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Tetraspanin membrane proteins form physical complexes with signaling molecules and have been suggested to influence the signaling events of associated molecules. Of the tetraspanin proteins, CD82 has been shown to promote homotypic cell-cell adhesion, which partially accounts for its role in suppressing cancer invasion and metastasis. We found here that CD82-induced cell-cell adhesion is attributed to increased E-cadherin expression through CD82-mediated downregulation of the E-cadherin repressor Snail. The Snail repression by CD82 resulted from the reduced binding of the Sp1 transcription factor to the Snail gene promoter. Notably, high CD82 expression did not allow the fibronectin matrix to induce Sp1 phosphorylation, implicating CD82 inhibition of the fibronectin-integrin signaling-dependent Sp1 activation. Meanwhile, E-cadherin upregulated by CD82 pulled β-catenin up to the membrane region, and consequently reduced the amount of cytoplasmic β-catenin that was able to move into to the nucleus. The Wnt signal-induced nuclear translocation of β-catenin was also inhibited by the CD82 function of upregulating E-cadherin. Overall, high CD82 expression was likely to suppress fibronectin adhesion-induced Sp1 activation signaling for Snail expression, resulting in continuous E-cadherin expression, which contributed not only to the maintenance of strong cell-cell adhesion but also to the blockage of nuclear β-catenin signaling.

// Jaeseob Lee 1, * , Hee-Jung Byun 1, * , Moon-Sung Lee 2 , Young-June Jin 1 , Dooil Jeoung 3 , Young-Myeong Kim 4 , Hansoo Lee 1, 2 1 Department of Biological Sciences, College of Natural Sciences, Kangwon National University, Chunchon, Kangwon-do 200-701, Republic of Korea 2 BIT Medical Convergence Graduate Program, Kangwon National University, Chunchon, Kangwon-do 200-701, Republic of Korea 3 Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chunchon, Kangwon-do 200-701, Republic of Korea 4 Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chunchon, Kangwon-do 200-701, Republic of Korea * These authors have contributed equally to this work Correspondence to: Hansoo Lee, email: hslee@kangwon.ac.kr Keywords: CD82, EMT, fibronectin matrix, integrin signaling, cancer invasion Received: July 22, 2016 Accepted: November 14, 2016 Published: December 01, 2016 ABSTRACT The transmembrane protein CD82/KAI1 suppresses the metastatic potential of various cancer cell types. Moreover, decrease or loss of CD82 expression is closely associated with malignancy and poor prognosis in many human cancers including prostate cancer. Despite intense scrutiny, the mechanisms underlying the metastasis-suppressing role of CD82 are still not fully understood. Here, we found that a fibronectin matrix induced mesenchymal phenotypes in human prostate cancer cells with no or low CD82 expression levels. However, high CD82 expression rendered prostate cancer cells to have intensified epithelial characteristics upon fibronectin engagement, along with decreased cell motility and invasiveness. The CD82 function of inhibiting fibronectin-induced epithelial-to-mesenchymal transition (EMT) was dependent not only on CD82 interactions with fibronectin-binding α 3 β 1 /α 5 β 1 integrins but also on the integrin-mediated intracellular signaling events. Notably, CD82 attenuated the FAK-Src and ILK pathways downstream of the fibronectin-receptor integrins. Immunofluorescence staining of human prostate cancer tissue specimens illustrated a negative association of CD82 with EMT-related gene expression as well as prostate malignancy. Altogether, these results suggest that CD82 suppresses EMT in prostate cancer cells adhered to the fibronectin matrix by repressing adhesion signaling through lateral interactions with the associated α 3 β 1 and α 5 β 1 integrins, leading to reduced cell migration and invasive capacities.

Due to increased multiculturalism in the US and abroad, there is a need for increased understanding of the different ways in which parenting stress is related to child problems across cultures. In the present study, we investigated (a) differences in reported parenting stress and childhood problem behaviors across a Korean (n = 71) and US (n = 71) sample, as well as (b) differences in the ways in which parenting stress and childhood problems were related across Korean and US children based on mothers' reports. Results revealed that Korean mothers reported significantly higher parenting stress yet significantly lower childhood problem behaviors compared to US mothers. In addition, mother-based reports of child problems were significantly associated with parenting stress in the US sample, but not in the Korean sample. Clinical implications and culturally-relevant issues relevant to these findings are addressed, including a potential under-reporting bias of child problems among Asian parents.

