Gene Summary

Gene:CD151; CD151 molecule (Raph blood group)
Aliases: GP27, MER2, RAPH, SFA1, PETA-3, TSPAN24
Summary:The protein encoded by this gene is a member of the transmembrane 4 superfamily, also known as the tetraspanin family. Most of these members are cell-surface proteins that are characterized by the presence of four hydrophobic domains. The proteins mediate signal transduction events that play a role in the regulation of cell development, activation, growth and motility. This encoded protein is a cell surface glycoprotein that is known to complex with integrins and other transmembrane 4 superfamily proteins. It is involved in cellular processes including cell adhesion and may regulate integrin trafficking and/or function. This protein enhances cell motility, invasion and metastasis of cancer cells. Multiple alternatively spliced transcript variants that encode the same protein have been described for this gene. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:CD151 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: CD151 (cancer-related)

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.

Yang CA, Huang HY, Yen JC, Chang JG
Prognostic Value of
Int J Mol Sci. 2018; 19(6) [PubMed] Article available free on PMC after 01/10/2019 Related Publications
The nucleotide degrading enzyme gene

Donnenberg VS, Zhang JJ, Moravcikova E, et al.
Antibody-based cell-surface proteome profiling of metastatic breast cancer primary explants and cell lines.
Cytometry A. 2018; 93(4):448-457 [PubMed] Related Publications
Flow cytometric cell surface proteomics provides a new and powerful tool to determine changes accompanying neoplastic transformation and invasion, providing clues to essential interactions with the microenvironment as well as leads for potential therapeutic targets. One of the most important advantages of flow cytometric cell surface proteomics is that it can be performed on living cells that can be sorted for further characterization and functional studies. Here, we document the surface proteome of clonogenic metastatic breast cancer (MBrCa) explants, which was strikingly similar to that of normal mesenchymal stromal cells (P = 0.017, associated with Pearson correlation coefficient) and transformed mammary epithelial cells (P = 0.022). Markers specifically upregulated on MBrCa included CD200 (Ox2), CD51/CD61 (Integrin α5/β3), CD26 (dipeptidyl peptidase-4), CD165 (c-Cbl), and CD54 (ICAM-1). Proteins progressively upregulated in a model of neoplastic transformation and invasion included CD26, CD63 (LAMP3), CD105 (Endoglin), CD107a (LAMP1), CD108 (Semaphorin 7A), CD109 (Integrin β4), CD151 (Raph blood group), and disialoganglioside G2. The proteome of the commonly used cell lines MDA-MB-231, MCF7, and BT-474 were uncorrelated with that of MBrCa (P = 1.0, 1.0, 0.9, respectively). The comparison has demonstrated the mesenchymal nature of clonogenic cells isolated by short-term culture of metastatic breast cancer, provided several leads for biomarkers and potential targets for anti-invasive therapy, including CD200, and highlighted the limitations of breast cancer cell lines for representing the cell surface biology of breast cancer. © 2017 International Society for Advancement of Cytometry.

Takashima Y, Murakami T, Inoue T, et al.
Manifestation of osteoblastic phenotypes in the sarcomatous component of epithelial carcinoma and sarcomatoid carcinoma.
Tumour Biol. 2017; 39(6):1010428317704365 [PubMed] Related Publications
Epithelial carcinomas occasionally have sarcomatous components that consist primarily of spindle and cuboidal cells, which often resemble osteoblasts. Sarcomatoid carcinomas consist of similar cells. Recent studies have characterized these phenomena as a manifestation of epithelial-mesenchymal transition in carcinoma cells, but the mesenchymal phenotypes that manifest in sarcomatous cells of epithelial carcinomas are not well understood. Here, we examined the expression profiles of four osteoblastic differentiation biomarkers in the sarcomatous components of multiple carcinoma types, including five renal clear cell, four breast invasive ductal, two esophageal, one maxillary squamous cell, three larynx, three lung, one liver, and one skin sarcomatoid carcinoma. Expression was analyzed by immunohistochemistry using antibodies against cell adhesion molecule 1, a member of the IgCAM superfamily, osterix transcription factor (Osterix), cluster of differentiation 151, a transmembrane 4 superfamily member, and alkaline phosphatase. Immunostaining intensity was rated in scale 0 (negative), 0.5 (weak), and 1 (strong) for each marker, and the four scale values were summed to calculate osteoblastic scores. In all, 10 cases had a osteoblastic score ≥3, and all of these 10 cases were cell adhesion molecule 1- and Osterix-positive. Eight and five of the nine samples with a osteoblastic score <3 were negative for cell adhesion molecule 1 ( p < 0.0001) and Osterix ( p = 0.006), respectively. The other markers showed no statistical significance. These results indicate that osteoblastic differentiation can occur in carcinoma cells and that cell adhesion molecule 1 could be a useful marker for identifying this phenomenon in carcinoma tissues.

