|Gene:||LAMB3; laminin, beta 3|
|Aliases: || LAM5, LAMNB1, BM600-125KDA |
|Summary:||The product encoded by this gene is a laminin that belongs to a family of basement membrane proteins. This protein is a beta subunit laminin, which together with an alpha and a gamma subunit, forms laminin-5. Mutations in this gene cause epidermolysis bullosa junctional Herlitz type, and generalized atrophic benign epidermolysis bullosa, diseases that are characterized by blistering of the skin. Multiple alternatively spliced transcript variants that encode the same protein have been found for this gene. [provided by RefSeq, Jul 2008]|
|Databases:||OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene|
|Protein:||laminin subunit beta-3|
|Updated:||12 December, 2014|
What does this gene/protein do?
What pathways are this gene/protein implicaed in?
- Cell Communication
- ECM-receptor interaction
- Focal adhesion
Data from KEGG and BioCarta [BIOCARTA terms] via CGAP
Graph generated 12 December 2014 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 12 December, 2014 using data from PubMed, MeSH and CancerIndex
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).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
Search the Epigenomics database and view relevant gene tracks of samples.
Latest Publications: LAMB3 (cancer-related)
Reis ST, Timoszczuk LS, Pontes-Junior J, et al.The role of micro RNAs let7c, 100 and 218 expression and their target RAS, C-MYC, BUB1, RB, SMARCA5, LAMB3 and Ki-67 in prostate cancer.
Clinics (Sao Paulo). 2013; 68(5):652-7 [PubMed
] Free Access to Full Article Related Publications
The aim of this study is to verify the expression of proteins that are controlled by miR-let7c, 100 and 218 using immunohistochemistry in tissue microarray representative of localized and metastasized the lymph nodes and bone prostate cancer.METHODS:
To verify the expression of proteins that are controlled by miR-let7c (C-MYC, BUB1, RAS) 100 (SMARCA5, RB) and 218 (LAMB3) and cell proliferation (Ki-67) we used immunohistochemistry and computerized image system ImageJ MacBiophotonics in three tissue microarrays representative of localized prostate cancer and lymph node and bone metastases. miRNA expression was evaluated by qRT-PCR using 60 paraffin blocks to construct the tissue microarray representative of localized disease.RESULTS:
RAS expression was increased in localized prostate cancer and bone metastases compared to the lymph nodes (p=0.017). RB showed an increase in expression from localized prostate cancer to lymph node and bone metastasis (p=0.036). LAMB3 was highly expressed in localized and lymph node metastases (p<0.001). Cell proliferation evaluated by Ki-67 showed an increase from localized prostate cancer to metastases (p<0.001). We did not found any relationship between C-MYC (p=0.253), BUB1 (p=0.649) and SMARCA5 (p=0.315) protein expression with prognosis or tumor behavior.CONCLUSION:
We found that the expression of RAS, RB, LAMB3 and Ki-67 changed in the different stages of prostate cancer. Furthermore, we confirmed the overexpression of the miRNAs let7c, 100 and 218 in localized prostate cancer but failed to show the control of protein expression by the putative controller miRNAs using immunohistochemistry.Related: MKI67 Prostate Cancer RB1
Wnt5a is a non-canonical signaling Wnt. Low expression of WNT5A is correlated with poor prognosis in breast cancer patients. The highly invasive breast cancer cell lines, MDA-MB-231 and 4T1, express very low levels of WNT5A. To determine if enhanced expression of WNT5A would affect metastatic behavior, we generated WNT5A expressing cells from the 4T1 and MDA-MB-231 parental cell lines. WNT5A expressing cells demonstrated cobblestone morphology and reduced in vitro migration relative to controls. Cell growth was not altered. Metastasis to the lung via tail vein injection was reduced in the 4T1-WNT5A expressing cells relative to 4T1-vector controls. To determine the mechanism of WNT5A action on metastasis, we performed microarray and whole-transcriptome sequence analysis (RNA-seq) to compare gene expression in 4T1-WNT5A and 4T1-vector cells. Analysis indicated highly significant alterations in expression of genes associated with cellular movement. Down-regulation of a subset of these genes, Mmp13, Nos2, Il1a, Cxcl2, and Lamb3, in WNT5A expressing cells was verified by semi-quantitative RT-PCR. Significant differences in transcript splicing were also detected in cell movement associated genes including Cd44. Cd44 is an adhesion molecule with a complex genome structure. Variable exon usage is associated with metastatic phenotype. Alternative spicing of Cd44 in WNT5A expressing cells was confirmed using RT-PCR. We conclude that WNT5A inhibits metastasis through down-regulation of multiple cell movement pathways by regulating transcript levels and splicing of key genes like Cd44.Related: Breast Cancer
Yamamoto N, Kinoshita T, Nohata N, et al.Tumor suppressive microRNA-218 inhibits cancer cell migration and invasion by targeting focal adhesion pathways in cervical squamous cell carcinoma.
