Gene Summary

Gene:CD82; CD82 molecule
Aliases: R2, 4F9, C33, IA4, ST6, GR15, KAI1, SAR2, TSPAN27
Summary:This metastasis suppressor gene product is a membrane glycoprotein that is a member of the transmembrane 4 superfamily. Expression of this gene has been shown to be downregulated in tumor progression of human cancers and can be activated by p53 through a consensus binding sequence in the promoter. Its expression and that of p53 are strongly correlated, and the loss of expression of these two proteins is associated with poor survival for prostate cancer patients. Two alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:CD82 antigen
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (8)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: CD82 (cancer-related)

Zhang Q, Huang F, Yao Y, et al.
Interaction of transforming growth factor-β-Smads/microRNA-362-3p/CD82 mediated by M2 macrophages promotes the process of epithelial-mesenchymal transition in hepatocellular carcinoma cells.
Cancer Sci. 2019; 110(8):2507-2519 [PubMed] Free Access to Full Article Related Publications
Abnormal tumor microenvironment and the epithelial-mesenchymal transition (EMT) are important features of tumor metastasis. However, it remains unknown how signals can form complicated networks to regulate the sustainability of the EMT process. The aim of our study is to explore the possible interaction between tumor-associated macrophages and tumor cells in the EMT process mediated by microRNA (miR)-362-3p. In this study, we found that by releasing TGF-β, M2 macrophages mediate binding of Smad2/3 to miR-362-3p promoter, leading to overexpression of miR-362-3p. MicroRNA-362-3p maintains EMT by regulating CD82, one of the most important members of the family of tetraspanins. Our finding suggests that miR-362-3p can serve as a core factor mediating cross-talk between the TGF-β pathway in tumor-associated macrophages and tetraspanins in tumor cells, and thus facilitates the EMT process.

Osmanov YI, Kogan EA, Rapoport LM, et al.
[Markers of stem cells and their prognostic values for urothelial carcinomas of the urinary tract].
Urologiia. 2019; (2):40-49 [PubMed] Related Publications
The fundamental question about the origin of cancer stem cells of urothelial carcinomas with luminal remains open. So far, no convincing evidence has been found to determine whether these events occur in a single cell, presumably basal, or are realized in different precursor cells of the urothelium. The potential of a number of potential stem markers as cancer stem cells in urothelial carcinomas and their prognostic significance are currently being investigated.
AIM: Our aim was to carry out a comparative analysis of the expression of stem markers in the molecular subtypes of urothelial carcinomas, including ALDH1A1, CXCR4, CD24, CD82, CD105, CD133, NANOG, OCT4 and SOX-2. In addition, the relationship between the pattern of expression and the pathological features of the tumor was determined.
PATIENTS AND METHODS: Surgical specimens from 196 patients with a diagnosis of urothelial carcinoma of the renal pelvis and bladder were studied. Immunohistochemical study was performed on paraffin sections using the standard protocol. Antibodies against ALDH1A1, CD82, CD133, CXCR4, NANOG, OCT4, SOX2 ("Abcam"), CD24, CD105 ("Invitrogen"), CD31, CD34 ("Novocastra") were used.
RESULTS: The stem cell markers used in the study were expressed in all molecular subtypes of urothelial carcinoma and there were no differences in frequency and intensity of expression between different phenotypes. However, the frequency and intensity of expression of the markers correlated with the tumor stage and the grade of cellular anaplasia.
CONCLUSION: Our results confirm that cancer stem cells with basal phenotype are not an exclusive subpopulation in urothelial tumors. Other progenitor cells with the immunophenotype of intermediate and/or umbrella cells can serve as cancer stem cells. These features of the expression in cancer stem cell markers will allow to develop new approaches to the treatment of urothelial carcinomas.

Taş İ, Han J, Park SY, et al.
Physciosporin suppresses the proliferation, motility and tumourigenesis of colorectal cancer cells.
Phytomedicine. 2019; 56:10-20 [PubMed] Related Publications
BACKGROUND: Lichens, which represent symbiotic associations of fungi and algae, are potential sources of numerous natural products. Physciosporin (PHY) is a potent secondary metabolite found in lichens and was recently reported to inhibit the motility of lung cancer cells via novel mechanisms.
PURPOSE: The present study investigated the anticancer potential of PHY on colorectal cancer (CRC) cells.
METHODS: PHY was isolated from lichen extract by preparative TLC. The effect of PHY on cell viability, motility and tumourigenicity was elucidated by MTT assay, hoechst staining, flow cytometric analysis, transwell invasion and migration assay, soft agar colony formation assay, Western blotting, qRT-PCR and PCR array in vitro as well as tumorigenicity study in vivo.
RESULTS: PHY decreased the viability of various CRC cell lines (Caco2, CT26, DLD1, HCT116 and SW620). Moreover, PHY elicited cytotoxic effects by inducing apoptosis at toxic concentrations. At non-toxic concentrations, PHY dose-dependently suppressed the invasion, migration and colony formation of CRC cells. PHY inhibited the motility of CRC cells by suppressing epithelial-mesenchymal transition and downregulating actin-based motility markers. In addition, PHY downregulated β-catenin and its downstream target genes cyclin-D1 and c-Myc. Moreover, PHY modulated KAI1 C-terminal-interacting tetraspanin and KAI1 expression, and downregulated the downstream transcription factors c-jun and c-fos. Finally, PHY administration showed considerable bioavailability and effectively decreased the growth of CRC xenografts in mice without causing toxicity.
CONCLUSION: PHY suppresses the growth and motility of CRC cells via novel mechanisms.