Yang ZP, Ma HS, Wang SS, et al.
LAMC1 mRNA promotes malignancy of hepatocellular carcinoma cells by competing for MicroRNA-124 binding with CD151.
IUBMB Life. 2017; 69(8):595-605 [PubMed] Related Publications
Specific RNAs can function as sinks for endogenous miRNAs, known as competing endogenous RNAs (ceRNAs). Here, we confirm a miR-124 mediated ceRNA crosstalk between LAMC1 and CD151 in hepatocellular carcinoma (HCC). miR-124 negatively regulates LAMC1 expression through two miRNA binding sites within its 3' untranslated region (3'UTR) and suppresses migration and invasion of HCC cells through regulating LAMC1. The wild type LAMC1 miRNA response elements (MREs) facilitate expression of CD151, and this regulation is miR-124 dependent. In clinical hepatic tissues, LAMC1 and CD151 mRNAs exhibit positive correlation. Importantly, LAMC1 MREs promote HCC malignancy by absorbing miR-124 and by assisting CD151 expression. We conclude that LAMC1 mRNA acts as a trans regulator to stimulate CD151 expression by competing for miR-124 binding in HCC cells. © 2017 IUBMB Life, 69(8):595-605, 2017.

Yue S, Zhao K, Erb U, et al.
Joint features and complementarities of Tspan8 and CD151 revealed in knockdown and knockout models.
Biochem Soc Trans. 2017; 45(2):437-447 [PubMed] Related Publications
Tetraspanins are highly conserved 4-transmembrane proteins which form molecular clusters with a large variety of transmembrane and cytosolic proteins. By these associations tetraspanins are engaged in a multitude of biological processes. Furthermore, tetraspanin complexes are located in specialized microdomains, called tetraspanin-enriched microdomains (TEMs). TEMs provide a signaling platform and are poised for invagination and vesicle formation. These vesicles can be released as exosomes (Exo) and are important in cell contact-independent intercellular communication. Here, we summarize emphasizing knockdown and knockout models' pathophysiological joint and selective activities of CD151 and Tspan8, and discuss the TEM-related engagement of CD151 and Tspan8 in Exo activities.

Richard V, Raju R, Paul AM, et al.
Analysis of MicroRNA-mRNA Interactions in Stem Cell-Enriched Fraction of Oral Squamous Cell Carcinoma.
Oncol Res. 2018; 26(1):17-26 [PubMed] Related Publications
This study is an integrated analysis of the transcriptome profile microRNA (miRNA) and its experimentally validated mRNA targets differentially expressed in the tumorigenic stem-like fraction of oral squamous cell carcinoma (OSCC). We had previously reported the coexistence of multiple drug-resistant tumorigenic fractions, termed side population (SP1, SP2, and MP2), and a nontumorigenic fraction, termed main population (MP1), in oral cancer. These fractions displayed a self-renewal, regenerative potential and expressed known stemness-related cell surface markers despite functional differences. Flow cytometrically sorted pure fractions of SP1 and MP1 cells were subjected to differential expression analysis of both mRNAs and miRNAs. A significant upregulation of genes associated with inflammation, cell survival, cell proliferation, drug transporters, and antiapoptotic pathways, in addition to enhanced transcriptome reprogramming mediated by DNA-histone binding proteins and pattern recognition receptor-mediated signaling, was found to play a crucial role in the transformation of the nontumorigenic MP1 fraction to the tumorigenic SP1 fraction. We also identified several differentially expressed miRNAs that specifically target genes distinctive of tumorigenic SP1 fraction. miRNA-mediated downregulation of stemness-associated markers CD44 and CD147 and upregulation of CD151 may also account for the emergence and persistence of multiple tumorigenic stem cell fractions with varying degrees of malignancy. The phenotypic switch of cancer cells to stem-like OSCC cells mediated by transcriptomal regulation is effectual in addressing biological tumor heterogeneity and subsequent therapeutic resistance leading to a minimal residual disease (MRD) condition in oral cancer. A detailed study of the interplay of miRNAs, mRNA, and the cellular phases involved in the gradual transition of nontumorigenic cancer cells to tumorigenic stem-like cells in solid tumors would enable detection and development of a treatment regimen that targets and successfully eliminates multiple, drug-resistant fractions of cancer cells.

Medrano M, Communal L, Brown KR, et al.
Interrogation of Functional Cell-Surface Markers Identifies CD151 Dependency in High-Grade Serous Ovarian Cancer.
Cell Rep. 2017; 18(10):2343-2358 [PubMed] Related Publications
The degree of genetic aberrations characteristic of high-grade serous ovarian cancer (HGSC) makes identification of the molecular features that drive tumor progression difficult. Here, we perform genome-wide RNAi screens and comprehensive expression analysis of cell-surface markers in a panel of HGSC cell lines to identify genes that are critical to their survival. We report that the tetraspanin CD151 contributes to survival of a subset of HGSC cell lines associated with a ZEB transcriptional program and supports the growth of HGSC tumors. Moreover, we show that high CD151 expression is prognostic of poor clinical outcome. This study reveals cell-surface vulnerabilities associated with HGSC, provides a framework for identifying therapeutic targets, and reports a role for CD151 in HGSC.

