• Advanced stage
• Biomarker
• CD63
• High-grade serous carcinoma
• Ovarian cancer
• Perforin

• Humans
• Female
• Tetraspanin 30/blood
• Ovarian Neoplasms/blood
• Ovarian Neoplasms/pathology
• Middle Aged
• Biomarkers, Tumor/blood
• Aged
• Adult
• Neoplasm Staging
• Prognosis
• Tetraspanin 29/blood
• Tetraspanin 29/metabolism
• Exosomes/metabolism
• Cystadenocarcinoma, Serous/blood
• Cystadenocarcinoma, Serous/pathology
• Tetraspanin 28/blood
• Tetraspanin 28/metabolism

• CD63
• CD9
• exosomes
• extracellular vesicles
• tetraspanin
• tetraspanin-enriched microdomains
• trafficking

• Tetraspanins
• digestive system tumors
• drug resistance
• therapeutic target
• tumor metastasis

• CD9
• EGFR
• Histological grade
• Immunohistochemistry
• P-Akt
• Tongue cancer

• Humans
• Carcinoma, Squamous Cell/pathology
• ErbB Receptors/metabolism
• Prognosis
• Proto-Oncogene Proteins c-akt
• Tetraspanin 29
• Tetraspanins
• Tongue/metabolism
• Tongue/pathology
• Tongue Neoplasms/pathology

• Cancer
• Extracellular vesicles
• Immunonology
• Metastasis
• Tetraspanin

• 81972285 National Natural Science Fund
• CSTB2022NSCQ-MSX1038 the Natural Science Foundation of Chongqing
• CSTB2022NSCQ-MSX0775 the Natural Science Foundation of Chongqing
• 13-004-009 Senior Medical Talents Program of Chongqing for Young and Middle-aged and Kuanren Talents Program of the Second Affiliated Hospital of Chongqing Medical University
• 13-002-011 Senior Medical Talents Program of Chongqing for Young and Middle-aged and Kuanren Talents Program of the Second Affiliated Hospital of Chongqing Medical University
• HZQB-KCZYZ-2021017 Hetao Shenzhen-Hong Kong Science and Technology Innovation Cooperation Zone Shenzhen Park Project

• EGFR
• ERBB2
• MET
• VEGFR
• ovarian cancer
• receptor tyrosine kinases
• targeted therapy

• CD44
• CD74
• CD9
• Parietal epithelial cells
• glomerular crescent

Head and neck cancers are diverse and complex diseases characterised by unregulated growth of tumour cells in various parts of the head and neck region, such as in the buccal mucosa, floor of the mouth, tongue, oropharynx, hypopharynx, oesophagus, nasopharynx and salivary glands. Partial or total glossectomy, radiation or chemotherapy greatly affect patient quality of life. However, even following treatment, patients may relapse. Nicotine-derived nitrosamines and alcohol are the major etiological factors underlying this deadly disease. These compounds induce DNA damage that may lead to mutation in crucial genes, such as p53 and p21, which are important to regulate cell proliferation, thus leading to cancer. CD9 is a tetraspanin, which are a group of transmembrane proteins that have a role in cell motility and adhesion. The present review aimed to explore the role of CD9 in head and neck cancer. Epidermal growth factor receptor activity and cell proliferation are regulated by the CD9-integrin/CD9-transforming growth factor interaction. Hence, CD9 can play a dual role in various types of cancer.