Wang X, Zhong W, Bu J, et al.
Exosomal protein CD82 as a diagnostic biomarker for precision medicine for breast cancer.
Mol Carcinog. 2019; 58(5):674-685 [PubMed] Related Publications
CD82, a member of the tetraspanin superfamily, has been proposed to exert its activity via tetra-transmembrane protein enriched microdomains (TEMs) in exosomes. The present study aimed to explore the potential of the exosome protein CD82 in diagnosing breast cancers of all stages and various histological subtypes in patients. The results strongly suggest that CD82 expression in breast cancer tissue was significantly lower than that in healthy and benign breast disease tissues. There was a significant negative correlation between CD82 expression in tissues and CD82 content in exosomes, which indicated that CD82 expression was redistributed from tissues to the blood with the development and metastasis of breast cancer.

Wang Y, Yang R, Wang X, et al.
Evaluation of the correlation of vasculogenic mimicry, Notch4, DLL4, and KAI1/CD82 in the prediction of metastasis and prognosis in non-small cell lung cancer.
Medicine (Baltimore). 2018; 97(52):e13817 [PubMed] Free Access to Full Article Related Publications
Vasculogenic mimicry (VM) is a new blood supply style in tumors and has long been treated as a useful factor in malignant tumor metastasis and prognosis. Notch4 (a marker of Notch signaling pathway receptors), DLL4 (a marker of Notch signaling pathway ligands) and KAI1/CD82 (a suppressor gene of tumor metastasis) are all effective predictive factors for tumor metastasis. In this study, we analyzed correlations among VM, Notch4, DLL4, and KAI1/CD82 in non-small cell lung cancer (NSCLC), and their respective associations with patients' clinicopathological parameters and survival rate in NSCLC.Positive rates of VM, Notch4, DLL4, and KAI1/CD82 in 189 whole NSCLC specimens were detected by histochemical and immunohistochemical staining. Moreover, patients' clinicopathological information was also collected.Positive rates of VM, Notch4, and DLL4 were significantly higher, and levels of KAI1/CD82 were significantly lower in NSCLC than in normal lung tissues. Positive rates of VM, Notch4, and DLL4 were positively associated with tumor size, lymph node metastasis (LNM), distant metastasis (DM) and tumor-node-metastasis (TNM) stage, and inversely with patients, overall survival (OS) time and positive rate of DLL4 were positively associated with tumor grade. Levels of KAI1/CD82 were negatively associated with tumor size, LNM, DM, and TNM stage. The KAI1/CD82+ subgroup had significantly longer OS time than did the KAI1/CD82- subgroup. In multivariate analysis, high VM, Notch4, DLL4 levels, tumor size, LNM, DM, TNM stage, and low KAI1/CD82 levels were potential to be independent prognostic factors for overall survival time (OST) in NSCLC patients.VM and the expression of Notch4, DLL4, and KAI1/CD82 represent promising markers for tumor metastasis and prognosis, and maybe potential therapeutic targets for NSCLC.

Nordor AV, Bellet D, Siwo GH
Cancer-malaria: hidden connections.
Open Biol. 2018; 8(10) [PubMed] Free Access to Full Article Related Publications
Cancer and malaria exemplify two maladies historically assigned to separated research spaces. Cancer, on the one hand, ranks among the top priorities in the research agenda of developed countries. Its rise is mostly explained by the ageing of these populations and linked to environment and lifestyle. Malaria, on the other hand, represents a major health burden for developing countries in the Southern Hemisphere. These two diseases also belong to separate fields of medicine: non-communicable diseases for cancer and communicable diseases for malaria.

Kussaibi H, Alkharsah KR, Altamimi D, et al.
Alternative splicing is an important mechanism behind KAI1 loss of function in breast cancer patients from Saudi Arabia.
Breast Cancer Res Treat. 2019; 173(1):87-91 [PubMed] Related Publications
PURPOSE: KAI1 (also called CD82) is a metastasis suppressor gene known to be downregulated in breast cancer and other solid tumors. The downregulation of KAI1 or loss of its function is usually associated with bad prognosis. The mechanism behind KAI1 loss of function is complex. In this study, we investigated "alternative splicing" as a possible mechanism that underlies KAI1 loss of function in breast cancer patients from a tertiary hospital in Saudi Arabia.
METHODS: Expression of KAI1 was studied in FFPE breast cancer and control tissue sections by IHC using two different antibodies targeting different domains of the protein. The TS82B antibody targets the extracellular loop, which constitutes most of the protein, while the second EPR4112 antibody targets the C-terminal intracellular domain of the protein.
RESULTS: Out of 90 breast cancer samples, 67% showed loss of KAI1 expression. The remaining 33% showed KAI1 expression with (TS82B) antibody; however, the protein was detected in only 11% of cancers when using the antibody (EPR4112) indicating a truncation of the protein at the C-terminus (truncated-KAI1) in 22% of the studied cancer samples. A significant correlation was found between truncated-KAI1 expression and advanced cancer stage (association with lymph node metastasis, P value 0.008).
CONCLUSION: Alternative splicing is an important mechanism underlying KAI1 loss of function in breast cancer, and it is associated with bad prognosis (advanced cancer stage).

Ci H, Xu Z, Xu J, et al.
Expressions of KAI1 and E-cadherin in nonsmall cell lung cancer and their correlation with vasculogenic mimicry.
Medicine (Baltimore). 2018; 97(40):e12293 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Metastasis and recurrence are the most common reasons for treatment failure of nonsmall cell lung cancer (NSCLC). Vasculogenic mimicry (VM, new blood supply formation in malignant tumors), E-Cadherin (a calcium-dependent transmembrane glycoprotein that mediates intercellular adhesion), KAI1 (a suppressor gene of tumor metastasis) are all valuable factors for metastasis and prognosis in diverse common human cancers. However, the correlation of VM, E-Cadherin, and KAI1 in NSCLC is still unclear. In this study, we analyzed the correlations among these factors as well as their respective correlations with clinicopathological parameters and survival in NSCLC.
METHODS: The level of VM, E-Cadherin, and KAI1 in 163 tissue samples of NSCLC was examined by immunhistochemistry. Clinical data were also collected.
RESULTS: Levels of VM was significantly higher, and levels of KAI1 and E-Cadherin significantly lower in NSCLC tissues than in normal lung tissues. Levels of VM were positively associated with lymph node metastasis (LNM), size, grade, and tumor node metastasis (TNM) stages, and negatively associated with patients' overall survival (OS). Levels of KAI1 and E-Cadherin were negatively correlated with LNM, size, grade, and TNM stage, and positively associated with patients' OS. In multivariate analysis, high levels of VM, E-Cadherin, and KAI1, as well as TNM stages were independently correlated with lower OS in patients with NSCLC.
CONCLUSION: VM and the expression of E-Cadherin and KAI1 may represent promising metastatic and prognostic biomarkers, as well as potential therapeutic targets for NSCLC.