Li T, Meng XL, Yang WQ
Long Noncoding RNA PVT1 Acts as a "Sponge" to Inhibit microRNA-152 in Gastric Cancer Cells.
Dig Dis Sci. 2017; 62(11):3021-3028 [PubMed] Related Publications
BACKGROUND: PVT1 was up-regulated in patients with gastric cancer (GC) and might be as a novel biomarker for predicting GC. However, the exact mechanism of PVT1 exerting functions in GC was still poorly understood. Emerging evidence suggests that long noncoding RNAs may act as endogenous microRNA (miRNA) sponges to bind to miRNAs and regulate their function.
AIM: This study aimed to determine the function of PVT1 on miR-152 expression in GC cells.
METHODS: The levels of PVT1 and miR-152 were determined in GC tissues by quantitative real-time PCR. The expression of miR-152 was detected in GC cells transfected with PVT1 plasmid or siPVT1. Luciferase assay was performed to verify the regulation of miR-152 to CD151 or FGF2 expression and PVT1 to miR-152 expression. The effects of PVT1 on the expression of CD151 and FGF2 were evaluated by Western blot.
RESULTS: PVT1 was up-regulated in GC tissues than that in the matched normal tissues, and mRNA level of miR-152 was decreased. MiR-152 was negatively associated with PVT1 expression in GC tissues. Based on the in silico analysis, we found that PVT1 have three binding sequences for miR-152. Moreover, PVT1 might inhibit the expression of miR-152 and increased the expression of CD151 and FGF2 through regulating miR-152. PVT1 was positively associated with CD151 and FGF2 expression in GC tissues.
CONCLUSIONS: PVT1 might act as a "sponge" to inhibit miR-152 in gastric cancer cells. PVT1 is a promising molecular target to improve the diagnosis and therapy of GC.

Kim JH, Badawi M, Park JK, et al.
Anti-invasion and anti-migration effects of miR-199a-3p in hepatocellular carcinoma are due in part to targeting CD151.
Int J Oncol. 2016; 49(5):2037-2045 [PubMed] Related Publications
Several studies have reported reduced miR-199a-3p expression in hepatocellular carcinoma (HCC). In an effort to discover important target genes for miR-199a-3p that may be related to HCC development or progression, we identified the tetraspanin, transmembrane glycoprotein CD151. Luciferase reporter assays and western blotting identified CD151 as a bona fide miR-199a-3p target gene. While CD151 protein was increased in the mesenchymal but not the epithelial HCC cell lines, CD151 knockdown with siRNA did not reduce HCC cell proliferation in either group of cells. miR-199a-3p reduced in vitro invasion and migration of CD151-positive HCC cells. Examination of the mRNA and protein expression in pairs of primary HCC tumors and adjacent benign tissues showed that not only was CD151 mRNA and protein increased in the tumors but also that an inverse correlation exists between the miR-199a-3p and CD151 RNA expression. We report that CD151 is a target of miR-199a-3p and that increased CD151 protein resulting from reduced miR-199a-3p could contribute to the development of metastatic HCC.

Fisher OM, Levert-Mignon AJ, Lehane CW, et al.
CD151 Gene and Protein Expression Provides Independent Prognostic Information for Patients with Adenocarcinoma of the Esophagus and Gastroesophageal Junction Treated by Esophagectomy.
Ann Surg Oncol. 2016; 23(Suppl 5):746-754 [PubMed] Related Publications
BACKGROUND: Esophageal and gastroesophageal junctional (GEJ) adenocarcinoma is one of the most fatal cancers and has the fastest rising incidence rate of all cancers. Identification of biomarkers is needed to tailor treatments to each patient's tumor biology and prognosis.
METHODS: Gene expression profiling was performed in a test cohort of 80 chemoradiotherapy (CRTx)-naïve patients with external validation in a separate cohort of 62 CRTx-naïve patients and 169 patients with advanced-stage disease treated with CRTx.
RESULTS: As a novel prognostic biomarker after external validation, CD151 showed promise. Patients exhibiting high levels of CD151 (≥median) had a longer median overall survival than patients with low CD151 tumor levels (median not reached vs. 30.9 months; p = 0.01). This effect persisted in a multivariable Cox-regression model with adjustment for tumor stage [adjusted hazard ratio (aHR), 0.33; 95 % confidence interval (CI), 0.14-0.78; p = 0.01] and was further corroborated through immunohistochemical analysis (aHR, 0.22; 95 % CI, 0.08-0.59; p = 0.003). This effect was not found in the separate cohort of CRTx-exposed patients.
CONCLUSION: Tumoral expression levels of CD151 may provide independent prognostic information not gained by conventional staging of patients with esophageal and GEJ adenocarcinoma treated by esophagectomy alone.

Ramovs V, Te Molder L, Sonnenberg A
The opposing roles of laminin-binding integrins in cancer.
Matrix Biol. 2017; 57-58:213-243 [PubMed] Related Publications
Integrins play an important role in cell adhesion by linking the cytoskeleton of cells to components in the extracellular matrix. In this capacity, integrins cooperate with different cell surface receptors, including growth factor receptors and G-protein coupled receptors, to regulate intracellular signaling pathways that control cell polarization, spreading, migration, survival, and gene expression. A distinct subfamily of molecules in the integrin family of adhesion receptors is formed by receptors that mediate cell adhesion to laminins, major components of the basement membrane that lie under clusters of cells or surround them, separating them from other cells and/or adjacent connective tissue. During the past decades, many studies have provided evidence for a role of laminin-binding integrins in tumorigenesis, and both tumor-promoting and suppressive activities have been identified. In this review we discuss the dual role of the laminin-binding integrins α3β1 and α6β4 in tumor development and progression, and examine the factors and mechanisms involved in these opposing effects.