Int J Oncol. 2013; 42(5):1523-32 [PubMed
] Free Access to Full Article Related Publications
Cervical cancer is one of the most common cancers in women. More than 275,100 women die from cervical cancer each year. Cervical squamous cell carcinoma (cervical SCC), one of the most frequent types of cervical cancers, is associated with high-risk human papilloma virus (HPV), although HPV infection alone may not be enough to induce malignant transformation. MicroRNAs (miRNAs), a class of small non-coding RNAs, regulate protein-coding gene expression by repressing translation or cleaving RNA transcripts in a sequence-specific manner. A growing body of evidence suggests that miRNAs contribute to cervical SCC progression, development and metastasis. miRNA expression signatures in SCC (hypopharyngeal SCC and esophageal SCC) revealed that miR-218 expression was significantly reduced in cancer tissues compared with adjacent non-cancerous epithelium, suggesting that miR-218 is a candidate tumor suppressor. The aim of this study was to investigate the functional significance of miR-218 in cervical SCC and to identify novel miR‑218-mediated cancer pathways in cervical SCC. Restoration of miR-218 significantly inhibited cancer cell migration and invasion in both HPV-positive and HPV-negative cervical SCC cell lines. These data indicated that miR-218 acts as a tumor suppressor in cervical SCC. Our in silico analysis showed that miR-218 appeared to be an important modulator of tumor cell processes through suppression of many targets, particularly those involved in focal adhesion signaling pathways. Gene expression data indicated that LAMB3, a laminin protein known to influence cell differentiation, migration, adhesion, proliferation and survival, was upregulated in cervical SCC clinical specimens, and silencing studies demonstrated that LAMB3 functioned as an oncogene in cervical SCC. The identification of novel tumor-suppressive miR-218-mediated molecular pathways has provided new insights into cervical SCC oncogenesis and metastasis.Related: Signal Transduction Cervical Cancer
To explore the key regulatory genes associated with lung cancer in order to reduce its occurrence and progress through silencing these key genes.METHODS:
To identify the key regulatory genes involved in lung cancer, we performed a combination of gene array and bioinformatics analyses to compare gene transcription profiles in 3 monoclonal cell strains with high, medium or low metastatic abilities, which were separated from the SPC-A-1sci and SPC-A-1 cell lines by limiting dilution monoclone assay. We then analyzed those genes' biological activities by knocking down their expression in SPC-A-1sci cells using siRNA and lenti-viral shRNA vectors, followed by determinations of the invasion and migration capabilities of the resulting cell lines in vitro as well as their potential for inducing occurrence and metastasis of lung cancer in vivo. To examine the clinical relevance of these findings, we analyzed the expression levels of the identified genes in human lung cancer tissues (n = 135) and matched adjacent normal tissues by immunohistochemical (IHC) staining.RESULTS:
Three monoclonal cell strains characterized with high, medium or low metastatic abilities were successfully selected. Gene array and bioinformatics analyses implied that osteopontin, LAMB3 and ITGB1 were key genes involved in lung cancer. Knockdown of these genes suppressed human lung cancer cell invasion and metastasis in vitro and in vivo. Clinical sample analyses indicated that osteopontin, LAMB3 and ITGB1 protein expression levels were higher in lung cancer patients, compared to non-cancerous adjacent tissues, and correlated with lymphatic metastasis.CONCLUSIONS:
We confirmed that osteopontin, LAMB3 and ITGB1 played important roles in the occurrence and metastasis of lung cancer, thus provided important clues to understanding the molecular mechanism of metastasis and contributing to the therapeutic treatment of lung cancer.Related: ITGB1 Lung Cancer
MicroRNA (miRNA)-related single nucleotide polymorphisms (SNPs) may compromise miRNA binding affinity and modify mRNA expression levels of the target genes, thus leading to cancer susceptibility. However, few studies have investigated roles of miRNA-related SNPs in the etiology of cervical carcinoma.METHODS:
In this case-control study of 1,584 cervical cancer cases and 1,394 cancer-free female controls, we investigated associations between two miR-218-related SNPs involved in the LAMB3-miR-218 pathway and the risk of cervical carcinoma in Eastern Chinese women.RESULTS:
We found that the pri-miR-218 rs11134527 variant GG genotype was significantly associated with a decreased risk of cervical carcinoma compared with AA/AG genotypes (adjusted OR=0.77, 95% CI=0.63-0.95, P=0.015). However, this association was not observed for the miR-218 binding site SNP (rs2566) on LAMB3. Using the multifactor dimensionality reduction analysis, we observed some evidence of interactions of these two SNPs with other risk factors, especially age at primiparity and menopausal status, in the risk of cervical carcinoma.CONCLUSIONS:
The pri-miR-218 rs11134527 SNP was significantly associated with the risk of cervical carcinoma in Eastern Chinese women. Larger, independent studies are warranted to validate our findings.Related: Cervical Cancer
Kinoshita T, Hanazawa T, Nohata N, et al.Tumor suppressive microRNA-218 inhibits cancer cell migration and invasion through targeting laminin-332 in head and neck squamous cell carcinoma.