• cell proliferation
• head and neck squamous cell carcinoma
• nicotine‑derived nitrosamines
• tetraspanin
• tobacco

• Cell Line, Tumor
• Immunotherapy/methods
• Multimodal Imaging
• Neoplasms/diagnostic imaging
• Neoplasms/drug therapy
• Optical Imaging/methods
• Photosensitizing Agents/pharmacology
• Photosensitizing Agents/therapeutic use
• Phototherapy

• P01 CA084203 NCI NIH HHS
• R01 CA231606 NCI NIH HHS
• R21 CA220143 NCI NIH HHS
• S10 OD012326 NIH HHS

• Chemoresistance
• Metastases
• TSPAN1
• Tetraspanins
• cancer

The Golgi apparatus plays a central role in normal cell physiology by promoting cell survival, facilitating proliferation, and enabling cell-cell communication and migration. These roles are partially mediated by well-known Golgi functions, including post-translational modifications, lipid biosynthesis, intracellular trafficking, and protein secretion. In addition, accumulating evidence indicates that the Golgi plays a critical role in sensing and integrating external and internal cues to promote cellular homeostasis. Indeed, the unique structure of the mammalian Golgi can be fine-tuned to adapt different Golgi functions to specific cellular needs. This is particularly relevant in the context of cancer, where unrestrained proliferation and aberrant survival and migration increase the demands in Golgi functions, as well as the need for Golgi-dependent sensing and adaptation to intrinsic and extrinsic stressors. Here, we review and discuss current understanding of how the structure and function of the Golgi apparatus is influenced by oncogenic transformation, and how this adaptation may facilitate cancer cell invasion and metastasis.

• Golgi
• cancer
• dissemination
• metastasis
• oncogenic transformation
• proliferation
• signaling
• tumorigenesis

Tetraspanins are a family of molecules abundantly expressed on the surface of normal or tumor cells. They have been implicated in recruiting or sequestering key molecular regulators of malignancy of a variety of human cancers, including breast and lung cancers, glioblastoma and leukemia. Yet, how their actions take place remains mysterious due to a lack of traditional platform for molecular interactions. The current review digs into this mystery by examining findings from recent studies of multiple tetraspanins, particularly CD151. The molecular basis for differential impact of tetraspanins on tumor development, progression, and spreading to secondary sites is highlighted, and the complexity and plasticity of their control over tumor cell activities and interaction with their surroundings is discussed. Finally, an outlook is provided regarding tetraspanins as candidate biomarkers and targets for the diagnosis and treatment of human cancer.

As a family of integral membrane proteins, tetraspanins have been functionally linked to a wide spectrum of human cancers, ranging from breast, colon, lung, ovarian, prostate, and skin carcinomas to glioblastoma. CD151 is one such prominent member of the tetraspanin family recently suggested to mediate tumor development, growth, and progression in oncogenic context- and cell lineage-dependent manners. In the current review, we summarize recent advances in mechanistic understanding of the function and signaling of integrin-associated CD151 and other tetraspanins in multiple cancer types. We also highlight emerging genetic and epigenetic evidence on the intrinsic links between tetraspanins, the epithelial-mesenchymal transition (EMT), cancer stem cells (CSCs), and the Wnt/β-catenin pathway, as well as the dynamics of exosome and cellular metabolism. Finally, we discuss the implications of the highly plastic nature and epigenetic susceptibility of CD151 expression, function, and signaling for clinical diagnosis and therapeutic intervention for human cancer.

• CD151
• Wnt pathway
• breast cancer
• cancer stem cells
• epithelial-mesenchymal transition (EMT)
• exosome
• integrins
• tetraspanins

• 5P20GM121327-03 NIH HHS

• VPS4B gene
• cell endocytosis
• embryonic lethality
• knockout mouse

• Antibody
• CD9
• cancer
• exosome
• extracellular vesicle
• immunotherapy
• tetraspanin

