lines and measured the survival after irradiation by colony-forming assay. Results: The AEG-1 expression was increased in the primary tumours compared with the normal mucosa independently of the RT ( P< 0.01). High AEG-1 expression in the primary tumour of the patients treated with RT correlated independently with higher risk of distant recurrence ( P =0.009) and worse disease-free survival ( P =0.007). Downregulation of AEG-1 revealed a decreased survival after radiation in radioresistant colon cancer cell lines. Conclusions: The AEG-1 expression was independently related to distant recurrence and disease-free survival in rectal cancer patients with RT and could therefore be a marker to discriminate patients for distant relapse.

Bisphenol-A (BPA), a well known endocrine disruptor, impairs learning and memory in rodents. However, the underlying molecular mechanism of BPA induced impairment in learning and memory is not well known. As synaptic plasticity is the cellular basis of memory, the present study investigated the effect of perinatal exposure to BPA on the expression of synaptic proteins neurexin1 (Nrxn1) and neuroligin3 (Nlgn3), dendritic spine density and spatial memory in postnatal male mice. The pregnant mice were orally administered BPA (50 µg/kgbw/d) from gestation day (GD) 7 to postnatal day (PND) 21 and sesame oil was used as a vehicle control. In Morris water maze (MWM) test, BPA extended the escape latency time to locate the hidden platform in 8 weeks male mice. RT-PCR and Immunoblotting results showed significant upregulation of Nrxn1 and Nlgn3 expression in both cerebral cortex and hippocampus of 3 and 8 weeks male mice. This was further substantiated by in-situ hybridization and immunofluorescence techniques. BPA also significantly increased the density of dendritic spines in both regions, as analyzed by rapid Golgi staining. Thus our data suggest that perinatal exposure to BPA impairs spatial memory through upregulation of expression of synaptic proteins Nrxn1 and Nlgn3 and increased dendritic spine density in cerebral cortex and hippocampus of postnatal male mice.

ObjectiveTo investigate the effects of atorvastatin on endothelial function and low-grade systemic inflammation in subjects with successful surgery for aortic coarctation repair (SCR).DesignOpen-label study.SettingOutpatients visiting the adult congenital heart disease department of our hospital.Patients34 young people with SCR.InterventionsPatients with SCR received atorvastatin 10 mg/day (n=17) or no treatment (n=17) for 4 weeks. At baseline and at 4 weeks, endothelial function was assessed by flow-mediated dilatation (FMD) of the right brachial artery, and blood samples were obtained. Serum levels of interleukin (IL) 1b, IL-6 and soluble vascular cell adhesion molecule-1 (sVCAM-1) were determined by ELISA.Main outcome measuresEffects of treatment on FMD and serum levels of IL-1b, IL-6 and sVCAM-1.ResultsFMD in the atorvastatin group was significantly improved after 4 weeks (from 6.46±0.95% to 11.24±1.38%, p<0.01), while remaining unchanged in the control group (from 6.74±0.58% to 6.95±0.53%, p=NS). Even though atorvastatin had no effect on serum IL-6 levels (0.62 (0.37–0.88) pg/ml to 0.53 (0.28–0.73) pg/ml, p=NS), it significantly reduced circulating levels of IL-1b (from 1.17 (0.92–1.77) pg/ml to 1.02 (0.75–1.55) pg/ml, p<0.05) and sVCAM-1 (from 883.4 (660.3–1093.1) ng/ml to 801.4 (566.7–1030.2) ng/ml, p<0.05). No changes were seen in serum levels of IL-6, IL-1b and sVCAM-1 in the control group after 4 weeks compared with baseline (p=NS for all).ConclusionsAtorvastatin treatment for 4 weeks in subjects with SCR significantly improved endothelial function and suppressed systemic inflammatory status by decreasing circulating levels of IL-1b and sVCAM-1.