Oncotarget. 2012; 3(11):1386-400 [PubMed
] Free Access to Full Article Related Publications
Recent our microRNA (miRNA) expression signature revealed that expression of microRNA-218 (miR-218) was reduced in cancer tissues, suggesting a candidate of tumor suppressor in head and neck squamous cell carcinoma (HNSCC). The aim of this study was to investigate the functional significance of miR-218 and its mediated moleculer pathways in HNSCC. Restoration of miR-218 in cancer cells led to significant inhibition of cell migration and invasion activities in HNSCC cell lines (FaDu and SAS). Genome-wide gene expression analysis of miR-218 transfectants and in silico database analysis showed that focal adhesion pathway was a promising candidate of miR-218 target pathways. The laminins are an important and biologically active part of the basal lamina, the function of that are various such as influencing cell differentiation, migration and adhesion as well as proliferation and cell survival. Interestingly, all components of laminin-332 (LAMA3, LAMB3 and LAMC2) are listed on the candidate genes in focal adhesion pathway. Furthermore, we focused on LAMB3 which has a miR-218 target site and gene expression studies and luciferase reporter assays showed that LAMB3 was directly regulated by miR-218. Silencing study of LAMB3 demonstrated significant inhibition of cell migration and invasion. In clinical specimens with HNSCC, the expression levels of laminin-332 were significantly upregulated in cancer tissues compared to adjacent non-cancerous tissues. Our analysis data showed that tumor suppressive miR-218 contributes to cancer cell migration and invasion through regulating focal adhesion pathway, especially laminin-332. Tumor suppressive miRNA-mediated novel cancer pathways provide new insights into the potential mechanisms of HNSCC oncogenesis.Related: Head and Neck Cancers Head and Neck Cancers - Molecular Biology
Targeting tumor metabolism by energy restriction-mimetic agents (ERMAs) has emerged as a strategy for cancer therapy/prevention. Evidence suggests a mechanistic link between ERMA-mediated antitumor effects and epigenetic gene regulation.METHODS:
Microarray analysis showed that a novel thiazolidinedione-derived ERMA, CG-12, and glucose deprivation could suppress DNA methyltransferase (DNMT)1 expression and reactivate DNA methylation-silenced tumor suppressor genes in LNCaP prostate cancer cells. Thus, we investigated the effects of a potent CG-12 derivative, CG-5, vis-à-vis 2-deoxyglucose, glucose deprivation and/or 5-aza-deoxycytidine, on DNMT isoform expression (Western blotting, RT-PCR), DNMT1 transcriptional activation (luciferase reporter assay), and expression of genes frequently hypermethylated in prostate cancer (quantitative real-time PCR). Promoter methylation was assessed by pyrosequencing analysis. SiRNA-mediated knockdown and ectopic expression of DNMT1 were used to validate DNMT1 as a target of CG-5.RESULTS:
CG-5 and glucose deprivation upregulated the expression of DNA methylation-silenced tumor suppressor genes, including GADD45a, GADD45b, IGFBP3, LAMB3, BASP1, GPX3, and GSTP1, but also downregulated methylated tumor/invasion-promoting genes, including CD44, S100A4, and TACSTD2. In contrast, 5-aza-deoxycytidine induced global reactivation of these genes. CG-5 mediated these epigenetic effects by transcriptional repression of DNMT1, which was associated with reduced expression of Sp1 and E2F1. SiRNA-mediated knockdown and ectopic expression of DNMT1 corroborated DNMT1's role in the modulation of gene expression by CG-5. Pyrosequencing revealed differential effects of CG-5 versus 5-aza-deoxycytidine on promoter methylation in these genes.CONCLUSIONS:
These findings reveal a previously uncharacterized epigenetic effect of ERMAs on DNA methylation-silenced tumor suppressor genes, which may foster novel strategies for prostate cancer therapy.Related: Azacitidine Prostate Cancer
Ii M, Yamamoto H, Taniguchi H, et al.Co-expression of laminin β3 and γ2 chains and epigenetic inactivation of laminin α3 chain in gastric cancer.