CD9 is a glycoprotein of the transmembrane 4 superfamily that is involved in various cellular processes. Studies related to the immune functions and activities of CD9 in teleost fish are limited. In this study, we characterized two CD9 homologs, PoCD9.1 and PoCD9.3, from Japanese flounder (Paralichthys olivaceus). Sequence analysis showed that PoCD9.1 and PoCD9.3 possess characteristic transmembrane 4 superfamily (TM4SF) structures. PoCD9.1 shares 70.61% sequence identity with PoCD9.3. The expression of PoCD9.1 and PoCD9.3 in the three main immune tissues was significantly induced in a time-dependent manner by extracellular and intracellular pathogen infection, which indicates that the two CD9 homologs play an important role in the response to pathogenic infection. Following infection with the extracellular pathogen Vibrio anguillarum, the expression profiles of both PoCD9.1 and PoCD9.3 were similar. After infection with the intracellular pathogen Edwardsiella piscicida, the expression levels of PoCD9.1 and PoCD9.3 were different at different stages of infection, especially in the spleen. The spleen was the most important tissue for the PoCD9.1 and PoCD9.3 responses to pathogen infection among the three examined immune tissues. Knockdown of PoCD9.1 and PoCD9.3 attenuated the ability of host cells to eliminate pathogenic bacteria, and PoCD9.1 knockdown was more lethal than PoCD9.3 knockdown for host cells with E. piscicida infection. Overexpression of PoCD9.1 and PoCD9.3 promoted host or host cell defence against E. piscicida infection. These findings suggest that PoCD9.1 and PoCD9.3 serve as immune-related factors, play an important role in the immune defence system of Japanese flounder, and display different functions in response to different pathogens at different stages of infection.

• Anti-infectious immunity
• CD9
• Paralichthys olivaceus
• Pathogen

• CD20
• CD37
• chronic lymphocytic leukemia
• immunotherapy
• monoclonal antibodies
• non-Hodgkin lymphoma
• tetraspanin

• Antibodies, Monoclonal/therapeutic use
• Antigens, Neoplasm/immunology
• Antigens, Neoplasm/metabolism
• Antineoplastic Agents, Immunological/therapeutic use
• B-Lymphocytes/immunology
• B-Lymphocytes/metabolism
• B-Lymphocytes/pathology
• Humans
• Immunotherapy/methods
• Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy
• Leukemia, Lymphocytic, Chronic, B-Cell/immunology
• Leukemia, Lymphocytic, Chronic, B-Cell/metabolism
• Lymphoma, B-Cell/drug therapy
• Lymphoma, B-Cell/immunology
• Lymphoma, B-Cell/metabolism
• Receptors, Chimeric Antigen/immunology
• Receptors, Chimeric Antigen/metabolism
• Tetraspanins/immunology
• Tetraspanins/metabolism

• Antiproliferative
• Apoptosis
• Cell cycle
• Cytotoxicity
• Migration and TNBC

The mechanisms driving the development of extracapillary lesions in focal segmental glomerulosclerosis (FSGS) and crescentic glomerulonephritis (CGN) remain poorly understood. A key question is how parietal epithelial cells (PECs) invade glomerular capillaries, thereby promoting injury and kidney failure. Here we show that expression of the tetraspanin CD9 increases markedly in PECs in mouse models of CGN and FSGS, and in kidneys from individuals diagnosed with these diseases. Cd9 gene targeting in PECs prevents glomerular damage in CGN and FSGS mouse models. Mechanistically, CD9 deficiency prevents the oriented migration of PECs into the glomerular tuft and their acquisition of CD44 and β1 integrin expression. These findings highlight a critical role for de novo expression of CD9 as a common pathogenic switch driving the PEC phenotype in CGN and FSGS, while offering a potential therapeutic avenue to treat these conditions.

In both focal segmental glomerulosclerosis (FSGS) and crescentic glomerulonephritis (CGN), kidney injury is characterised by the invasion of glomerular tufts by parietal epithelial cells (PECs). Here Lazareth et al. identify the tetraspanin CD9 as a key regulator of PEC migration, and find its upregulation in FSGS and CGN contributes to kidney injury in both diseases.

We investigated the prognostic significance of CD9 expression in tumor cells of patients with invasive lobular carcinoma (ILC).

CD9 expression was evaluated by immunohistochemistry in 113 ILC tissue samples. Correlation of CD9 expression with the patients' clinicopathological parameters and overall survival was assessed.