The activity of matrix metalloproteinases (MMPs), which selectively degrades the extracellular matrix (ECM), is critical in angiogenesis. Conversely, changes in ECM composition/structure alter the expression and activity of MMPs in various cell types. In the present study, we examined whether changes in ECM composition affect MMPs expression/activity of endothelial cells and thereby alter the surrounding ECM structure. Among the ECM molecules examined, fibronectin (FN) and vitronectin (VN) increased the expression and activity of MMP-9 in human umbilical vein endothelial cells (HUVECs). Both α(5)β(1) and α(v)β(3) integrins were involved in FN-induced MMP-9 expression. Also, FN-induced MMP-9 expression was found to be mediated by AP-1 transcription factors, including c-Jun, JunB, and JunD. Inhibitors or siRNAs specific to AP-1 activating signal transducers, including FAK-Src, PI3K/Akt, ERK, and JNK, abolished both FN-induced AP-1 activation and MMP-9 expression. VN-induced AP-1 activation and MMP-9 expression were also mediated by these AP-1 activating signal transducers in addition to p38 MAPK. Moreover, treatment with FN or VN resulted in increased degradation of collagen on HUVEC culture plates. Taken together, our data suggest that both fibronectin and vitronectin induce MMP-9 expression via the AP-1-activating signaling pathways in endothelial cells, and thereby stimulate degradation of surrounding collagen, leading to alterations in ECM structure and potentially the promotion of angiogenesis.

The authors investigated the subjective cognitive dysfunction associated with drug-induced parkinsonism (DIP) among 58 stabilized schizophrenic outpatients. Subjective cognitive dysfunction was comprehensively assessed using the Frankfurt Complaint Questionnaire (FCQ). Multivariate analysis revealed that the DIP group scored significantly higher on the total FCQ score than the non-DIP group. In phenomenological subscale scores, the DIP group had significantly higher scores on “deterioration of discrimination”, “psychomotor disorder”, and “perceptual disorder” than the non-DIP group. These results suggest that DIP is significantly associated with subjective cognitive-perceptual dysfunction, reflecting the complex nature of DIP that includes motor and cognitive aspects.

The tetraspanin membrane protein CD151 has been suggested to regulate cancer invasion and metastasis by initiating signaling events. The CD151-mediated signaling pathways involved in this regulation remain to be revealed. In this study, we found that stable transfection of CD151 into MelJuSo human melanoma cells lacking CD151 expression significantly increased cell motility, matrix metalloproteinase-9 (MMP-9) expression, and invasiveness. The enhancement of cell motility and MMP-9 expression by CD151 overexpression was abrogated by inhibitors and small interfering RNAs targeted to focal adhesion kinase (FAK), Src, p38 MAPK, and JNK, suggesting an essential role of these signaling components in CD151 signaling pathways. Also, CD151-induced MMP-9 expression was shown to be mediated by c-Jun binding to AP-1 sites in the MMP-9 gene promoter, indicating AP-1 activation by CD151 signaling pathways. Meanwhile, CD151 was found to be associated with alpha(3)beta(1) and alpha(6)beta(1) integrins in MelJuSo cells, and activation of associated integrins was a prerequisite for CD151-stimulated MMP-9 expression and activation of FAK, Src, p38 MAPK, JNK, and c-Jun. Furthermore, CD151 on one cell was shown to bind to neighboring cells expressing CD151, suggesting that CD151 is a homophilic interacting protein. The homophilic interactions of CD151 increased motility and MMP-9 expression of CD151-transfected MelJuSo cells, along with FAK-, Src-, p38 MAPK-, and JNK-mediated activation of c-Jun in an adhesion-dependent manner. Furthermore, C8161 melanoma cells with endogenous CD151 were also shown to respond to homophilic CD151 interactions for the induction of adhesion-dependent activation of FAK, Src, and c-Jun. These results suggest that homophilic interactions of CD151 stimulate integrin-dependent signaling to c-Jun through FAK-Src-MAPKs pathways in human melanoma cells, leading to enhanced cell motility and MMP-9 expression.

The metric properties of the Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS) were examined in 182 subjects treated with antipsychotics. Inter-rater reliability, test-retest reliability, and concurrent validity with other rating scales for EPS were high. Four factors were identified and the optimal diagnostic cut-off scores were obtained. These results suggest that the DIEPSS is a reliable and valid multidimensional rating scale.