Int J Oncol. 2011; 39(3):593-9 [PubMed
] Related Publications
Laminin-332 (LM-332, formerly termed laminin-5) is a heterotrimeric glycoprotein that regulates cell adhesion and migration. Molecular alterations of LM-332 are involved in cancer progression. The aim of this study was to clarify alterations of LM-332 in gastric carcinoma. The expression of LM-332 subunits in 10 gastric carcinoma cell lines was investigated by RT-PCR, Western blotting, and immuno-cytochemical/immunofluorescent analyses. The promoter methylation status of LM-332-encoding genes (LAMA3, LAMB3 and LAMC2) was analyzed by methylation-specific PCR (MSP). The relationship between cell migration and LM-332 expression was assessed by the scratch assay. The expression of LM-332 was analyzed immunohistochemically in 90 gastric cancer tissues. Co-expression of laminin β3 and γ2 chains was often observed in gastric carcinoma cell lines at mRNA and protein levels. In contrast, there was no expression of laminin α3 at either the mRNA or protein levels. Extra-cellular secretion of laminin β3 and γ2 chains was found in 2 of the 10 cell lines. The LAMA3 gene was transcriptionally silenced by methylation of the promoter CpG islands in all of the cell lines, while the LAMB3 and LAMC2 genes were silenced in several cell lines. Treatment with a demethylating agent, 5-aza-2'-deoxycytidine (5-aza-dC), restored expression of the LM-332-encoding genes. Methylation frequency of LAMA3 was higher than those of the LAMB2 and LAMC2 genes in gastric cancer tissues. Migration distances were significantly correlated with cytoplasmic laminin γ2 chain expression. Immunohistochemistry showed frequent co-expression of laminin β3 and γ2 chains in gastric carcinoma cells, which was significantly correlated with depth of invasion and advanced tumor stage. The results suggest that the laminin β3 and γ2 chains accumulate intracellularly and play a role in gastric cancer progression, while epigenetic silencing of the laminin α3 chain may lead to inability to synthesize the basement membrane and may affect cancer cell invasion. Cancer cell motility appears to be associated with the cyto-plasmic laminin γ2 chain in vitro.Related: Stomach Cancer Gastric Cancer
Kwon OH, Park JL, Kim M, et al.Aberrant up-regulation of LAMB3 and LAMC2 by promoter demethylation in gastric cancer.
Biochem Biophys Res Commun. 2011; 406(4):539-45 [PubMed
] Related Publications
The LAMB3 and LAMC2 genes encode the laminin-5 β3 and γ2 chains, respectively, which are parts of laminin-5, one of the major components of the basement membrane zone. Here, we report the frequent up-regulation of LAMB3 and LAMC2 by promoter demethylation in gastric cancer. Gene expression data analysis showed that LAMB3 and LAMC2 were up-regulated in various tumor tissues. Combined analyses of DNA methylation and gene expression of both genes in gastric cancer cell lines and tissues showed that DNA hypomethylation was associated with the up-regulation of both genes. Treatment with a methylation inhibitor induced LAMB3 and LAMC2 expression in gastric cancer cell lines in which both genes were silenced. By chromatin immunoprecipitation assay, we showed the activation histone mark H3K4me3 was associated with the expression of both genes. The expression level of LAMB3 affected multiple malignant phenotypes in gastric cancer cell lines. These results suggest that epigenetic activation of LAMB3 and LAMC2 may play an important role in gastric carcinogenesis.Related: Stomach Cancer Gastric Cancer
Todorovic V, Sersa G, Mlakar V, et al.Metastatic potential of melanoma cells is not affected by electrochemotherapy.
Melanoma Res. 2011; 21(3):196-205 [PubMed
] Related Publications
Cisplatin is among the most widely used cytotoxic anticancer agents in solid tumors; however, the development of secondary resistance remains a major obstacle to clinical efficacy. Treatment-related DNA hypermethylation may play a role in creating drug-resistant phenotypes by inactivating genes that are required for cytotoxicity. We applied a pharmacologic unmasking approach to detect hypermethylated genes whose inactivation contributes to cisplatin resistance. Using three pairs of isogeneic, cisplatin-sensitive, and cisplatin-resistant cell lines derived from two parental cell lines (KB-3-1 and SCC25), we identified several hundred genes that were downregulated in each resistant cell line and reactivated by the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine. Among them, 30 genes were common to two or more cell lines and/or reported to be downregulated in previous studies. Bisulfite sequencing confirmed that 14 genes were hypermethylated in resistant cell lines but not in the sensitive parental cell lines. Six of 14 genes (SAT, C8orf4, LAMB3, TUBB, G0S2, and MCAM) were cisplatin inducible in sensitive but not in resistant cell lines. Small interfering RNA knockdown of two genes, SAT and S100P, increased cell viability with cisplatin treatment in sensitive parental cell lines. S100P knockdown significantly decreased the S-phase fraction of parental sensitive cell lines and slowed cell proliferation, which was associated with decreased sensitivity to cisplatin. Based on these findings, we conclude that DNA methylation is a frequent event in cells that are chronically exposed to cisplatin and that methylation-induced gene silencing may play a role in the development of resistance to cytotoxic chemotherapeutic agents.Related: Azacitidine Cisplatin
Zboralski D, Böckmann M, Zapatka M, et al.Divergent mechanisms underlie Smad4-mediated positive regulation of the three genes encoding the basement membrane component laminin-332 (laminin-5).