Choi D, Montermini L, Kim DK, et al.
The Impact of Oncogenic EGFRvIII on the Proteome of Extracellular Vesicles Released from Glioblastoma Cells.
Mol Cell Proteomics. 2018; 17(10):1948-1964 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Glioblastoma multiforme (GBM) is a highly aggressive and heterogeneous form of primary brain tumors, driven by a complex repertoire of oncogenic alterations, including the constitutively active epidermal growth factor receptor (EGFRvIII). EGFRvIII impacts both cell-intrinsic and non-cell autonomous aspects of GBM progression, including cell invasion, angiogenesis and modulation of the tumor microenvironment. This is, at least in part, attributable to the release and intercellular trafficking of extracellular vesicles (EVs), heterogeneous membrane structures containing multiple bioactive macromolecules. Here we analyzed the impact of EGFRvIII on the profile of glioma EVs using isogenic tumor cell lines, in which this oncogene exhibits a strong transforming activity. We observed that EGFRvIII expression alters the expression of EV-regulating genes (vesiculome) and EV properties, including their protein composition. Using mass spectrometry, quantitative proteomic analysis and Gene Ontology terms filters, we observed that EVs released by EGFRvIII-transformed cells were enriched for extracellular exosome and focal adhesion related proteins. Among them, we validated the association of pro-invasive proteins (CD44, BSG, CD151) with EVs of EGFRvIII expressing glioma cells, and downregulation of exosomal markers (CD81 and CD82) relative to EVs of EGFRvIII-negative cells. Nano-flow cytometry revealed that the EV output from individual glioma cell lines was highly heterogeneous, such that only a fraction of vesicles contained specific proteins (including EGFRvIII). Notably, cells expressing EGFRvIII released EVs double positive for CD44/BSG, and these proteins also colocalized in cellular filopodia. We also detected the expression of homophilic adhesion molecules and increased homologous EV uptake by EGFRvIII-positive glioma cells. These results suggest that oncogenic EGFRvIII reprograms the proteome and uptake of GBM-related EVs, a notion with considerable implications for their biological activity and properties relevant for the development of EV-based cancer biomarkers.

Pehkonen H, Lento M, von Nandelstadh P, et al.
Liprin-α1 modulates cancer cell signaling by transmembrane protein CD82 in adhesive membrane domains linked to cytoskeleton.
Cell Commun Signal. 2018; 16(1):41 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
BACKGROUND: PPFIA1 is located at the 11q13 region commonly amplified in cancer. The protein liprin-α1 encoded by PPF1A1 contributes to the adhesive and invasive structures of cytoskeletal elements and is located at the invadosomes in cancer cells. However, the precise mechanism of liprin-α1 function in cancer progression has remained elusive.
METHODS: Invasion regulating activity of liprin-α1 was examined by analyzing the functions of squamous cell carcinoma of head and neck (HNSCC) cell lines in three-dimensional collagen I after RNAi mediated gene knockdown. Transcriptome profiling and Gene Set Enrichment Analysis from HNSCC and breast cancer cells were used to identify expression changes relevant to specific cellular localizations, biological processes and signaling pathways after PPFIA1 knockdown. The significance of the results was assessed by relevant statistical methods (Wald and Benjamini-Hochberg). Localization of proteins associated to liprin-α1 was studied by immunofluorescence in 2D and 3D conditions. The association of PPFIA1 amplification to HNSCC patient survival was explored using The Cancer Genome Atlas data.
RESULTS: In this study, we show that liprin-α1 regulates biological processes related to membrane microdomains in breast carcinoma, as well as protein trafficking, cell-cell and cell-substrate contacts in HNSCC cell lines cultured in three-dimensional matrix. Importantly, we show that in all these cancer cells liprin-α1 knockdown leads to the upregulation of transmembrane protein CD82, which is a suppressor of metastasis in several solid tumors.
CONCLUSIONS: Our results provide novel information regarding the function of liprin-α1 in biological processes essential in cancer progression. The results reveal liprin-α1 as a novel regulator of CD82, linking liprin-α1 to the cancer cell invasion and metastasis pathways.

Luan M, He X, Huang X, et al.
The peptide mimicking small extracellular loop domain of CD82 inhibits tumor cell migration, adhesion and induces apoptosis by inhibiting integrin mediated signaling.
Biochem Biophys Res Commun. 2018; 503(4):2206-2211 [PubMed] Related Publications
Within the extracellular domains of metastasis suppressor CD82, the large extracellular loop (EC2) has received much of the attention and its structure and function have been studied in detail. However, little attention has been given to the small extracellular loop (EC1 domain). To investigate the function role of EC1 in metastasis suppression of CD82, the peptide mimicking EC1 amino acid sequence (EC1-mP) was synthesized and its effect on cancer cells behavior was examined. Here, we reported that EC1-mP strongly inhibited cancer cell migration in vitro, attnuated the ability of cancer cells adhesion to fibronectin, and induced the apoptosis. Furthermore, the EC1-mP was showed to supprese the expressions of integrins α5 and β1, as well as decreased the phosphorylation of FAK and expression of ILK in SW620 cells. Taken together, these results demonstrate that this small peptide has the functional role of CD82 intact molecule. This novel finding will improve our understanding of the mechanism by which CD82 inhibits metastasis, and suggested that EC1 mimic peptide may be a promising candidate for developing anti-metastasis drugs.