CD9 expression was detected in 48 (42.5%) ILC patients. However, no significant relation could be determined between CD9 expression and the clinicopathological parameters of the patient including tumor size, lymph node metastasis, lymphovascular invasion, histologic grade, expression of hormone receptors, human epidermal growth factor receptor 2 status, and Ki-67 labeling index. Patients with CD9 expression had worse overall survival (p = 0.051) and disease-free survival (DFS, p = 0.014) compared to patients without CD9 expression. Multivariate analysis revealed that CD9 expression was an independent prognostic factor for DFS (p = 0.049).

CD9 expression in tumor cells could be a significant prognostic marker in patients with ILC.

• Breast neoplasms
• CD9 protein, human
• Immunohistochemistry
• Lobular carcinoma
• Prognosis

The tetraspanin CD9 is expressed by all the major subsets of leukocytes (B cells, CD4⁺ T cells, CD8⁺ T cells, natural killer cells, granulocytes, monocytes and macrophages, and immature and mature dendritic cells) and also at a high level by endothelial cells. As a typical member of the tetraspanin superfamily, a prominent feature of CD9 is its propensity to engage in a multitude of interactions with other tetraspanins as well as with different transmembrane and intracellular proteins within the context of defined membranal domains termed tetraspanin-enriched microdomains (TEMs). Through these associations, CD9 influences many cellular activities in the different subtypes of leukocytes and in endothelial cells, including intracellular signaling, proliferation, activation, survival, migration, invasion, adhesion, and diapedesis. Several excellent reviews have already covered the topic of how tetraspanins, including CD9, regulate these cellular processes in the different cells of the immune system. In this mini-review, however, we will focus particularly on describing and discussing the regulatory effects exerted by CD9 on different adhesion molecules that play pivotal roles in the physiology of leukocytes and endothelial cells, with a particular emphasis in the regulation of adhesion molecules of the integrin and immunoglobulin superfamilies.

• ADAM17
• CD9
• ICAM1
• activated leukocyte cell adhesion molecule
• integrins
• lymphocyte function-associated antigen 1
• tetraspanins
• very late activation antigen 4

Tetraspanins are a family of proteins with four transmembrane domains that associate between themselves and cluster with other partner proteins, conforming a distinct class of membrane domains, the tetraspanin-enriched microdomains (TEMs). These TEMs constitute macromolecular signaling platforms that regulate key processes in several cellular settings controlling signaling thresholds and avidity of receptors. In this study, we investigated the role of CD9, a tetraspanin that regulates major biological processes such as cell migration and immunological responses, in two mouse models of colitis that have been used to study the pathogenesis of inflammatory bowel disease (IBD). Previous in vitro studies revealed an important role in the interaction of leukocytes with inflamed endothelium, but in vivo evidence of the involvement of CD9 in inflammatory diseases is scarce. Here, we studied the role of CD9 in the pathogenesis of colitis in vivo. Colitis was induced by administration of dextran sodium sulfate (DSS), a chemical colitogen that causes epithelial disruption and intestinal inflammation. CD9^−/− mice showed less severe colitis than wild-type counterparts upon exposure to DSS (2% solution) and enhanced survival in response to a lethal DSS dose (4%). Decreased neutrophil and macrophage cell infiltration was observed in colonic tissue from CD9^−/− animals, in accordance with their lower serum levels of TNF-α, IL-6, and other proinflammatory cytokines in the colon. The specific role of CD9 in IBD was further dissected by transfer of CD4⁺ CD45RB^hi naive T cells into the Rag1^−/− mouse colitis model. However, no significant differences were observed in these settings between both groups, ruling out a role for CD9 in IBD in the lymphoid compartment. Experiments with bone marrow chimeras revealed that CD9 in the non-hematopoietic compartment is involved in colon injury and limits the proliferation of epithelial cells. Our data indicate that CD9 in non-hematopoietic cells plays an important role in colitis by limiting epithelial cell proliferation. Future strategies to repress CD9 expression may be of therapeutic benefit in the treatment of IBD.