Wang Z, Wang C, Zhou Z, et al.
CD151-mediated adhesion is crucial to osteosarcoma pulmonary metastasis.
Oncotarget. 2016; 7(37):60623-60638 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
CD151, a tetraspanin family protein involved in cell-cell and cell-extracellular matrix interaction, is differentially expressed in osteosarcoma cell membranes. Thus, this study aimed to investigate the role of CD151 in osteosarcoma metastasis. We analyzed CD151 expression in patient tissue samples using immunohistochemistry. CD151 expression was also silenced with shRNA in osteosarcoma cells of high metastatic potential, and cell adhesion, migration and invasion were evaluated in vitro and pulmonary metastasis was investigated in vivo. Mediators of cell signaling pathways were also examined following suppression of CD151 expression. Overall survival for patients with low versus high CD151 expression level was 94 vs. 41 months (p=0.0451). CD151 expression in osteosarcoma cells with high metastatic potential was significantly higher than in those with low metastatic potential (p<0.001). shRNA-mediated silencing of CD151 did not influence cell viability or proliferation; however, cell adhesion, migration and invasion were all inhibited (all p<0.001). In mice inoculated with shRNA-transduced osteosarcoma cells, the number and size of lung metastatic lesions were reduced compared to the mice inoculated with control-shRNA transduced cells (p<0.001). In addition, CD151 knockdown significantly reduced Akt, p38, and p65 phosphorylation as well as focal adhesion kinase, integrin β1, p70s6, and p-mTOR levels. Taken together, CD151 induced osteosarcoma metastasis likely by regulating cell function through adhesion signaling. Further studies are necessary to fully explore the diagnostic and prognostic value of determining CD151 expression in osteosarcoma patients.

Olsen TK, Panagopoulos I, Gorunova L, et al.
Novel fusion genes and chimeric transcripts in ependymal tumors.
Genes Chromosomes Cancer. 2016; 55(12):944-953 [PubMed] Related Publications
We have previously identified two ALK rearrangements in a subset of ependymal tumors using a combination of cytogenetic data and RNA sequencing. The aim of this study was to perform an unbiased search for fusion transcripts in our entire series of ependymal tumors. Fusion analysis was performed using the FusionCatcher algorithm on 12 RNA-sequenced ependymal tumors. Candidate transcripts were prioritized based on the software's filtering and manual visualization using the BLAST (Basic Local Alignment Search Tool) and BLAT (BLAST-like alignment tool) tools. Genomic and reverse transcriptase PCR with subsequent Sanger sequencing was used to validate the potential fusions. Fluorescent in situ hybridization (FISH) using locus-specific probes was also performed. A total of 841 candidate chimeric transcripts were identified in the 12 tumors, with an average of 49 unique candidate fusions per tumor. After algorithmic and manual filtering, the final list consisted of 24 potential fusion events. Raw RNA-seq read sequences and PCR validation supports two novel fusion genes: a reciprocal fusion gene involving UQCR10 and C1orf194 in an adult spinal ependymoma and a TSPAN4-CD151 fusion gene in a pediatric infratentorial anaplastic ependymoma. Our previously reported ALK rearrangements and the RELA and YAP1 fusions found in supratentorial ependymomas were until now the only known fusion genes present in ependymal tumors. The chimeric transcripts presented here are the first to be reported in infratentorial or spinal ependymomas. Further studies are required to characterize the genomic rearrangements causing these fusion genes, as well as the frequency and functional importance of the fusions. © 2016 Wiley Periodicals, Inc.

Liu T, Zu CH, Wang SS, et al.
PIK3C2A mRNA functions as a miR-124 sponge to facilitate CD151 expression and enhance malignancy of hepatocellular carcinoma cells.
Oncotarget. 2016; 7(28):43376-43389 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Competing endogenous RNAs (ceRNAs) are RNA transcripts that can crosstalk with each other by competing for shared microRNAs (miRNAs) through miRNA response elements (MREs). Involved in ceRNA networks, the RNA transcripts may be in a balance, disruption of which could lead to tumorigenesis. Here we reveal a ceRNA interaction between PIK3C2A and CD151 mRNAs in hepatocellular carcinoma (HCC) cells. PIK3C2A is a candidate ceRNA of CD151 because mRNA 3' untranslated regions (3'UTRs) of these two genes contain miR-124 binding sites. miR-124 is downregulated, while PIK3C2A and CD151 are upregulated in HCC cells compared with normal hepatocytes. Direct and negative regulation of PIK3C2A and CD151 by miR-124 was confirmed in HCC cells. miR-124 and the two potential ceRNAs are all recruited to the RNA-induced silencing complex (RISC). In HCC cell lines QGY- 7703 and SMMC-7721, and normal hepatic cell line HL-7702, miR-124 plays a tumor suppressor role by targeting PIK3C2A and CD151. The MREs within PIK3C2A 3'UTR can independently stimulate CD151 expression level by acting as miR-124 decoys. PIK3C2A MREs enhance HCC cell malignancy by absorbing endogenous miR-124 and activating CD151 in HCC cells. We conclude that PIK3C2A 3'UTR functions as a trans activator to stimulate CD151 by competing for miR-124 binding in HCC cells. The collaboration of PIK3C2A and CD151 through ceRNA mechanism may be implicated in HCC initiation and development.