Murray NP, Aedo S, Fuentealba C, Reyes E
10 Year Biochemical Failure Free Survival of Men with CD82 Positive Primary Circulating Prostate Cells Treated by Radical Prostatectomy
Asian Pac J Cancer Prev. 2018; 19(6):1577-1583 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Objective: The biological characteristics of circulating prostate cells (CPCs) are probably more important than their mere presence. CD82 is a tumor suppressor, we present the outcome of radical prostatectomy (RP) in men with CD82 positive CPCs. Methods and Patients: consecutive men treated with RP were studied, age, total PSA, Gleason, stage, the presence of extra-capsular extension, positive surgical margens and infiltration of the seminal vesicles and lymph nodes were registered. Biochemical failure was defined as a PSA >0.2ng/ml. Immediately before the RP, 8ml of venous blood was taken to detect CPCs. Mononuclear cells were separated using differential gel centrifugation and CPCs identified using immunocytochemistry with anti-PSA and anti-CD82. The men were divided into three groups; 1) CPC (-), 2) CPC (+) CD82 (+) and 3) CPC (+) CD82 (-). The groups were compared with respect to clinical-pathological findings and biochemical free survival using Kaplan Meier and Cox regression models. Results: 285 men, mean age 65.9 years participated, 61 (21%) were CPC (-); 57 (20%) were CPC (+) CD82 (+) and 167 (59%) were CPC (+) CD82 (-). Group 1 had low grade small volume cancer, in Group 2, low grade but a larger volume than Group 1 and Group 3 high grade cancer. Kaplan Meier biochemical free survival curves at 36, 60 and 120 months were; Group 1 98%, 96% and 90%; for Group 2 93%, 93% and 69% and for Group 3 62%, 44% and 16% respectively. Conclusions: Kaplan Meier survival curves for Group 1 and Group 2 were similar, although Group 2 men had higher PSA values, more advanced staging but a similar Gleason score. Group 3 men had a worse prognosis. The results support that biological characteristics of CPCs are more important than their mere presence identifying men with a high risk of biochemical failure.

Wang G, Zhang L, Zhou Y, et al.
KAI1/CD82 Genetically Engineered Endothelial Progenitor Cells Inhibit Metastasis of Human Nasopharyngeal Carcinoma in a Mouse Model.
Med Sci Monit. 2018; 24:3146-3152 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
BACKGROUND Endothelial progenitor cells (EPCs) are regarded as promising targeted vectors for delivering therapeutic genes or agents in cancer therapy. The purpose of this study was to investigate the role of intravenously administered KAI1/CD82 genetically transduced EPCs in the tumorigenesis and metastasis of nasopharyngeal carcinoma (NPC). MATERIAL AND METHODS EPCs were isolated from human umbilical cord blood, expanded in culture, and stably transduced with lentiviral vectors expressing KAI1/CD82. The KAI1/CD82 EPCs were injected intravenously into nude mice bearing human NPC xenografts. Tumor growth and the incidence of liver and lung metastases were observed. Expression of KAI1/CD82 was determined by immunofluorescent staining. RESULTS The NPC model was successfully established. Tumor growth was not suppressed when mice were injected with KAI1/CD82 EPCs (KAI1/CD82 EPCs group) compared with when non-transduced EPCs was present (EPCs group) or the control (1.485±0.234, 1.388±0.204, and 1.487±0.223g, respectively; P>0.05). However, the incidence of lung metastasis was significantly reduced in the KAI1/CD82+ EPCs group compared with the EPCs group and the control group (10%, 55% and 45%, respectively; P=0.005), and there was a significant decrease in the number of metastatic foci on the lung surface (17.50±3.54, 34.27±5.35, and 38.44±9.63 respectively; P=0.007). Moreover, KAI1/CD82 was expressed in lung metastatic foci of the KAI1/CD82 EPCs group, but not in the EPCs group and control group. CONCLUSIONS EPCs can be used as a delivery vehicle for suppressor genes KAI1/CD82 to NPC, and the migration of KAI1/CD82 genetically engineered EPCs can inhibit NPC lung metastasis in a mouse model.

Yunusova NV, Tugutova EA, Tamkovich SN, Kondakova IV
[The role of exosomal tetraspanins and proteases in tumor progression].
Biomed Khim. 2018; 64(2):123-133 [PubMed] Related Publications
Major (CD9, CD63, CD81) and others (CD82, CD151, Tspan8) tetraspanins are widely represented in exosomes, where they interact with various proteins and form functional tetraspanin complexes. Tetraspanin complexes include proteases. Tetraspanin-associated exosomal proteases (ADAM proteases, MMPs, EMMPRIN) play an important role in the processes of cell motility, migration, invasion and formation of metastases. Also, a significant contribution to tumor progression is made by proteases that are not associated with tetraspanins. They destabilize intercellular contacts, promote migration and invasion of tumor cells, participate in the regulation of the expression IGF-I, VEGF and transcription factors activation/deactivation. The role of other proteases of exosomes in the processes of tumor progression is being clarified.