BMC Cancer. 2008; 8:215 [PubMed
] Free Access to Full Article Related Publications
Functional inactivation of the tumor suppressor Smad4 in colorectal and pancreatic carcinogenesis occurs coincident with the transition to invasive growth. Breaking the basement membrane (BM) barrier, a prerequisite for invasive growth, can be due to tumor induced proteolytic tissue remodeling or to reduced synthesis of BM molecules by incipient tumor cells. Laminin-332 (laminin-5), a heterotrimeric BM component composed of alpha 3-, beta 3- and gamma 2-chains, has recently been identified as a target structure of Smad4 and represents the first example for expression control of an essential BM component by a tumor and invasion suppressor. Biochemically Smad4 is a transmitter of signals of the TGFbeta superfamily of cytokines. We have reported previously, that Smad4 functions as a positive transcriptional regulator of constitutive and of TGFbeta-induced transcription of all three genes encoding Laminin-332, LAMA3, LAMB3 and LAMC2.METHODS:
Promoter-reporter constructs harboring 4 kb upstream regions, each of the three genes encoding Laminin-322 as well as deletion and mutations constructs were established. Promoter activities and TGFbeta induction were assayed through transient transfections in Smad4-negative human cancer cells and their stable Smad4-positive derivatives. Functionally relevant binding sites were subsequently confirmed through chromatin immunoprecipitation.RESULTS:
Herein, we report that Smad4 mediates transcriptional regulation through three different mechanisms, namely through Smad4 binding to a functional SBE site exclusively in the LAMA3 promoter, Smad4 binding to AP1 (and Sp1) sites presumably via interaction with AP1 family components and lastly a Smad4 impact on transcription of AP1 factors. Whereas Smad4 is essential for positive regulation of all three genes, the molecular mechanisms are significantly divergent between the LAMA3 promoter as compared to the LAMB3 and LAMC2 promoters.CONCLUSION:
We hypothesize that this divergence in modular regulation of the three promoters may lay the ground for uncoupled regulation of Laminin-332 in Smad4-deficient tumor cells in response to stromally expressed cytokines acting on budding tumor cells.Related: Colorectal (Bowel) Cancer Cytokines Cancer of the Pancreas Pancreatic Cancer MADH4
The pathogenesis of nasopharyngeal carcinoma (NPC) is a complicated process involving genetic predisposition, Epstein-Bar Virus infection, and genetic alterations. Although some oncogenes and tumor suppressor genes have been previously reported in NPC, a complete understanding of the pathogenesis of NPC in the context of global gene expression, transcriptional pathways and biomarker assessment remains to be elucidated.METHODS:
Total RNA from 32 pathologically-confirmed cases of poorly-differentiated NPC was divided into pools inclusive of four consecutive specimens and each pool (T1 to T8) was co-hybridized with pooled RNA from 24 normal non-cancerous nasopharyngeal tissues (NP) to a human 8K cDNA array platform. The reliability of microarray data was validated for selected genes by semi-quantitative RT-PCR and immunohistochemistry.RESULTS:
Stringent statistical filtering parameters identified 435 genes to be up-regulated and 257 genes to be down-regulated in NPC compared to NP. Seven up-regulated genes including CYC1, MIF, LAMB3, TUBB2, UBE2C and TRAP1 had been previously proposed as candidate common cancer biomarkers based on a previous extensive comparison among various cancers and normal tissues which did not, however, include NPC or NP. In addition, nine known oncogenes and tumor suppressor genes, MIF, BIRC5, PTTG1, ATM, FOXO1A, TGFBR2, PRKAR1A, KLF5 and PDCD4 were identified through the microarray literature-based annotation search engine MILANO, suggesting these genes may be specifically involved in the promotion of the malignant conversion of nasopharyngeal epithelium. Finally, we found that these differentially expressed genes were involved in apoptosis, MAPK, VEGF and B cell receptor signaling pathways and other functions associated with cell growth, signal transduction and immune system activation.CONCLUSION:
This study identified potential candidate biomarkers, oncogenes/tumor suppressor genes involved in several pathways relevant to the oncogenesis of NPC. This information may facilitate the determination of diagnostic and therapeutic targets for NPC as well as provide insights about the molecular pathogenesis of NPC.Related: Nasopharyngeal Cancer Signal Transduction
Kita Y, Mimori K, Tanaka F, et al.Clinical significance of LAMB3 and COL7A1 mRNA in esophageal squamous cell carcinoma.