Stewart RL, West D, Wang C, et al.
Elevated integrin α6β4 expression is associated with venous invasion and decreased overall survival in non-small cell lung cancer.
Hum Pathol. 2016; 54:174-83 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Lung cancer carries a poor prognosis and is the most common cause of cancer-related death worldwide. The integrin α6β4, a laminin receptor, promotes carcinoma progression in part by cooperating with various growth factor receptors to facilitate invasion and metastasis. In carcinoma cells with mutant TP53, the integrin α6β4 promotes cell survival. TP53 mutations and integrin α6β4 overexpression co-occur in many aggressive malignancies. Because of the high frequency of TP53 mutations in lung squamous cell carcinoma (SCC), we sought to investigate the association of integrin β4 expression with clinicopathologic features and survival in non-small cell lung cancer (NSCLC). We constructed a lung cancer tissue microarray and stained sections for integrin β4 subunit expression using immunohistochemistry. We found that integrin β4 expression is elevated in SCC compared with adenocarcinoma (P<.0001), which was confirmed in external gene expression data sets (P<.0001). We also determined that integrin β4 overexpression associates with the presence of venous invasion (P=.0048) and with reduced overall patient survival (hazard ratio, 1.46; 95% confidence interval, 1.01-2.09; P=.0422). Elevated integrin β4 expression was also shown to associate with reduced overall survival in lung cancer gene expression data sets (hazard ratio, 1.49; 95% confidence interval, 1.31-1.69; P<.0001). Using cBioPortal, we generated a network map demonstrating the 50 most highly altered genes neighboring ITGB4 in SCC, which included laminins, collagens, CD151, genes in the EGFR and PI3K pathways, and other known signaling partners. In conclusion, we demonstrate that integrin β4 is overexpressed in NSCLC where it is an adverse prognostic marker.

Tilghman J, Schiapparelli P, Lal B, et al.
Regulation of Glioblastoma Tumor-Propagating Cells by the Integrin Partner Tetraspanin CD151.
Neoplasia. 2016; 18(3):185-98 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Glioblastoma (GBM) stem cells (GSCs) represent tumor-propagating cells with stem-like characteristics (stemness) that contribute disproportionately to GBM drug resistance and tumor recurrence. Understanding the mechanisms supporting GSC stemness is important for developing therapeutic strategies for targeting GSC-dependent oncogenic mechanisms. Using GBM-derived neurospheres, we identified the cell surface tetraspanin family member CD151 as a novel regulator of glioma cell stemness, GSC self-renewal capacity, migration, and tumor growth. CD151 was found to be overexpressed in GBM tumors and GBM neurospheres enriched in GSCs. Silencing CD151 inhibited neurosphere forming capacity, neurosphere cell proliferation, and migration and attenuated the expression of markers and transcriptional drivers of the GSC phenotype. Conversely, forced CD151 expression promoted neurosphere self-renewal, cell migration, and expression of stemness-associated transcription factors. CD151 was found to complex with integrins α3, α6, and β1 in neurosphere cells, and blocking CD151 interactions with integrins α3 and α6 inhibited AKT phosphorylation, a downstream effector of integrin signaling, and impaired sphere formation and neurosphere cell migration. Additionally, targeting CD151 in vivo inhibited the growth of GBM neurosphere-derived xenografts. These findings identify CD151 and its interactions with integrins α3 and α6 as potential therapeutic targets for inhibiting stemness-driving mechanisms and stem cell populations in GBM.

Zhang Z, Wang F, Li Q, et al.
CD151 knockdown inhibits osteosarcoma metastasis through the GSK-3β/β-catenin/MMP9 pathway.
Oncol Rep. 2016; 35(3):1764-70 [PubMed] Related Publications
Osteosarcoma (OS) is a primary bone malignancy with a high early metastatic propensity. It is crucial to find specific protein targets to develop therapeutic strategies against this lethal disease. Tetraspanin CD151 is involved in facilitating tumor metastasis. However, the role and molecular mechanism of CD151 in promoting OS metastasis remain enigmatic. In the present study, we used small interfering RNA (siRNA) to inhibit CD151 expression in highly metastatic OS cells and the results demonstrated that CD151 knockdown inhibited their migration, invasion and metastasis. We further investigated the molecular mechanism of CD151 by inhibiting genes known to be involved in metastasis in OS cells and found that CD151 modulated matrix metalloproteinase 9 (MMP9) expression through the glycogen synthase kinase 3 (GSK-3β)/β-catenin signaling pathway. We conclude that CD151 knockdown inhibits the expression of MMP9 through the GSK-3β/β‑catenin pathway and also inhibits OS migration and invasion in vitro and metastasis in vivo in highly metastatic OS. This suggests that CD151 may be a useful antimetastatic target for OS.

Liu T, wang S, Wang L, et al.
Targeting CD151 by lentivirus-mediated RNA interference inhibits luminal and basal-like breast cancer cell growth and invasion.
Mol Cell Biochem. 2015; 407(1-2):111-21 [PubMed] Related Publications
CD151 is a member of the tetraspanin family, which is involved in diverse cellular processes, including proliferation, motility, and invasion. However, the role of CD151 in breast cancer especially luminal and basal-like subtype breast cancer remains obscure. Here, we report the role of CD151 in the biological behaviors of luminal and basal-like subtype cell lines and the underlying molecular mechanism. A eukaryotic expression vector expressing both CD151 shRNA and GFP was transfected into MCF-7 and MDA-MB-468 cells. The CD151 gene-silencing effect is authenticated by real-time PCR and Western blot. Our data show that the capacity for proliferation, migration, and invasion of two kinds of cells is diminished after Knockdown of CD151 via lentivirus-mediated CD151 specific shRNA. Tumor cells are arrested in G0/G1 phase. Apoptosis is increased. Moreover, we also demonstrate that the expressions of mmp26 and CD147 are inhibited by knockdown of CD151. But the inhibition depends on the cell type. We can conclude that silencing gene CD151 inhibits expression of properties that are associated with the malignant phenotype of MCF-7 and MDA-MB-468 cells. It may become a potential target in breast cancer therapy especially for luminal and basal subtypes.