Long J, Luo J, Yin X
MiR-338-5p promotes the growth and metastasis of malignant melanoma cells via targeting CD82.
Biomed Pharmacother. 2018; 102:1195-1202 [PubMed] Related Publications
BACKGROUND: Melanoma has been a severe threat to human health, microRNAs play vital roles in the oncogenesis and progression of cancers. In this report, the roles and mechanism of miR-338-5p were investigated in the development of melanoma.
MATERIALS AND METHODS: A total of 46 melanoma samples and 25 normal nevi samples were collected. Real time reverse transcriptase polymerase chain reaction and Western blot were used to detect the expression of mRNA and protein. Cell proliferation, migration and invasion were detected by CCK-8 assay, wound healing assay and transwell assay. A luciferase reporter assay was performed to identify whether miR-338-5p targeted the 3'-UTR of CD82 mRNA. Nude mice experiment was applied to determine the effect of miR-338-5p on melanoma development.
RESULTS: miR-338-5p expression was upregulated in melanoma tissues and cell lines. MiR-338-5p level in tumor tissues was correlated with tumor stage, metastasis and patients survival rate. High miR-338-5p expression promoted the proliferation and metastasis of A375 cells. The inhibition of miR-338-5p suppressed growth and metastasis of A375 cells. CD82 mRNA was identified as a direct target mRNA of miR-338-5p. MiR-338-5p could regulate the expression of CD82 protein. MiR-338-5p mimics improved the growth and metastasis of A375 cells transfected with CD82 vector, while inhibition of miR-338-5p attenuated the pro-tumor function of si-CD82 in A375 cells. Lastly, the high level of miR-338-5p promoted xenograft tumor growth in vivo.
CONCLUSION: The oncogenic mechanisms of miR-338-5p are elucidated on the procession of melanoma. Downregulation of miR-338-5p maybe a vital therapeutic strategy against melanoma.

Prabhu VV, Devaraj SN
KAI1/CD82, Metastasis Suppressor Gene as a Therapeutic Target for Non-Small-Cell Lung Carcinoma.
J Environ Pathol Toxicol Oncol. 2017; 36(3):269-275 [PubMed] Related Publications
Lung cancer is the most frequent malignancy and the leading cause of cancer-related death worldwide; it is the second most common cancer, comprising 1.69 million deaths worldwide per year. Among these, 85% of lung cancers are non-small-cell lung carcinoma (NSCLC). Metastasis is common in NSCLC patients and are responsible for most deaths. Kang-Ai 1 (KAI1), a tumor metastasis suppressor gene also known as Cluster of Differentiation 82 (CD82), is a member of the membrane tetraspanin protein family, which are capable of inhibiting the metastatic process in NSCLC. KAI1/CD82 suppresses metastasis via multiple mechanisms regulating inhibition of cell motility, adhesion, fusion, and proliferation. KAI1 may attenuate signaling to shut down metastatic colonization through attenuation of epidermal growth factor receptor (EGFR) signaling and inhibition of the Wnt signaling pathways. In this review, we focus on the differential expression of KAI1/CD82, a tumor metastasis suppressor gene that can inhibit cancer invasion and cell metastasis during NSCLC. The differential expression of KAI1/CD82 could prove to be of novel therapeutic significance in treating malignant tumors and in reducing their metastatic potential.

Bae WK, Hong CS, Park MR, et al.
TAp73 inhibits cell invasion and migration by directly activating KAI1 expression in colorectal carcinoma.
Cancer Lett. 2018; 415:106-116 [PubMed] Related Publications
p73 is a member of the p53 family of transcription factors and, like p53, plays a role as a tumor suppressor. p73 is involved in development, proliferation, apoptosis and metastasis. However, the precise molecular mechanisms underlying its function in inhibiting metastasis remain largely unknown. Here, we show that induction of TAp73 decreased invasion and migration activity of colorectal cancer cells, whereas knockdown of TAp73 led to increased invasion and migration activity. KAI1 was identified as a transcriptional target of TAp73 and its expression is indispensable for TAp73-mediated inhibition of cell invasion and migration. Furthermore, induction of TAp73 in colorectal cancer cells elevated KAI1 expression and decreased the frequency of hepatic metastasis in vivo. Whereas, the decreased invasion and migration activities caused by TAp73 induction were abrogated by knockdown of KAI1. Interestingly, TAp73 and KAI1 are overexpressed in primary colorectal cancers and a significant correlation between TAp73 and KAI1 expression was detected, but their expressions were significantly down-regulated in metastatic cancers. Taken together, our results support a novel role for TAp73 in controlling colorectal cancer cell invasion, migration and metastasis by regulating transcription of KAI1.

Zheng Z, Tian R, Wang P
Roles of KAI1 and nm23 in lymphangiogenesis and lymph metastasis of laryngeal squamous cell carcinoma.
World J Surg Oncol. 2017; 15(1):211 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
BACKGROUND: Lymphatic metastasis contributes to the poor prognosis of laryngeal squamous cell carcinoma (LSCC). This study aimed to investigate the roles of two metastasis suppressor genes, KAI1 and nm23, in lymphangiogenesis and lymph metastasis of LSCC.
METHODS: A total of 45 LSCC patients were enrolled in this study. The positive expression rates of KAI1 and nm23 protein were detected via immunohistochemistry in 45 LSCC and 22 normal laryngeal mucosa adjacent to LSCC. Micro-lymphatic vessel density (MLVD) was detected via immunohistochemistry with the specific antibody D2-40. Associations between KAI1 and nm23 expression and clinical characteristics of LSCC were then evaluated.
RESULTS: The positive expression rates of KAI1 and nm23 were significantly lower in LSCC than normal laryngeal mucosa (P < 0.05). Significantly lower positive rates of KAI1 and nm23 were found in LSCC with lymphatic metastasis than those without lymphatic metastasis (P < 0.05), whereas MLVD was negatively correlated with the expression of KAI1 and nm23 (P < 0.05). However, no significant associations were found between KAI1 and nm23 expression and clinical characteristics of LSCC (sex, age, disease position, differentiation, and T-stage).
CONCLUSIONS: Both KAI1 and nm23 can inhibit lymphangiogenesis and lymphatic metastasis in LSCC.