Backgroud Accumulating evidences indicate that circular RNAs (circRNAs), a class of non-coding RNAs, play important roles in tumorigenesis. However, the function of circRNAs in hepatocellular cancer (HCC) is largely unknown. Methods We performed circRNA microarrays to identify circRNAs that are aberrantly expressed in HCC tissues. Expression levels of a significantly upregulated circRNA, circFBLIM1, was detected by quantitative real-time PCR (qRT-PCR) in HCC cell lines and tissues. Then, we examined the functions of circFBLIM1 in HCC by cell proliferation, apoptosis, invasion and mouse xenograft assay. In addition, luciferase assay and RNA immunoprecipitation (RIP) assay were used to explore the miRNA sponge function of circFBLIM1 in HCC. Results Microarray analysis and qRT-PCR verified a circRNA termed circFBLIM1 that was upregulated in HCC tissues and cell lines. Knockdown of circFBLIM1 inhibited proliferation, invasion and promoted apoptosis in HCC. Via luciferase reporter assays, circFBLIM1 and FBLIM1 were observed to directly bind to miR-346. Subsequent experiments showed that circFBLIM1 and FBLIM1 regulated the expression of each other by sponging miR-346. Conclusions Taken together, we conclude that circFBLIM1 may function as a competing endogenous RNA (ceRNA) to regulate FBLIM1 expression through sponging miR-346 to exert regulatory functions in HCC. circFBLIM1 may be a diagnostic biomarker and potential target for HCC therapy.

In the zebrafish (Danio rerio), regeneration and fibrosis after cardiac injury are not mutually exclusive responses. Upon cardiac cryoinjury, collagen and other extracellular matrix (ECM) proteins accumulate at the injury site. However, in contrast to the situation in mammals, fibrosis is transient in zebrafish and its regression is concomitant with regrowth of the myocardial wall. Little is known about the cells producing this fibrotic tissue or how it resolves. Using novel genetic tools to mark periostin b- and collagen 1alpha2 (col1a2)-expressing cells in combination with transcriptome analysis, we explored the sources of activated fibroblasts and traced their fate. We describe that during fibrosis regression, fibroblasts are not fully eliminated but become inactivated. Unexpectedly, limiting the fibrotic response by genetic ablation of col1a2-expressing cells impaired cardiomyocyte proliferation. We conclude that ECM-producing cells are key players in the regenerative process and suggest that antifibrotic therapies might be less efficient than strategies targeting fibroblast inactivation.

Natural killer (NK) cells hold promise for adoptive cancer immunotherapy but are dependent on cytokines such as interleukin (IL)-2 for growth and cytotoxicity. Here, we investigated the consequences of ectopic expression of IL-15 in human NK cells. IL-2 and IL-15 belong to the common γ chain family of cytokines and have overlapping activities. Transduction of clinically applicable NK-92 cells with lentiviral vectors encoding human IL-15 resulted in predominantly intracellular expression of the cytokine, and STAT5 activation, proliferation and cytotoxicity of the producer cells in the absence of IL-2. Growth of non-transduced bystander cells was not supported, allowing rapid enrichment of gene-modified cells solely by IL-2 withdrawal. This was also the case upon transduction of NK-92 and NKL cells with a bicistronic lentiviral vector encoding IL-15 and a chimeric antigen receptor (CAR) targeting the pancarcinoma antigen EpCAM. Effector cells co-expressing CAR and IL-15 continued to proliferate in the absence of exogenous cytokines and displayed high and selective cell-killing activity against EpCAM-expressing breast carcinoma cells that were resistant to the natural cytotoxicity of unmodified NK cells. This strategy facilitates rapid isolation and continuous expansion of retargeted NK cells and may extend their potential clinical utility.