Li P, Zeng H, Qin J, et al.
Effects of tetraspanin CD151 inhibition on A549 human lung adenocarcinoma cells.
Mol Med Rep. 2015; 11(2):1258-65 [PubMed] Related Publications
Tetraspanin protein CD151 is overexpressed in a wide variety of cancer types, including lung cancer, and is closely associated with metastasis and poor prognosis of carcinoma. To investigate whether knockdown of CD151 expression can inhibit the malignant biological behavior of lung adenocarcinoma (LAC), RNA interference technology (RNAi) was used to silence CD151 expression in the A549 LAC cell line. Specific small interfering RNA (siRNA) for targeting human endogenous CD151 were delivered into A549 cells in order to examine the effects on cell proliferation, survival, migration, invasion and colony formation. The expression levels of CD151 were assayed by western blotting, proliferation was evaluated by MTT method and apoptosis was determined by flow cytometry. The invasive and metastatic ability of A549 cells was investigated by wound healing and Boyden chamber assays. Colony formation analysis was used to determine the A549 cell growth properties. Finally, the expression of phosphorylated FAK, PI3K‑AKT, MEK‑Erk1/2, MMPs, and VEGF was detected by western blotting. The results demonstrated that CD151‑siRNA significantly decreased the expression level of CD151 in A549 cells. Reduced CD151 expression in A549 cells lead to the inhibition of cellular proliferation, migration, invasion and colony formation and an enhancement of apoptosis. Furthermore, the expression of tumor development‑related proteins, including FAK, PI3K‑AKT, MEK‑ERK1/2MAPK as well as the expression of MMP9 and VEGF, were restrained. Taken together, the present study has shown that CD151 expression is essential for LAC progression. Thus, knockdown CD151 expression by targeted siRNA could inhibit the related downstream intercellular signaling pathways, and this may provide a novel gene therapy for patients with LAC.

Schimmer BP, Cordova M
Corticotropin (ACTH) regulates alternative RNA splicing in Y1 mouse adrenocortical tumor cells.
Mol Cell Endocrinol. 2015; 408:5-11 [PubMed] Related Publications
The stimulatory effect of ACTH on gene expression is well documented and is thought to be a major mechanism by which ACTH maintains the functional and structural integrity of the gland. Previously, we showed that ACTH regulates the accumulation of over 1200 transcripts in Y1 adrenal cells, including a cluster with functions in alternative splicing of RNA. On this basis, we postulated that some of the effects of ACTH on the transcription landscape of Y1 cells are mediated by alternative splicing. In this study, we demonstrate that ACTH regulates the alternative splicing of four transcripts - Gnas, Cd151, Dab2 and Tia1. Inasmuch as alternative splicing potentially affects transcripts from more than two-thirds of the mouse genome, we suggest that these findings are representative of a genome-wide effect of ACTH that impacts on the mRNA and protein composition of the adrenal cortex.

Zhai R, Kan X, Wang B, et al.
miR-152 suppresses gastric cancer cell proliferation and motility by targeting CD151.
Tumour Biol. 2014; 35(11):11367-73 [PubMed] Related Publications
We aimed to study the post-translational regulation of CD151 by the microRNA miR-152. CD151 is highly expressed in gastric cancer (GC) and has been shown to accelerate GC by enhancing invasion and metastasis; however, its regulation is still unclear. Our results showed decreased expression of miR-152 in GC tissue samples and cell lines. In addition, miR-152 complementation significantly inhibits both the proliferation and motility of GC cells. CD151 was found to be a target of miR-152, and overexpression of CD151 attenuated the suppressive effect of miR-152. Our findings highlight an essential role of miR-152 in the regulation of proliferation and motility of GC cells and suggest a potential application of miR-152 in GC treatment.

Wang X, Yu H, Lu X, et al.
MiR-22 suppresses the proliferation and invasion of gastric cancer cells by inhibiting CD151.
Biochem Biophys Res Commun. 2014; 445(1):175-9 [PubMed] Related Publications
Gastric cancer (GC) is the second common cause of cancer-related death worldwide. microRNAs (miRNAs) play important roles in the carcinogenesis of GC. Here, we found that miR-22 was significantly decreased in GC tissue samples and cell lines. Ectopic overexpression of miR-22 remarkably suppressed cell proliferation and colony formation of GC cells. Moreover, overexpression of miR-22 significantly suppressed migration and invasion of GC cells. CD151 was found to be a target of miR-22. Furthermore, overexpression of CD151 significantly attenuated the tumor suppressive effect of miR-22. Taken together, miR-22 might suppress GC cells growth and motility partially by inhibiting CD151.