• CD9
• colitis
• dextran sodium sulfate
• mucosal healing
• tetraspanins

• biomarker
• circulating tumor cells (CTCs)
• exosome
• extracellular vesicle
• prostate cancer

• Biomarkers, Tumor/analysis
• Biomarkers, Tumor/blood
• Decision Support Techniques
• Extracellular Vesicles/metabolism
• Extracellular Vesicles/pathology
• Humans
• Male
• Neoplasm Staging
• Neoplastic Cells, Circulating/pathology
• Patient Selection
• Precision Medicine/methods
• Prostatic Neoplasms/blood
• Prostatic Neoplasms/pathology
• Prostatic Neoplasms/therapy

Tetraspanins are molecular scaffolds that distribute proteins into highly organized microdomains consisting of adhesion, signaling, and adaptor proteins. Many reports have identified interactions between tetraspanins and signaling molecules, finding unique downstream cellular consequences. In this review, we will explore these interactions as well as the specific cellular responses to signal activation, focusing on tetraspanin regulation of adhesion-mediated (integrins/FAK), receptor-mediated (EGFR, TNF-α, c-Met, c-Kit), and intracellular signaling (PKC, PI4K, β-catenin). Additionally, we will summarize our current understanding for how tetraspanin post-translational modifications (palmitoylation, N-linked glycosylation, and ubiquitination) can regulate signal propagation. Many of the studies outlined in this review suggest that tetraspanins offer a potential therapeutic target to modulate aberrant signal transduction pathways that directly impact a host of cellular behaviors and disease states.

• adhesion-mediated signaling
• receptor-mediated signal transduction
• signal transduction
• tetraspanin-enriched microdomains
• tetraspanins

• CD151
• CD81
• CD82
• CD9
• ErbB ligands
• ErbB receptors
• Tetraspanins

• CD9
• biomarker
• glioblastoma stem cells
• neural stem cells
• tetraspanin

• Animals
• Biomarkers, Tumor/genetics
• Biomarkers, Tumor/metabolism
• Blotting, Western
• Brain Neoplasms/genetics
• Brain Neoplasms/metabolism
• Brain Neoplasms/pathology
• Cell Line, Tumor
• Cell Proliferation/genetics
• Cell Survival/genetics
• Gene Expression Profiling/methods
• Gene Expression Regulation, Neoplastic
• Glioblastoma/genetics
• Glioblastoma/metabolism
• Glioblastoma/pathology
• Humans
• Neoplastic Stem Cells/metabolism
• Organ Culture Techniques
• RNA Interference
• Rats, Nude
• Reverse Transcriptase Polymerase Chain Reaction
• Survival Analysis
• Tetraspanin 29/genetics
• Tetraspanin 29/metabolism
• Transplantation, Heterologous
• Up-Regulation

• OD000008-007 NIH HHS

• Clathrin
• Dorsal ruffle
• Lipid rafts
• Receptor signaling
• Signal transduction
• Spatial organization
• Tetraspanin

There are 33 human tetraspanin proteins, emerging as key players in malignancy, the immune system, fertilization, cellular signaling, adhesion, morphology, motility, proliferation, and tumor invasion. CD9, a member of the tetraspanin family, associates with and influences a variety of cell-surface molecules. Through these interactions, CD9 modifies multiple cellular events, including adhesion, migration, proliferation, and survival. CD9 is therefore considered to play a role in several stages during cancer development. Reduced CD9 expression is generally related to venous vessel invasion and metastasis as well as poor prognosis. We found that treatment of mice bearing human gastric cancer cells with anti-CD9 antibody successfully inhibited tumor progression via antiproliferative, proapoptotic, and antiangiogenic effects, strongly indicating that CD9 is a possible therapeutic target in patients with gastric cancer. Here, we describe the possibility of CD9 manipulation as a novel therapeutic strategy in gastric cancer, which still shows poor prognosis.