Background: Vasculopathy is one of the hallmarks of systemic sclerosis (SSc), characterized by endothelial activation and over expression of adhesion molecules. A preliminary in vitro study has suggested that aminaftone, a naphtohydrochinone used in the treatment of capillary disorders, may downregulate the expression of adhesion molecules in endothelial cells. Objective: This study investigated the ex vivo effects of aminaftone on soluble adhesion molecule concentrations in patients with SSc. Methods: This randomized, open-label pilot study was conducted in patients with SSc. Patients received baseline treatment for Raynaud's phenomenon (eg, calcium channel blockers and IV cyclic iloprost) with (test) or without (control) aminaftone 75 mg or placebo TID for 12 weeks. Standard treatment for Raynaud's phenomenon was allowed as long as the dose was stable for ≥3 months prior to randomization. Concentrations of soluble E-selectin adhesion molecule 1 (sELAM-1), soluble vascular cell adhesion molecule 1 (sVCAM-1), and soluble intracellular adhesion molecule 1 (sICAM-1) were measured at baseline and 12 weeks, and their variation was tested using the analysis of variance for repeated measures with statistical correction. Laboratory analyses were performed by experienced personnel blinded to treatment assignment. Results: A total of 24 patients were enrolled (21 women, 3 men; mean age, 53.4 years; aminaftone, 12 patients; control, 12 patients). Decreases in mean (SD) sELAM-1 and sVCAM-1 concentrations were significantly greater in treated patients (sELAM-1, from 17.0 [7.8] to 11.9 [9.0] pg/mL; sVCAM-1, from 51.2 [12.9] to 40.8 [13.8] ng/mL) compared with controls (sELAM-1, from 20.3 [9.9] to 20.4 [10.5] pg/mL; sVCAM-1, from 56.8 [49.6] to 62.7 [40.6] ng/mL) (both, P < 0.05 [analysis of variance or repeated measures after Bonferroni correction]). No significant changes in sICAM-1 concentrations versus controls were observed. Conclusions: In this small pilot study in this select group of patients with SSc, aminaftone was associated with downregulation of sELAM-1 and sVCAM-1 concentrations. Studies evaluating the potential role of aminaftone in the treatment of vascular sclerodermal disease and SSc are warranted.

Metastasis is a life-threatening feature of cancer and is primarily responsible for cancer patient mortality. Cross talk between tumor cells and endothelium is important for tumor progression and metastasis. However, very little is known about the mechanisms by which endothelial cells (ECs) that are close to tumor cells, respond to the tumor cells during tumor progression and metastasis. In this study, we exploited the use of EC-specific signal transducer activator of transcription 3 (STAT3) knockout mice to investigate the role of STAT3 in ECs in tumor progression and metastasis. We found that the loss of STAT3 in ECs did not affect primary Lewis lung carcinoma (LLC) tumor growth, but it reduced in vivo LLC metastasis in experimental and spontaneous metastasis models. Mechanistically, STAT3 activation upregulated cell adhesion molecule expression, including E-selectin and P-selectin, in murine endothelial MS-1 cells treated with tumor cell-conditioned media in vitro and in pre-metastatic lungs of tumor-bearing mice in vivo . We also found that both E-selectin and P-selectin were, at least in part, responsible for STAT3-induced adhesion and invasion of LLC cells through an EC monolayer. However, tumor cell-conditioned media from B16F10 melanoma cells did not activate STAT3 in MS-1 cells. As a result, EC STAT3 knockout did not affect B16F10 melanoma cell metastasis. In addition, various human cancer cells activated STAT3 in human ECs (HUVECs), resulting in increased cell adhesion molecule expression. Collectively, our findings demonstrate that STAT3 activation in ECs promotes tumor metastasis through the induction of cell adhesion molecules, demonstrating a role for ECs in response to tumor cells during tumor metastasis.

Background: Epithelial cell adhesion molecule (EpCAM) is frequently expressed in breast cancer, and its expression has been associated with poor prognosis. Breast cancer can be subdivided into intrinsic subtypes, differing in prognosis and response to therapy. Methods: To investigate the association between EpCAM expression and prognosis in the intrinsic subtypes of breast cancer, we performed immunohistochemical studies on a tissue microarray encompassing a total of 1365 breast cancers with detailed clinicopathological annotation and outcomes data. Results: We observed EpCAM expression in 660 out of 1365 (48%) cases. EpCAM expression varied significantly in the different intrinsic subtypes. In univariate analyses of all cases, EpCAM expression was associated with a significantly worse overall survival. In the intrinsic subtypes, EpCAM expression was associated with an unfavourable prognosis in the basal-like and luminal B HER2 + subtypes but associated with a favourable prognosis in the HER2 subtype. Consistently, specific ablation of EpCAM resulted in increased cell viability in the breast cancer cell line SKBR3 (ER − , PR − , and HER2 + ) but decreased viability in the breast cancer cell line MDA-MB-231 (ER − , PR − , and HER2 − ). Conclusion: The differential association of EpCAM expression with prognosis in intrinsic subtypes has important implications for the development of EpCAM-targeted therapies in breast cancer.