Zhou R, Yang Y, Park SY, et al.
The lichen secondary metabolite atranorin suppresses lung cancer cell motility and tumorigenesis.
Sci Rep. 2017; 7(1):8136 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Lichens are symbiotic organisms that produce various secondary metabolites. Here, different lichen extracts were examined to identify secondary metabolites with anti-migratory activity against human lung cancer cells. Everniastrum vexans had the most potent inhibitory activity, and atranorin was identified as an active subcomponent of this extract. Atranorin suppressed β-catenin-mediated TOPFLASH activity by inhibiting the nuclear import of β-catenin and downregulating β-catenin/LEF and c-jun/AP-1 downstream target genes such as CD44, cyclin-D1 and c-myc. Atranorin decreased KAI1 C-terminal interacting tetraspanin (KITENIN)-mediated AP-1 activity and the activity of the KITENIN 3'-untranslated region. The nuclear distribution of the AP-1 transcriptional factor, including c-jun and c-fos, was suppressed in atranorin-treated cells, and atranorin inhibited the activity of Rho GTPases including Rac1, Cdc42, and RhoA, whereas it had no effect on epithelial-mesenchymal transition markers. STAT-luciferase activity and nuclear STAT levels were decreased, whereas total STAT levels were moderately reduced. The human cell motility and lung cancer RT² Profiler PCR Arrays identified additional atranorin target genes. Atranorin significantly inhibited tumorigenesis in vitro and in vivo. Taken together, our results indicated that E. vexans and its subcomponent atranorin may inhibit lung cancer cell motility and tumorigenesis by affecting AP-1, Wnt, and STAT signaling and suppressing RhoGTPase activity.

Guo Z, Wang Y, Yang J, et al.
KAI1 overexpression promotes apoptosis and inhibits proliferation, cell cycle, migration, and invasion in nasopharyngeal carcinoma cells.
Am J Otolaryngol. 2017 Sep - Oct; 38(5):511-517 [PubMed] Related Publications
OBJECTIVES: The purpose of this study is to characterize the effect of KAI1 overexpression on the biological behavior of nasopharyngeal carcinoma (NPC) cells.
BACKGROUND: Nasopharyngeal carcinoma is a highly malignant tumor with a high rate of incidence in China. Currently, there are no ideal therapeutic options for patients with NPC, but a targeted therapy would have great potential for treating it. Therefore, there is an urgent need for novel therapeutic targets to provide new options for treating NPC. The KAI1 gene was originally identified as a metastasis suppressor gene for advanced human cancer. In NPC cell lines and tissues, the expression of KAI1 decreased as the metastatic potential of cells increased, but its potential as a therapeutic target has not been elucidated.
METHODS: Non-transformed nasopharyngeal epithelium cell NP69 and NPC cell line C666-1 were cultured and KAI1 expression in these cells was detected by qRT-PCR and Western blot. After the transfection of KAI1-pCDNA3.1 to NP69 and C666-1, the KAI1 expression in these cells was detected by qRT-PCR and Western blot, the proliferation was performed by MTS, the cell cycle and apoptosis were performed by flow cytometry, the migration and invasion were examined by transwell.
RESULTS: Our results showed that KAI1 was significantly upregulated in C666-1 cells compared to that in NP69 cells. In addition, KAI1 overexpression significantly inhibited the proliferation, cell cycle, migration, and invasion, and promoted apoptosis of C666-1 cells, but had no significant effect on NP69 cells.
CONCLUSION: Our findings suggest that KAI1 overexpression promotes apoptosis and inhibits proliferation, cell cycle, migration, and invasion in NPC cells. We hypothesize that KAI1 overexpression could be a potential therapeutic target for NPC.

Li W, Hu M, Wang C, et al.
A viral microRNA downregulates metastasis suppressor CD82 and induces cell invasion and angiogenesis by activating the c-Met signaling.
Oncogene. 2017; 36(38):5407-5420 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Kaposi's sarcoma (KS) as the most common AIDS-associated malignancy is etiologically caused by KS-associated herpesvirus (KSHV). KS is a highly disseminated and vascularized tumor. KSHV encodes 12 pre-microRNAs that yield 25 mature microRNAs (miRNAs), but their roles in KSHV-induced tumor metastasis and angiogenesis remain largely unclear. KSHV-encoded miR-K12-6 (miR-K6) can generate two mature miRNAs, miR-K6-5p and miR-K6-3p. Recently, we have shown that miR-K6-3p induced cell migration and angiogenesis via directly targeting SH3 domain binding glutamate-rich protein (SH3BGR). Here, by using mass spectrometry, bioinformatics analysis and luciferase reporter assay, we showed that miR-K6-5p directly targeted the coding sequence of CD82 molecule (CD82), a metastasis suppressor. Ectopic expression of miR-K6-5p specifically inhibited the expression of endogenous CD82 and strongly promoted endothelial cells invasion and angiogenesis. Overexpression of CD82 significantly inhibited cell invasion and angiogenesis induced by miR-K6-5p. Mechanistically, CD82 directly interacted with c-Met to inhibit its activation. MiR-K6-5p directly repressed CD82, relieving its inhibition on c-Met activation and inducing cell invasion and angiogenesis. Lack of miR-K6 abrogated KSHV suppression of CD82 resulting in compromised KSHV activation of c-Met pathway, and KSHV induction of cell invasion and angiogenesis. In conclusion, our data show that by reducing CD82, KSHV miR-K6-5p expedites cell invasion and angiogenesis by activating the c-Met pathway. Our findings illustrate that KSHV miRNAs may be critical for the dissemination and angiogenesis of KSHV-induced malignant tumors.