• CD9
• Tetraspanin
• Gastric cancer
• Tumorigenicity
• Therapeutic target

• Animals
• Antibodies/adverse effects
• Antibodies/therapeutic use
• Antineoplastic Agents/adverse effects
• Antineoplastic Agents/therapeutic use
• Humans
• Molecular Targeted Therapy
• Signal Transduction/drug effects
• Stomach Neoplasms/drug therapy
• Stomach Neoplasms/immunology
• Stomach Neoplasms/metabolism
• Stomach Neoplasms/pathology
• Tetraspanin 29/antagonists & inhibitors
• Tetraspanin 29/immunology
• Tetraspanin 29/metabolism
• Treatment Outcome

Niacin has been demonstrated to activate a PI3K/Akt signaling cascade to prevent brain damage after stroke and UV-induced skin damage; however, the underlying molecular mechanisms for HCA₂-induced Akt activation remain to be elucidated. Using CHO-K1 cells stably expressing HCA₂ and A431 cells, a human epidermoid cell line with high levels of endogenous expression of functional HCA₂ receptors, we first demonstrated that niacin induced a robust Akt phosphorylation at both Thr³⁰⁸ and Ser⁴⁷³ in a time-dependent fashion, with a maximal activation at 5 min and a subsequent reduction to baseline by 30 min through HCA₂, and that the activation was significantly blocked by pertussis toxin. The HCA₂-mediated activation of Akt was also significantly inhibited by the PKC inhibitors GF109203x and Go6983 in both cell lines, by the PDGFR-selective inhibitor tyrphostin A9 in CHO-HCA₂ cells and by the MMP inhibitor GM6001 and EGFR-specific inhibitor AG1478 in A431 cells. These results suggest that the PKC pathway and PDGFR/EGFR transactivation pathway play important roles in HCA₂-mediated Akt activation. Further investigation indicated that PI3K and the G_βγ subunit were likely to play an essential role in HCA₂-induced Akt activation. Moreover, Immunobloting analyses using an antibody that recognizes p70S6K1 phosphorylated at Thr³⁸⁹ showed that niacin evoked p70S6K1 activation via the PI3K/Akt pathway. The results of our study provide new insight into the signaling pathways involved in HCA₂ activation.

• Animals
• CHO Cells
• Cricetinae
• Cricetulus
• Enzyme Activation/drug effects
• ErbB Receptors/genetics
• ErbB Receptors/metabolism
• Humans
• Mice
• Niacin/pharmacology
• Phosphatidylinositol 3-Kinases/genetics
• Phosphatidylinositol 3-Kinases/metabolism
• Protein Kinase C/genetics
• Protein Kinase C/metabolism
• Proto-Oncogene Proteins c-akt/genetics
• Proto-Oncogene Proteins c-akt/metabolism
• Receptors, G-Protein-Coupled/genetics
• Receptors, G-Protein-Coupled/metabolism
• Receptors, Nicotinic/genetics
• Receptors, Nicotinic/metabolism
• Signal Transduction/drug effects
• Transcriptional Activation/drug effects

• K22 AA020303 NIAAA NIH HHS

The most prevalent cardiovascular diseases arise from alterations in vascular smooth muscle cell (VSMC) morphology and function. Tetraspanin CD9 has been previously implicated in regulating vascular pathologies; however, insight into how CD9 may regulate adverse VSMC phenotypes has not been provided. We utilized a human model of aortic smooth muscle cells to understand the consequences of CD9 deficiency on VSMC phenotypes. Upon knocking down CD9, the cells developed an abnormally small and rounded morphology. We determined that this morphological change was due to a lack of typical parallel actin arrangement. We also found similar total RhoA but decreased GTP-bound (active) RhoA levels in CD9 deficient cells. As a result, cells lacking a full complement of CD9 were less contractile than their control treated counterparts. Upon restoration of RhoA activity in the CD9 deficient cells, the phenotype was reversed and cell contraction was restored. Conversely, inhibition of RhoA activity in the control cells mimicked the CD9-deficient cell phenotype. Thus, alteration in CD9 expression was sufficient to profoundly disrupt cellular actin arrangement and endogenous cell contraction by interfering with RhoA signaling. This study provides insight into how CD9 may regulate previously described vascular smooth muscle cell pathophysiology.