Eur J Surg Oncol. 2009; 35(1):52-8 [PubMed
] Related Publications
LAMB3 and COL7A1 genes code for the laminin-5beta3 chain and type VII collagen, respectively. They constitute the major components of the basement membrane zone. The aim of the current study was to clarify the clinical significance of LAMB3 and COL7A1 mRNA expression in esophageal squamous cell carcinoma (ESC).METHODS:
We quantitated the expression of LAMB3 mRNA and COL7A1 mRNA in malignant esophageal tissues (T) and corresponding normal tissues (N) by real-time quantitative reverse transcription-polymerase chain reaction assays. The clinicopathologic significance of LAMB3 and COL7A1 expression was also determined. Paired T and N tissues were obtained from 66 patients who underwent curative esophagectomy.RESULTS:
The expression levels of LAMB3 and COL7A1 mRNAs were higher in malignant tissues than in the corresponding normal tissues. The level of LAMB3 expression was significantly correlated with the depth of invasion and venous invasion (p=0.007 and 0.001, respectively). COL7A1 expression was significantly correlated with depth of tumor invasion and lymphatic invasion (p=0.046, 0.013, respectively). The five-year survival rate was better in the 22 patients with relatively low expression of both LAMB3 and COL7A1 in comparison with the other 44 cases (p<0.05).CONCLUSION:
The evaluation of LAMB3 and COL7A1 mRNA expression is useful for predicting the malignant properties of ESC and may prove valuable in predicting the future course of the disease.Related: Cancer of the Esophagus Esophageal Cancer
Human papillomaviruses (HPVs) are involved in the pathogenesis of cancer of the cervix (CaCx). MicroRNA (miRNA) expression analysis using Ambion (Austin, TX, USA) arrays showed that three miRNAs were overexpressed and 24 underexpressed in cervical cell lines containing integrated HPV-16 DNA compared to the normal cervix. Furthermore, nine miRNAs were overexpressed and one underexpressed in integrated HPV-16 cell lines compared to the HPV-negative CaCx cell line C-33A. Based on microarray and/or quantitative real-time PCR and northern blot analyses, microRNA-218 (miR-218) was specifically underexpressed in HPV-positive cell lines, cervical lesions and cancer tissues containing HPV-16 DNA compared to both C-33A and the normal cervix. Expression of the E6 oncogene of high-risk HPV-16, but not that of low-risk HPV-6, reduced miR-218 expression, and conversely, RNA interference of E6/E7 oncogenes in an HPV-16-positive cell line increased miR-218 expression. We also demonstrate that the epithelial cell-specific marker LAMB3 is a target of miR-218. We also show that LAMB3 expression is increased in the presence of the HPV-16 E6 oncogene and this effect is mediated through miR-218. These findings may contribute to a better understanding of the molecular mechanisms involved in cervical carcinogenesis.Related: Cervical Cancer
Zhang HY, Rumilla KM, Jin L, et al.Association of DNA methylation and epigenetic inactivation of RASSF1A and beta-catenin with metastasis in small bowel carcinoid tumors.
Endocrine. 2006; 30(3):299-306 [PubMed
] Related Publications
We analyzed promoter methylation of RASSF1A, CTNNB1, CDH1, LAMB3, LAMC2, RUNX3, NORE1A, and CAV1 using methylation-specific PCR in 33 cases of small bowel carcinoid with both matched primary and metastatic tumors. The methylation status of RASSF1A and CTNNB1 were also determined in six primary appendiceal carcinoid tumors. Two neuroendocrine cell lines, NCI-H727 and HTB-119, were analyzed for promoter methylation. Immunohistochemical analyses for RASSF1A and beta-catenin were performed in 28 matched primary and metastatic tumors. Western blot analysis for RASSF1A and beta-catenin was also performed. Normal enterochromaffin cells were unmethylated in all eight genes examined. RASSF1A and CTNNB1 were unmethylated in appendiceal carcinoids. Methylation of RASSF1A and CTNNB1 promoters was more frequent in metastatic compared to primary tumors (p = 0.013 and 0.004, respectively). The NCI-H727 and HTB-119 cells lines were methylated in the RASSF1A promoter region, and after treatment with 5-aza-2'-deoxycytidine (5-AZA), RASSF1A mRNA was expressed in both cell lines. Western blot results for RASSF1A and beta-catenin supported the methylation-specific PCR findings. The other six genes did not show significant differences. These results suggest that increased methylation of RASSF1A and CTNNB1 may play important roles in progression and metastasis of small bowel carcinoid tumors.Related: Azacitidine Gastrointestinal Carcinoid Tumours CTNNB1 gene RASSF1
Suguro M, Tagawa H, Kagami Y, et al.Expression profiling analysis of the CD5+ diffuse large B-cell lymphoma subgroup: development of a CD5 signature.