Zhu B, Zhou L, Yu L, et al.
Evaluation of the correlation of vasculogenic mimicry, ALDH1, KAI1 and microvessel density in the prediction of metastasis and prognosis in colorectal carcinoma.
BMC Surg. 2017; 17(1):47 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
BACKGROUND: Metastasis and recurrence are the most common reasons for treatment failure of colorectal carcinoma (CRC). Vasculogenic mimicry (VM, blood supply formation often seen in highly aggressive tumors), Aldehyde dehydrogenase 1 (ALDH1, a biomarker of cancer stem cells), KAI1 (a suppressor gene of tumor metastasis) are all valuable factors for metastasis and prognosis in diverse human cancers. However, the correlation of VM, ALDH1, KAI1 and microvessel density (MVD) in CRC is unclear. In this study, we analyzed the correlations among VM, ALDH1, KAI1 and MVD, as well as their respective correlations with clinicopathological parameters and survival in CRC.
METHODS: The level of VM, ALDH1, KAI1 and MVD in 204 whole tissue samples of CRC were examined by immunhistochemistry. Clinical data was also collected.
RESULTS: Levels of VM, ALDH1 and MVD were significantly higher, and levels of KAI1 significantly lower, in CRC tissues than in normal colorectal tissues. Levels of VM, ALDH1 and MVD were positively associated with invasion of depth, lymph node metastasis (LNM), distant metastasis and tumor-node-metastasis (TNM) stages, and negatively with patients' overall survival (OS). Levels of KAI1 was negatively correlated with invasion of depth, LNM, distant metastasis and TNM stages, and the KAI1 positive expression subgroup had significantly longer OS than did the KAI1- subgroup. In multivariate analysis, high levels of VM, ALDH1 and KAI1, as well as TNM stages were independently correlated with lower OS in patients with CRC.
CONCLUSIONS: VM, MVD and the expression of ALDH1 and KAI1 may represent promising metastatic and prognostic biomarkers, as well as potential therapeutic targets for CRC.

Di Giacomo V, Tian TV, Mas A, et al.
ΔNp63α promotes adhesion of metastatic prostate cancer cells to the bone through regulation of CD82.
Oncogene. 2017; 36(31):4381-4392 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
ΔNp63α is a critical mediator of epithelial development and stem cell function in a variety of tissues including the skin and breast, while overexpression of ΔNp63α acts as an oncogene to drive tumor formation and cancer stem cell properties in squamous cell carcinoma. However, with regards to the prostate, while ΔNp63α is expressed in the basal stem cells of the mature gland, during adenocarcinoma development, its expression is lost and its absence is used to clinically diagnose the malignant state. Surprisingly, here we identify a sub-population of bone metastatic prostate cancer cells in the PC3 cell line that express ΔNp63α. Interestingly, we discovered that ΔNp63α favors adhesion and stem-like growth of these cells in the bone microenvironment. In addition, we show that these properties require expression of the target gene CD82. Together, this work uncovers a population of bone metastatic prostate cancer cells that express ΔNp63α, and provides important information about the mechanisms of bone metastatic colonization. Finally, we identify metastasis-promoting properties for the tetraspanin family member CD82.

Chai J, Du L, Ju J, et al.
Overexpression of KAI1/CD82 suppresses in vitro cell growth, migration, invasion and xenograft growth in oral cancer.
Mol Med Rep. 2017; 15(4):1527-1532 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
KAI1/CD82 is a metastatic suppressor gene in human prostate cancer and several other types of cancer in humans. The present study aimed to examine the role of the overexpression of KAI1 in the progression of oral cancer. Human KAI1/CD82 cDNA was transfected into OSCC‑15 and 293T cell lines, and its effects on OSCC‑15 cell proliferation, invasion and apoptosis were assessed by performing a 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay, Matrigel invasion and Annexin V‑FITC staining, respectively. In addition, a xenograft model was used to assess the effect of KAI1/CD82 on the in vivo growth of tumors. The overexpression of KAI1/CD82 inhibited the proliferation and invasion of OSCC-15 cells. It also enhanced the apoptotic rate of the OSCC‑15 cells. Furthermore, the overexpression of KAI1/CD82 inhibited tumor growth in the xenograft model. The results demonstrated that the overexpression of KAI1/CD82 significantly inhibited the proliferation and invasion of human oral cancer cells, and inhibited tumor growth in the xenograft model. Therefore, KAI1/CD82 may be considered as a potential therapeutic target in oral cancer.

Xu L, Hou Y, Tu G, et al.
Nuclear Drosha enhances cell invasion via an EGFR-ERK1/2-MMP7 signaling pathway induced by dysregulated miRNA-622/197 and their targets LAMC2 and CD82 in gastric cancer.
Cell Death Dis. 2017; 8(3):e2642 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Drosha is an RNA III-like enzyme that has an aberrant expression in some tumors. Our previous studies showed the aberrant Drosha in gastric tumors. However, the roles of nuclear Drosha, the main regulator of microRNA (miRNA) biogenesis, in gastric cancer (GC) progression remain poorly understood. In this study, we demonstrated that nuclear Drosha is significantly associated with cell invasion of GC and that Drosha silence impedes the tumor invasion. Knockdown of Drosha led to a set of dysregulated miRNAs in GC cells. Multiple targets of these miRNAs were the members in cell migration, invasion and metastasis-associated signaling (e.g. ECM-receptor interaction, focal adhesion, p53 signaling and MAPK signaling pathway) revealed by bioinformatics analysis. LAMC2 (a key element of ECM-receptor signaling) and CD82 (a suppressor of p53 signaling) are the targets of miR-622 and miR-197, respectively. High levels of LAMC2 and low levels of CD82 were significantly related to the worse outcome for GC patients. Furthermore, overexpression of LAMC2 and knockdown of CD82 markedly promoted GC cell invasion and activated EGFR/ERK1/2-MMP7 signaling via upregulation of the expression of phosphorylated (p)-EGFR, p-ERK1/2 and MMP7. Our findings suggest that nuclear Drosha potentially has a role in the development of GC.