Teicher BA
Targets in small cell lung cancer.
Biochem Pharmacol. 2014; 87(2):211-9 [PubMed] Related Publications
Recurrent small cell lung cancer is a recalcitrant malgnancy. The application of genomic technologies has begun to elucidate the large number of genetic abnormalities in SCLC. Several cell surface receptors are known to be overexpressed by SCLC in clinic specimens and cell in culture including GPCRs such as the bradykinin receptor, the chemokine receptor CXCR4, the vasopression receeptor and the three bomebsin receptors. The glucose transporter GLUT1, the tetraspanin family member PETA/CD151 and the immunoglobulin superfamily member ALCAM/CD166 are also overexpressed by SCLC. NCAM/CD56 is overexpressed by nearly all SCLC and is currently the target for an antibody drug conjugate in Phase II trial. Although SCLC is not considered a RTK driven disease, IGF1R and FGFRs are often overexpressed by SCLC. SCLC abberantly expresses several developmental transcription factors including ASCL1, SOX2, 4, and 11, OCT4, NANOG, PAX5; however, overexpression of MYC may be a driver in SCLC. Like other cancers, SCLC expresses survival factors and uses aerobic glycolysis as a major source of ATP. The drawback of many potential targets overexpressed by SCLC is expression of the same proteins by normal tissues. We are slowly learning more about the molecular abnormalities that occur in SCLC; however, therapeutic impact from new findings remains a goal to work toward.

Han ZB, Yang Z, Chi Y, et al.
MicroRNA-124 suppresses breast cancer cell growth and motility by targeting CD151.
Cell Physiol Biochem. 2013; 31(6):823-32 [PubMed] Related Publications
BACKGROUND: CD151 is highly expressed in breast cancer cells and has been shown to accelerate breast cancer by enhancing cell growth and motility, but its regulation is poorly understood. To explore post-translation regulation of CD151, for example microRNAs, will be of great importance to claim the mechanism.
METHODS: A luciferase reporter assay was used to determine whether CD151 was a target of miR-124. The levels of CD151 mRNA were detected by real-time PCR and CD151 protein expression was measured by western blot and flow cytometry. The effects of miR-124 expression on growth, apoptosis, cell cycle and motility of breast cancer cells were determined.
RESULTS: We discovered that miR-124 directly targets the 3' untranslated region (3'-UTR) of CD151 mRNAs and suppresses its mRNA expression and protein translation. Both siRNA of CD151 and miR-124 mimics could significantly inhibit proliferation of breast cancer cell lines via cell cycle arrest but does not induce apoptosis. Meanwhile, miR-124 mimics significantly inhibited the motility of breast cancer cells.
CONCLUSION: miR-124 plays a critical role in inhibiting the invasive and metastatic potential of breast cancer cells, probably by directly targeting the CD151 genes. Our findings highlight an important role of miR-124 in the regulation of invasion and metastasis by breast cancer cells and suggest a potential application for miR-124 in breast cancer treatment.

Fernandez SV, Robertson FM, Pei J, et al.
Inflammatory breast cancer (IBC): clues for targeted therapies.
Breast Cancer Res Treat. 2013; 140(1):23-33 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Inflammatory breast cancer (IBC) is the most aggressive type of advanced breast cancer characterized by rapid proliferation, early metastatic development and poor prognosis. Since there are few preclinical models of IBC, there is a general lack of understanding of the complexity of the disease. Recently, we have developed a new model of IBC derived from the pleural effusion of a woman with metastatic secondary IBC. FC-IBC02 cells are triple negative and form clusters (mammospheres) in suspension that are strongly positive for E-cadherin, β-catenin and TSPAN24, all adhesion molecules that play an important role in cell migration and invasion. FC-IBC02 cells expressed stem cell markers and some, but not all of the characteristics of cells undergoing epithelial mesenchymal transition (EMT). Breast tumor FC-IBC02 xenografts developed quickly in SCID mice with the presence of tumor emboli and the development of lymph node and lung metastases. Remarkably, FC-IBC02 cells were able to produce brain metastasis in mice on intracardiac or intraperitoneal injections. Genomic studies of FC-IBC02 and other IBC cell lines showed that IBC cells had important amplification of 8q24 where MYC, ATAD2 and the focal adhesion kinase FAK1 are located. MYC and ATAD2 showed between 2.5 and 7 copies in IBC cells. FAK1, which plays important roles in anoikis resistance and tumor metastasis, showed 6-4 copies in IBC cells. Also, CD44 was amplified in triple-negative IBC cells (10-3 copies). Additionally, FC-IBC02 showed amplification of ALK and NOTCH3. These results indicate that MYC, ATAD2, CD44, NOTCH3, ALK and/or FAK1 may be used as potential targeted therapies against IBC.

Arora H, Qureshi R, Park WY
miR-506 regulates epithelial mesenchymal transition in breast cancer cell lines.
PLoS One. 2013; 8(5):e64273 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Epithelial-mesenchymal transition (EMT) is an important parameter related to breast cancer survival. Among several microRNAs predicted to target EMT-related genes, miR-506 is a novel miRNA found to be significantly related to breast cancer patient survival in a meta-analysis. miR-506 suppressed the expression of mesenchymal genes such as Vimentin, Snai2, and CD151 in MDA-MB-231 human breast cancer cell line. Moreover, NF-κB bound to the upstream promoter region of miR-506 to suppress transcription. Overexpression of miR-506 inhibited TGFβ-induced EMT and suppressed adhesion, invasion, and migration of MDA-MB-231 cells. From these results, we concluded that miR-506 plays a key role in the process of EMT through posttranslational control of EMT-related genes.