• Branch fusion
• Drosophila
• Fusion cells
• Gene expression
• Trachea

• Autocrine singaling
• Basolateral trafficking
• EGFR, epidermal growth factor receptor
• Ménétrier's disease
• Polarized epithelial cells
• TGFA, transforming growth factor alpha

• CD9
• Cell invasion
• Epidermal growth factor receptor
• MMP-9
• Matrix metalloproteinase
• Tetraspanin

Prognostic biomarkers aim to improve on the current inadequate method of histological assessment to identify patients with oral epithelial dysplasia at greatest risk of malignant transformation. We aimed to assess the prognostic ability of six protein biomarkers linked to the epidermal growth factor receptor (EGFR) pathway, including three tetraspanins, in a large multicentre oral dysplasia cohort.

One hundred and forty-eight cases with varying degrees of epithelial dysplasia underwent immunohistochemical assessment for CD9, CD151, CD82, EGFR, Her-2, and COX-2. Scoring was performed independently by two observers. Univariate analyses using both logistic and Cox regression models and a multivariate regression were performed.

Malignant progression was significantly greater in those cases with decreased expression of CD9 (P=0.02), and increased expression of CD151 (P=0.02), EGFR (P=0.04), and COX-2 (P=0.003). Histological grade (P=0.0002) and morphology (P=0.03) were also prognostic, whereas smoking and alcohol were not. The optimal combination by backward-variable selection was of histological grade (hazard ratio (HR) 1.64; 95% CI 1.12, 2.40), COX-2 overexpression (HR 1.12; 1.02, 1.24) and CD9 underexpression (HR 0.88; 0.80, 0.97). CD82 and Her-2 demonstrated no prognostic ability.

This is the first study of the expression and prognostic potential of the tetraspanins in oral dysplasia. A combination of certain biomarkers with clinical factors appeared to improve the accuracy of determining the risk of malignancy in individuals with oral dysplasia. These findings may also offer potential new therapeutic approaches for this condition.

• EGFR
• Imaginal disc
• Palmitoylation
• Rhomboid
• Spitz

MiR-7 acts as a tumour suppressor in many cancers and abrogates proliferation of CHO cells in culture. In this study we demonstrate that miR-7 targets key regulators of the G1 to S phase transition, including Skp2 and Psme3, to promote increased levels of p27^KIP and temporary growth arrest of CHO cells in the G1 phase. Simultaneously, the down-regulation of DNA repair-specific proteins via miR-7 including Rad54L, and pro-apoptotic regulators such as p53, combined with the up-regulation of anti-apoptotic factors like p-Akt, promoted cell survival while arrested in G1. Thus miR-7 can co-ordinate the levels of multiple genes and proteins to influence G1 to S phase transition and the apoptotic response in order to maintain cellular homeostasis. This work provides further mechanistic insight into the role of miR-7 as a regulator of cell growth in times of cellular stress.

• Adenosine Triphosphatases/genetics
• Adenosine Triphosphatases/metabolism
• Animals
• Autoantigens/genetics
• Autoantigens/metabolism
• CHO Cells
• Cricetulus
• Cyclin-Dependent Kinase Inhibitor p27/genetics
• Cyclin-Dependent Kinase Inhibitor p27/metabolism
• G1 Phase Cell Cycle Checkpoints/genetics
• Gene Expression Regulation
• Humans
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Proteasome Endopeptidase Complex/genetics
• Proteasome Endopeptidase Complex/metabolism
• Proto-Oncogene Proteins c-akt/genetics
• Proto-Oncogene Proteins c-akt/metabolism
• S-Phase Kinase-Associated Proteins/genetics
• S-Phase Kinase-Associated Proteins/metabolism
• Signal Transduction
• Stress, Physiological
• Tumor Suppressor Protein p53/genetics
• Tumor Suppressor Protein p53/metabolism