Nishioka C, Ikezoe T, Pan B, et al.
MicroRNA-9 plays a role in interleukin-10-mediated expression of E-cadherin in acute myelogenous leukemia cells.
Cancer Sci. 2017; 108(4):685-695 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
We previously showed that the CD82/signal transducer and activator of transcription/interleukin-10 (IL-10) axis is activated in CD34

Zhang J, Wu T, Zhan S, et al.
TIMP-1 and CD82, a promising combined evaluation marker for PDAC.
Oncotarget. 2017; 8(4):6496-6512 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Tissue inhibitor of metalloproteinases-1 (TIMP-1) is a widely secreted protein that regulates cell motility, proliferation, and apoptosis. Although it is recognized that TIMP-1-tetraspanin CD63 regulates epithelial cell apoptosis and proliferation, how TIMP-1 controls cell motility is not well understood. In this study, we identify tetraspanin CD82 (also called KAI1) as a component of the promiscuous TIMP-1 interacting protein complex on cell surface of human pancreatic adenocarcinoma cells. CD82 directly binds to TIMP-1 N-terminal region through its large extracellular loop and co-localizes with TIMP-1 in both cancer cell lines and clinical samples. Moreover, CD82 facilitates membrane-bound TIMP-1 endocytosis, which significantly contributes to the anti-migration effect of TIMP-1. CD82 silencing partially eliminates these functions. TIMP-1 and CD82 expression status in patients with pancreatic ductal adenocarcinoma (PDAC) might demonstrate future usefulness as a differentiation marker and give us new insight into tumorigenic metastatic potential.

Lee J, Byun HJ, Lee MS, et al.
The metastasis suppressor CD82/KAI1 inhibits fibronectin adhesion-induced epithelial-to-mesenchymal transition in prostate cancer cells by repressing the associated integrin signaling.
Oncotarget. 2017; 8(1):1641-1654 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
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 α3β1/α5β1 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 α3β1 and α5β1 integrins, leading to reduced cell migration and invasive capacities.

Lee J, Lee MS, Jeoung DI, et al.
Promoter CpG-Site Methylation of the KAI1 Metastasis Suppressor Gene Contributes to Its Epigenetic Repression in Prostate Cancer.
Prostate. 2017; 77(4):350-360 [PubMed] Related Publications
BACKGROUND: Repression of the KAI1 metastasis suppressor gene is closely associated with malignancy and poor prognosis in many human cancer types including prostate cancer. Since gene repression in human cancers frequently results from epigenetic alterations by DNA methylation and histone modifications, we examined whether the KAI1 gene becomes silenced through these epigenetic mechanisms in prostate cancer.
METHODS: KAI1 mRNA and protein levels were determined by RT-PCR and immunoblotting analyses, respectively. Methylation status of the KAI1 promoter DNA in prostate cancer cell lines and tissues was evaluated by methylation-specific PCR analysis of bisulfite-modified genomic DNAs. Methylated CpG sites in the KAI1 promoter were identified by sequencing the PCR clones of the bisulfite-modified KAI1 promoter DNA. KAI1 protein levels in human prostate cancer tissue samples were examined by immunofluorescence staining of the tissues with an anti-KAI1 antibody.
RESULTS: Among the three human prostate cancer cell lines examined, PC3 and DU145 cells exhibited markedly decreased levels of KAI1 mRNA and protein as compared to LNCaP cells, even though the exogenous KAI1 promoter not being methylated was normally functional in all these cell lines. Treatment of the low KAI1-expressing cell lines with a demethylating agent, 5'-aza-2'-deoxycytidine, significantly elevated KAI1 expression levels, implicating the involvement of DNA methylation in KAI1 downregulation. Methylation of CpG islands within the KAI1 promoter region was observed in the low KAI1-expressing cells, but not in the high KAI1-expressing cells. Also, methyl CpG-binding proteins such as MBD2 and MeCP2 were complexed to the KAI1 promoter in the low KAI1-expressing cells. Bisulfite sequencing analysis identified the intensively methylated CpG residues in the KAI1 promoter clones derived from prostate cancer cells and tissues with no or low KAI1 expression. As in prostate cancer cell lines, prostate cancer tissues from patients also displayed a negative association between KAI1 expression levels and methylation status of the KAI1 promoter.
CONCLUSIONS: The present data suggest that the KAI1 gene might be repressed by epigenetic alterations through the promoter CpG-site methylation during prostate cancer progression. This epigenetic mechanism could provide a clue for understanding how the KAI1 gene was silenced in metastatic prostate cancers. Prostate 77: 350-360, 2017. © 2016 Wiley Periodicals, Inc.

Lu G, Zhou L, Zhang X, et al.
The expression of metastasis-associated in colon cancer-1 and KAI1 in gastric adenocarcinoma and their clinical significance.
World J Surg Oncol. 2016; 14(1):276 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
BACKGROUND: The most common reason for malignant tumor treatment failure is recurrence and metastasis. Metastasis-associated in colon cancer-1 (MACC1) was originally identified as a metastatic and prognostic biomarker for colon cancer and later other solid tumors. Kangai 1 (KAI1), a marker of suppressor of metastasis, is also associated with metastasis and poor prognosis in many tumors. However, the prognostic value of either MACC1 or KAI1 in gastric adenocarcinoma (GAC) is unclear. In this study, we explored the relationship between MACC1 and KAI1 expression, as well as their respective correlation with clinicopathological features, to determine if either could be helpful for improvement of survival prognosis in GAC patients.
METHODS: The expression levels of both MACC1 and KAI1 in 325 whole-tissue sections of GAC were examined by immunohistochemistry. Clinical data was also collected.
RESULTS: MACC1 was significantly overexpressed in GAC tissues when compared to levels in normal gastric tissues; KAI1 was significantly down-expressed in GAC tissues when compared to levels in normal gastric tissues. Investigation of association between MACC1 and KAI1 protein levels with clinicopathological parameters of GAC indicated association between the expression of each with tumor grade, lymph node metastasis, invasive depth, and TNM stages. The overall survival time of patients with MACC1- or KAI1-positive GAC tumors was significantly shorter or longer than that of those who were negative. Importantly, multivariate analysis suggested that positive expression of either MACC1 or KAI1, as well as TNM stage, could be independent prognostic factors for overall survival in patients with GAC.
CONCLUSIONS: MACC1 and KAI1 may represent promising metastatic and prognostic biomarkers, as well as potential therapeutic targets, for GAC.

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