Gustafson-Wagner E, Stipp CS
The CD9/CD81 tetraspanin complex and tetraspanin CD151 regulate α3β1 integrin-dependent tumor cell behaviors by overlapping but distinct mechanisms.
PLoS One. 2013; 8(4):e61834 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Integrin α3β1 potently promotes cell motility on its ligands, laminin-332 and laminin-511, and this may help to explain why α3β1 has repeatedly been linked to breast carcinoma progression and metastasis. The pro-migratory functions of α3β1 depend strongly on lateral interactions with cell surface tetraspanin proteins. Tetraspanin CD151 interacts directly with the α3 integrin subunit and links α3β1 integrin to other tetraspanins, including CD9 and CD81. Loss of CD151 disrupts α3β1 association with other tetraspanins and impairs α3β1-dependent motility. However, the extent to which tetraspanins other than CD151 are required for specific α3β1 functions is unclear. To begin to clarify which aspects of α3β1 function require which tetraspanins, we created breast carcinoma cells depleted of both CD9 and CD81 by RNA interference. Silencing both of these closely related tetraspanins was required to uncover their contributions to α3β1 function. We then directly compared our CD9/CD81-silenced cells to CD151-silenced cells. Both CD9/CD81-silenced cells and CD151-silenced cells showed delayed α3β1-dependent cell spreading on laminin-332. Surprisingly, however, once fully spread, CD9/CD81-silenced cells, but not CD151-silenced cells, displayed impaired α3β1-dependent directed motility and altered front-rear cell morphology. Also unexpectedly, the CD9/CD81 complex, but not CD151, was required to promote α3β1 association with PKCα in breast carcinoma cells, and a PKC inhibitor mimicked aspects of the CD9/CD81-silenced cell motility defect. Our data reveal overlapping, but surprisingly distinct contributions of specific tetraspanins to α3β1 integrin function. Importantly, some of CD9/CD81's α3β1 regulatory functions may not require CD9/CD81 to be physically linked to α3β1 by CD151.

Copeland BT, Bowman MJ, Ashman LK
Genetic ablation of the tetraspanin CD151 reduces spontaneous metastatic spread of prostate cancer in the TRAMP model.
Mol Cancer Res. 2013; 11(1):95-105 [PubMed] Related Publications
Tetraspanins are integral membrane proteins that associate with motility-related molecules such as integrins. Experimental studies have indicated that they may be important regulators of tumor invasion and metastasis, and high expression of the tetraspanin CD151 has been linked to poor prognosis in a number of cancers. Here, we show for the first time that genetic ablation of CD151 inhibits spontaneous metastasis in a transgenic mouse model of de novo tumorigenesis. To evaluate the effects of CD151 on de novo prostate cancer initiation and metastasis, a Cd151(-/-) (KO) murine model was crossed with the Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) model. Mice were analyzed for initiation of prostate tumor by palpation and primary tumors were analyzed by immunohistochemistry. Liver and lungs were examined for incidence and size of spontaneous metastatic lesions by histopathology. Knocking-out Cd151 had no significant effect on prostate cancer initiation or on expression of markers of proliferation, apoptosis, or angiogenesis in primary tumors. However, it did significantly decrease metastasis in a site-specific fashion, notably to the lungs but not the liver. Thus, CD151 acts principally as promoter of metastasis in this model. Prostate cancer is the second highest cause of cancer-related deaths in men in most Western countries, with the majority of deaths attributed to late-stage metastatic disease. CD151 may prove to be a valuable prognostic marker for treatment stratification and is a possible antimetastatic target.

Deng X, Li Q, Hoff J, et al.
Integrin-associated CD151 drives ErbB2-evoked mammary tumor onset and metastasis.
Neoplasia. 2012; 14(8):678-89 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
ErbB2+ human breast cancer is a major clinical problem. Prior results have suggested that tetraspanin CD151 might contribute to ErbB2-driven breast cancer growth, survival, and metastasis. In other cancer types, CD151 sometimes supports tumor growth and metastasis. However, a definitive test of CD151 effects on de novo breast cancer initiation, growth, and metastasis has not previously been done. We used CD151 gene-deleted mice expressing the MMTV-ErbB2 transgene to show that CD151 strongly supports ErbB2+ mammary tumor initiation and metastasis. Delayed tumor onset (by 70-100 days) in the absence of CD151 was accompanied by reduced survival of mammary epithelial cells and impaired activation of FAK- and MAPK-dependent pathways. Both primary tumors and metastatic nodules showed smooth, regular borders, consistent with a less invasive phenotype. Furthermore, consistent with impaired oncogenesis and decreased metastasis, CD151-targeted MCF-10A/ErbB2 cells showed substantial decreases in three-dimensional colony formation, EGF-stimulated tumor cell motility, invasion, and transendothelial migration. These CD151-dependent functions were largely mediated through α6β4 integrin. Moreover, CD151 ablation substantially prevented PKC- and EGFR/ERK-dependent α6β4 integrin phosphorylation, consistent with retention of epithelial cell polarity and intermediate filament cytoskeletal connections, which helps to explain diminished metastasis. Finally, clinical data analyses revealed a strong correlation between CD151 and ErbB2 expression and metastasis-free survival of breast cancer patients. In conclusion, we provide strong evidence that CD151 collaborates with LB integrins (particularly α6β4 and ErbB2 (and EGFR) receptors to regulate multiple signaling pathways, thereby driving mammary tumor onset, survival, and metastasis. Consequently, CD151 is a useful therapeutic target in malignant ErbB2+ breast cancer.

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