Despite the importance of multiple tetraspanin proteins in cancer invasion and metastasis, little is known about the role and significance of tetraspanin CD81 in these processes. In the present study, we examined CD81 effects on melanoma cell invasiveness and metastasis. Transfection of CD81 into melanoma cells lacking endogenous CD81 expression significantly enhanced the migrating, invasive, and metastatic abilities of melanoma cells. Interestingly, membrane type 1 matrix metalloproteinase (MT1-MMP) expression was found in CD81-expressing melanoma cells but not in CD81-deficient cells. siRNA knockdown of CD81 in melanoma cells with endogenous CD81 demonstrated decreased MT1-MMP levels and cell motility. Notably, CD81-induced cell migration was abrogated by antibody blocking and siRNA knockdown of MT1-MMP, indicating that MT1-MMP is responsible for CD81-stimulated melanoma cell migration. Promoter analysis revealed an essential role of the Sp1 transcription factor in CD81-induced MT1-MMP transcription. We also demonstrate that the Sp1-activating Akt pathway is involved in adhesion-dependent CD81 signaling to induce MT1-MMP expression and cell motility. Importantly, human skin cancer tissue specimens displayed a positive correlation of CD81 with MT1-MMP expression levels and a close association of CD81 with malignant melanomas. Taken together, these results strongly suggest that CD81 stimulates melanoma cell motility by inducing MT1-MMP expression through the Akt-dependent Sp1 activation signaling pathway, leading to increased melanoma invasion and metastasis.

KAI1/CD82, a tetraspanin membrane protein functions as a metastasis suppressor in many types of human cancers and has been shown to regulate cell adhesion properties. In the present study, we investigated the underlying mechanism of KAI1/CD82-mediated changes in cell adhesion to the extracellular matrix using human prostate cancer cells. We found that high KAI1/CD82 expression attenuated short-term cell adhesion to uncoated- or fibronectin-coated plates. Moreover, high KAI1/CD82 expression generated an extracellular environment unfavorable for cell adhesion as compared to low KAI1/CD82 expression, suggesting KAI1/CD82-dependent regulation of extracellular matrix (ECM) molecule(s) expression and/or secretion. Among ECM components examined, fibronectin exhibited decreased expression and secretion in high KAI1/CD82-expressing cells. Furthermore, high KAI1/CD82 expression interfered with the activation of β (1) integrin at the cell surface while total β (1) integrin levels remained unchanged, concomitant with reduced formation of focal adhesion complex and decreased bundling of actin filaments. Finally, high KAI1/CD82 expression significantly retarded cell motility in a scratch wound assay. Taken together, our results strongly suggest that KAI1/CD82 attenuates the activation of β (1) integrin, and thereby down-regulates outside-in signaling of β (1) integrin, leading to the reduction of focal adhesion formation and fibronectin expression/secretion, which subsequently interferes with cell adhesion properties and motility.

Objective: Subjective experiences are subtle, self-experienced disturbances, a thorough description of which is provided within the framework of the concept of basic symptoms. Recent studies have shown that subjective experiences have important diagnostic implications for schizophrenia and related disorders. The purpose of the present study was to examine the relationship between subjective experiences and psychopathological dimensions in schizophrenia. Method: Sixty-seven outpatients with schizophrenia were evaluated. Subjective experiences were comprehensively assessed using the Frankfurt Complaint Questionnaire (FCQ). Symptoms of schizophrenia were evaluated using the Manchester Scale (MS). Pearson's partial correlation analysis was performed between the FCQ and the MS scores, controlling for the influence of extrapyramidal adverse effects. Results: The analysis revealed that the MS positive symptom score had significant positive correlations with the FCQ total score and subscales scores. The MS negative symptom score did not have significant correlations with the FCQ scores. Conclusions: The results of our study suggest that subjective experiences are significantly associated with positive symptomatology in schizophrenia, suggesting that they may share a common underlying neural basis. Future prospective studies are necessary to confirm the stability of these relationships and to explore the diagnostic and therapeutic implications of subjective experiences in a diverse group of patients at different stages of illness.