To determine how tetraspanin KAI1/CD82, a tumor metastasis suppressor, inhibits cell migration, we assessed which cellular events critical for motility are altered by KAI1/CD82 and how KAI1/CD82 regulates these events. We found that KAI1/CD82-expressing cells typically exhibited elongated cellular tails and diminished lamellipodia. Live imaging demonstrated that the polarized protrusion and retraction of the plasma membrane became deficient upon KAI1/CD82 expression. The deficiency in developing these motility-related cellular events was caused by poor formations of actin cortical network and stress fiber and by aberrant dynamics in actin organization. Rac1 activity was reduced by KAI1/CD82, consistent with the diminution of lamellipodia and actin cortical network; while the growth factor-stimulated RhoA activity was blocked by KAI1/CD82, consistent with the loss of stress fiber and attenuation in cellular retraction. Upon KAI1/CD82 expression, Rac effector cofilin was not enriched at the cell periphery to facilitate lamellipodia formation while Rho kinase exhibited a significantly lower activity leading to less retraction. Phosphatidylinositol 4, 5-biphosphate, which initiates actin polymerization from the plasma membrane, became less detectable at the cell periphery in KAI1/CD82-expressing cells. Moreover, KAI1/CD82-induced phenotypes likely resulted from the suppression of multiple signaling pathways such as integrin and growth factor signaling. In summary, at the cellular level KAI1/CD82 inhibited polarized protrusion and retraction events by disrupting actin reorganization; at the molecular level, KAI1/CD82 deregulated Rac1, RhoA, and their effectors cofilin and Rho kinase by perturbing the plasma membrane lipids.

• Actins/metabolism
• Cell Adhesion/drug effects
• Cell Adhesion/physiology
• Cell Line, Tumor
• Cell Membrane/drug effects
• Cell Membrane/metabolism
• Cell Membrane/physiology
• Cell Movement/drug effects
• Cell Movement/physiology
• Cell Surface Extensions/metabolism
• Cell Surface Extensions/physiology
• Genes, Tumor Suppressor
• HT29 Cells
• Humans
• Integrins/metabolism
• Intercellular Signaling Peptides and Proteins/metabolism
• Kangai-1 Protein/metabolism
• Male
• Membrane Lipids/metabolism
• Phosphatidylinositol 4,5-Diphosphate/pharmacology
• Pseudopodia/drug effects
• Pseudopodia/metabolism
• Pseudopodia/physiology
• Signal Transduction/drug effects
• Stress Fibers/metabolism
• rac1 GTP-Binding Protein/metabolism
• rhoA GTP-Binding Protein/metabolism

• R01 CA096991 NCI NIH HHS
• CA096991 NCI NIH HHS

• tetraspanins
• mmp
• adams
• α-secretases
• shedding
• rip

• ADAM Proteins/metabolism
• Animals
• Humans
• Matrix Metalloproteinases/metabolism
• Membrane Proteins/metabolism
• Peptide Hydrolases/metabolism
• Tetraspanins

• tetraspanins
• cd9
• adam17
• tace
• tnf-α
• icam-1

• ADAM Proteins/genetics
• ADAM Proteins/metabolism
• ADAM Proteins/physiology
• ADAM17 Protein
• Antigens, CD/genetics
• Antigens, CD/metabolism
• Antigens, CD/physiology
• Cell Line
• Endothelial Cells/metabolism
• Gene Silencing
• Humans
• Intercellular Adhesion Molecule-1/metabolism
• Leukocytes/metabolism
• Membrane Glycoproteins/genetics
• Membrane Glycoproteins/metabolism
• Membrane Glycoproteins/physiology
• Tetraspanin 29
• Tumor Necrosis Factor-alpha/metabolism