Cancer Sci. 2006; 97(9):868-74 [PubMed
] Related Publications
Diffuse large B-cell lymphoma (DLBCL) accounts for 30% of non-Hodgkin's lymphomas and is known to comprise heterogeneous groups. We previously reported that CD5+ DLBCL is a clinically distinct subgroup of these tumors that is associated with poor prognosis. In our current study, we have used gene expression profiling technology in an attempt to identify new markers and to further characterize the biological features of CD5+ DLBCL. Candidate genes, which showed the greatest difference in expression between 22 CD5+ and 26 CD5- DLBCL cases, were selected from our screening and subjected to clustering analysis. This resulted in identification of a specific mRNA profile (a CD5 signature) for CD5+ DLBCL. The CD5 signature included downregulated extracellular matrix genes such as POSTN, SPARC, COL1A1, COL3A1, CTSK, MMP9 and LAMB3, and comprised upregulated genes including TRPM4. We tested this CD5 signature for its potential use as a relevant marker for CD5+ DLBCL and found that it did indeed recognize this subgroup. The tumors identified by the CD5 signature contained most of the CD5+ DLBCL cases and some CD5- DLBCL cases. Moreover, the subgroup of cases with this CD5 signature showed a poorer prognosis. The subsequent application of the CD5 signature to the analysis of an independent series of DLBCL microarray data resulted in identification of a subgroup of DLBCL cases with a similar clinical outcome, further suggesting that the CD5 signature can be used as a clinically relevant marker of this disease.
Irifune H, Nishimori H, Watanabe G, et al.Aberrant laminin beta3 isoforms downstream of EWS-ETS fusion genes in Ewing family tumors.
Cancer Biol Ther. 2005; 4(4):449-55 [PubMed
] Related Publications
Ewing family tumors (EFTs) are associated with a chromosomal translocation resulting in a fusion of the amino-terminus of EWS with the DNA-binding domain of an ETS transcription factor. Although previous reports suggested that these chimeric proteins would act as aberrant transcription factors, their downstream targets have not been fully elucidated. To identify downstream targets of these EWS-ETS fusion proteins, we introduced EWS-ETS fusion constructs into a human fibrosarcoma cell line, HT-1080, by retroviral transduction. Here we report that the LAMB3 gene encoding the beta3 chain of basement membrane protein laminin-5 is induced to a significantly higher level in cells expressing EWS-ETSs than in cells expressing normal ETSs. Additionally through use of an antisense oligonucleotide for EWS-ERG in the W-ES EFT cell line, laminin beta3 protein was reduced coordinately with EWS-ERG fusion protein expression. Furthermore, we found small mRNAs were preferentially transcribed from the LAMB3 gene in EFT cell lines. Molecular cloning of the entire coding region shows that the alternative transcripts from different promoter(s) located within the intron 14, which encode small proteins, likely are major products of the LAMB3 gene in EFT cells. We show that the small isoforms conferred increased anchorage-independent proliferation to NIH3T3 cells. Together with previous studies showing that laminin-5 is involved in the invasive and malignant phenotype of several tumor types, our data suggest that the oncogenic effect of EWS-ETS may be mediated in part by upregulation of LAMB3 expression.Related: Ewing's Sarcoma
Interactions between extracellular matrix proteins and prostate carcinoma cells change dramatically during prostate tumor progression. We have concentrated on two key modifications that occur in the hemidesmosome in prostate carcinoma: loss of laminin-5 protein expression and altered basal cell polarity of the alpha6beta4 integrin. We previously demonstrated two cell line-specific isoforms (beta3A and beta3B) of the LAMB3 message. Cells expressing only the beta3B isoform did not translate the beta3 protein and were unable to assemble the laminin-5 trimer. One such cell line, LNCaP, was selected to determine whether restoration of the laminin-5 beta3A isoform would cause expression of a functional laminin-5 beta3 chain, assembly and secretion of the laminin-5 trimer, and reversion to a non-neoplastic phenotype. Laminin-5 beta3A cDNA was cloned and stably transfected into LNCaP cells. We observed the restoration of the beta3 protein, but a laminin-5 trimer was not secreted. Moreover, increased cell migration was demonstrated, and tumorigenicity was increased in SCID mice. A microarray analysis, performed between transfected and nontransfected LNCaP cells, showed most changing genes to be associated with signal transduction. The beta3 chain of laminin-5 may thus play an important role in signal transduction, which may enhance cell motility and tumorigenesis.Related: Prostate Cancer Signal Transduction
Sathyanarayana UG, Maruyama R, Padar A, et al.Molecular detection of noninvasive and invasive bladder tumor tissues and exfoliated cells by aberrant promoter methylation of laminin-5 encoding genes.