Akathisia remains a significant issue even in the era of atypical antipsychotics. The purpose of the present study was to examine the association of akathisia with various domains of subjective tolerability in order to contribute to the renewed interest in akathisia and the subjective experience of antipsychotic treatment. Fifty schizophrenic outpatients receiving stable doses of risperidone were evaluated for akathisia, schizophrenic symptoms, and subjective tolerability. Subjective tolerability was comprehensively assessed using the Liverpool University Neuroleptic Side Effect Rating Scale. Analysis of covariance revealed that the akathisia group had a significantly higher total score as well as higher subscale scores of extrapyramidal side effect, psychic side effect, and autonomic side effect on the Liverpool University Neuroleptic Side Effect Rating Scale. Further analysis using binary logistic regression analysis revealed that these variables were significantly associated with akathisia. The results of our study suggest that akathisia is significantly associated with a wide range of subjective tolerability profiles, implying the necessity to effectively manage akathisia even its mild forms considering its strong association with subjective tolerability in general.

A cancer/testis antigen, CAGE, is widely expressed in various cancer tissues and cancer cell lines but not in normal tissues except the testis. In the present study, ectopic expression of CAGE in fibroblast cells resulted in foci formation, suggesting its cell-transforming ability. Using stable HeLa transfectant clones with the tetracycline-inducible CAGE gene, we found that CAGE overexpression stimulated both anchorage-dependent and -independent cell growth in vitro and promoted tumor growth in a xenograft mouse model. Cell cycle analysis showed that CAGE augments the levels of cyclin D1 and E, thereby activating cyclin-associated cyclin-dependent kinases and subsequently accelerating the G1 to S progression. Moreover, increased cyclin D1 and E levels in CAGE-overexpressing cells were observed even in a growth arrested state, indicating a direct effect of CAGE on G1 cyclin expression. CAGE-induced expression of cyclins D1 and E was found to be mediated by AP-1 and E2F-1 transcription factors, and among the AP-1 members, c-Jun and JunD appeared to participate in CAGE-mediated up-regulation of cyclin D1. CAGE overexpression also enhanced retinoblastoma phosphorylation and subsequent E2F-1 nuclear translocation. In contrast, small interfering RNA-mediated knockdown of CAGE suppressed the expression of G1 cyclins, activation of AP-1 and E2F-1, and cell proliferation in both HeLa cervical cancer cells and Malme-3M melanoma cells. These results suggest that the cancer/testis antigen CAGE possesses oncogenic potential and promotes cell cycle progression by inducing AP-1- and E2F-dependent expression of cyclins D1 and E.

Objective The purpose of the present study was to examine the relationship between drug-induced parkinsonism (DIP) and subjective non-motor cognitive impairments in schizophrenia by performing comprehensive assessments of extrapyramidal side effects (EPS) and the subjective cognitive-perceptual functioning. Methods Ninety-one outpatients with schizophrenia were evaluated for DIP and other EPS. Subjective cognitive-perceptual dysfunction was comprehensively assessed using the Frankfurt Complaint Questionnaire (FCQ). To examine the association between DIP and non-motor cognitive-perceptual dysfunction, Pearson's partial correlation analysis was performed between the FCQ scores and the severity of DIP, controlling for relevant variables. Results The analysis revealed that the severity of DIP had a significant correlation with the total FCQ score (p

Antipsychotic-induced akathisia leads to poor compliance with medication and is still a source of concern in the treatment with antipsychotic drugs. Regarding clinical characteristics, the distinguishing features of akathisia in comparison with other extrapyramidal syndromes are prominent subjective symptoms. The purpose of the present study was to examine the subjective cognitive dysfunction associated with antipsychotic-induced akathisia.Sixty-seven outpatients with schizophrenia receiving stable doses of risperidone or haloperidol were evaluated for akathisia and other extrapyramidal side effects. Subjective cognitive dysfunction was comprehensively assessed using the Frankfurt Complaint Questionnaire (FCQ). The severity of subjective cognitive deficits was compared between the groups with and without akathisia using analysis of covariance with relevant variables as covariates.The akathisia group (n = 25) scored significantly higher on the total FCQ score than the non-akathisia group (n = 42) (P0.05). In phenomenological subscale scores, the akathisia group had significantly higher scores on various subscales, i.e. 'anxiety', 'disorder of selective attention', 'deterioration of discrimination', 'perceptual disorder' and 'disorder of coping responses' than the non-akathisia group (P0.05).These results suggest that akathisia is significantly associated with a variety of subjective cognitive-perceptual deficits. Early therapeutic interventions for akathisia should be performed considering its significant association with the subjective cognitive dysfunction and the impairment of coping responses.

The CD99 gene encodes two distinct transmembrane proteins by alternative splicing of its transcript. To examine the effects of two CD99 isoforms on the invasive phenotypes of breast cancer cells, MDA-MB-231 and MCF-7 human breast cancer cell lines were stably transfected with CD99 cDNAs encoding the major wild-type form (type I) or a minor splice variant (type II). As a result, expression of CD99 type II, but not type I, markedly elevated the motility, binding to fibronectin, MMP-9 expression, and invasiveness of MDA-MB-231 and MCF-7 breast cancer cells. In MDA-MB-435 breast cancer cells expressing both CD99 type I and type II, invasion-related cellular activities were inhibited by the transfection of small interfering RNA (siRNA) targeted to CD99 type II. Meanwhile, CD99 type II-induced MMP-9 expression in MDA-MB-231 cells was shown to be mediated by the binding of AP-1 factors to the MMP-9 gene promoter. Gel shift assay revealed that ligation of CD99 type II with antibody resulted in the binding of JunD to the AP-1 site of the MMP-9 promoter region. Initiation of CD99 type II signaling by antibody ligation increased expression of JunD and FosB AP-1 factors, along with phosphorylation of Src, Akt, p38 MAPK, ERK, and JNK. Knockdown of JunD and FosB by siRNA transfection abolished the positive effects of CD99 type II on the motility and MMP-9 expression of MDA-MB-231 cells. Increased expression of JunD and FosB as well as elevated cell motility and MMP-9 expression by CD99 type II ligation were also abrogated by inhibitors, dominant-negative forms, and siRNAs for Akt1, ERK1/2, and JNK1 but not for p38 MAPK. These results suggest that expression of a splice variant of CD99 contributes to the invasive ability of human breast cancer cells by up-regulating AP-1-mediated gene expression through the Akt-dependent ERK and JNK signaling pathways.

The primary distinguishing features of akathisia in comparison with other extrapyramidal syndromes are the prominent subjective manifestations, which include various sensory symptoms. The sensory symptoms are multidimensional in nature and encompass various forms of bodily and mental sensations. The purpose of the present study was to elucidate the multidimensional aspects of the sensory phenomena associated with antipsychotic-induced akathisia. Seventy stable and chronic schizophrenic subjects receiving maintenance antipsychotic treatment were evaluated for akathisia and other extrapyramidal side effects. Subjective sensory phenomena were evaluated in 3 dimensions (ie, bodily sensations, mental sensations, and autonomic sensations). The frequency of each dimension of these sensory phenomena was compared between the groups with and without akathisia using X 2 test with Bonferroni correction. The akathisia group (n = 29) reported significantly more frequent focal or generalized bodily sensations than the non-akathisia group (n = 41) (P < 0.001). The akathisia group also showed significantly more frequent mental sensations such as mental urge and a feeling of inner tension/pressure (P < 0.001). In autonomic phenomena, there was a trend for the akathisia group to show more frequent autonomic sensations. The most common autonomic phenomena associated with akathisia were palpitation and difficulty breathing. The results of the present study suggest that the sensory phenomena of antipsychotic-induced akathisia are characterized by multidimensional features such as bodily sensations, mental sensations, and several autonomic sensations. The assessment of these multidimensional sensory phenomena would be useful in evaluating the important phenotypic features of akathisia.

Akathisia is a complex syndrome that is characterized by subjective inner restlessness and objective motor manifestations, and it can be classified into several subtypes. The purpose of this study was to examine the prevalence of subjective akathisia, objective akathisia, and mixed akathisia, and to evaluate their relationships with other drug-induced movement disorders, in chronic schizophrenic subjects treated with antipsychotics. One hundred and forty-two in-patients were assessed for akathisia, drug-induced parkinsonism, and tardive dyskinesia. The subtypes of akathisia were specified according to the Barnes Akathisia Rating Scale. Drug-induced parkinsonism and tardive dyskinesia were assessed using the Simpson-Angus Scale and the Abnormal Involuntary Movement Scale, respectively. The prevalence of subjective, objective, and mixed akathisia was 11.3%, 6.3%, and 16.9%, respectively. Regarding concurrence rates of akathisia subtypes and other extrapyramidal syndromes, the comorbidity rates of mixed akathisia with parkinsonism and tardive dyskinesia were higher. In conclusion, the present study presented the prevalence of subjective, objective, and mixed akathisia among hospitalized schizophrenic subjects. Mixed akathisia showed an association with parkinsonism and tardive dyskinesia, suggesting a common vulnerability involved in these drug-induced movement disorders. Further studies are required to elucidate more detailed clinical characteristics of each subtype of akathisia.