Cancer Res. 2004; 64(4):1425-30 [PubMed
] Related Publications
Laminin-5 (LN5) anchors epithelial cells to the underlying basement membrane, and it is encoded by three distinct genes: LAMA3, LAMB3, and LAMC2. To metastasize and grow, cancer cells must invade and destroy the basement membrane. Our previous work has shown that epigenetic inactivation is a major mechanism of silencing LN5 genes in lung cancers. We extended our methylation studies to resected bladder tumors (n = 128) and exfoliated cell samples (bladder washes and voided urine; n = 71) and correlated the data with clinicopathologic findings. Nonmalignant urothelium had uniform expression of LN5 genes and lacked methylation. The methylation frequencies for LN5 genes in tumors were 21-45%, and there was excellent concordance between methylation in tumors and corresponding exfoliated cells. Methylation of LAMA3 and LAMB3 and the methylation index were correlated significantly with several parameters of poor prognosis (tumor grade, growth pattern, muscle invasion, tumor stage, and ploidy pattern), whereas methylation of LAMC2 and methylation index were associated with shortened patient survival. Of particular interest, methylation frequencies of LAMA3 helped to distinguish invasive (72%) from noninvasive (12%) tumors. These results suggest that methylation of LN5 genes has potential clinical applications in bladder cancers.Related: Bladder Cancer Bladder Cancer - Molecular Biology
Sathyanarayana UG, Padar A, Suzuki M, et al.Aberrant promoter methylation of laminin-5-encoding genes in prostate cancers and its relationship to clinicopathological features.
Clin Cancer Res. 2003; 9(17):6395-400 [PubMed
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Laminin-5 (LN5) is an essential component of the basement membrane (BM) and is composed of three chains that are the products of three distinct genes (LAMA3, LAMB3, and LAMC2). Differential expression of LN5 genes has been reported in prostate and other cancers. Recently, in lung cancers, we developed methylation-specific PCR assays for each gene and demonstrated that the aberrant methylation as the mechanism of inactivation of genes. In this study, we investigated the aberrant promoter methylation of LN5 genes in prostate cancers and correlated the data with clinicopathological features.EXPERIMENTAL DESIGN:
Promoter methylation of LN5-encoding genes was analyzed in 101 prostate cancer samples by methylation-specific PCR assay. In addition, we analyzed 32 nonmalignant prostate tissue samples. The methylation index (MI) was determined as the methylated fraction of the genes examined.RESULTS:
The frequencies of loss of expression for the LAMA3, LAMB3, and LAMC2 genes in six prostate cancer cell lines were 83, 67, and 50%, respectively, whereas the methylation frequencies were 83, 67, and 33%, respectively. The concordances between loss of expression and methylation for the three genes were 100, 100, and 83%, respectively. The frequency of methylation of LN5-encoding genes in prostate cancers and nonmalignant prostate tissues, respectively, were: 44 and 12% for LAMA3 (P = 0.001); 18 and 6% for LAMB3; and 41 and 9% for LAMC2 (P = 0.001). In addition, methylation frequencies of any one or two genes, frequencies of at least one-gene methylation and mean chain MI were significantly higher in prostate cancers than in nonmalignant prostate tissues. For clinicopathological correlations, the high Gleason score (GS) group, high preoperative serum prostate-specific antigen (PSA) group, and high stage group had significantly higher methylation frequencies of LAMA3 than their corresponding low groups. Methylation frequency of at least one gene and mean chain MI was significantly higher in the high PSA group and high-stage group than their respective low groups. There was significant correlation between MI and PSA. The high GS group had higher frequencies of at least one gene methylation and mean chain MI than the low GS group.CONCLUSIONS:
Our results demonstrate frequent epigenetic silencing of LN5-encoding genes in prostate cancers and it correlates with clinicopathological features of poor prognosis. These findings are of biological interest and potentially of clinical importance.Related: Prostate Cancer
Sathyanarayana UG, Padar A, Huang CX, et al.Aberrant promoter methylation and silencing of laminin-5-encoding genes in breast carcinoma.
Clin Cancer Res. 2003; 9(17):6389-94 [PubMed
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Down-regulation of Laminin-5 (LN5)-encoding genes (LAMA3, LAMB3, and LAMC2) has been reported in various human cancers. However, the mechanism of inactivation was not clearly understood until recently. In this study, we investigated the loss of expression of three LN5-encoding genes in breast cancer cell lines and elucidated the mechanism of silencing of the genes in breast cancer cell lines and tumors.EXPERIMENTAL DESIGN:
We examined the expression of the three LN5-encoding genes by reverse transcription-PCR in breast cancer cell lines (n = 20). To elucidate the mechanism of silencing, we treated expression negative cell lines (n = 5) with a demethylating agent and examined restoration of expression by reverse transcription-PCR. By using methylation-specific primers designed by us, we validated the methylation status of the promoter regions in breast cancer cell lines using methylation-specific PCR. We additionally studied the methylation patterns in primary breast tumors (n = 74) and correlated the data with clinical parameters.RESULTS:
We observed varied losses of expression (10-55%) of LN5-encoding genes in breast cancer cell lines. Expression of one or more genes was lost in 65% of breast cancer cell lines. Treatment of expression negative cell lines with demethylating agent restored expression in all cases. Methylation frequencies of LAMA3, LAMB3, and LAMC2 genes in 20 breast cancer cell lines were 40, 5, and 15%, respectively. The concordances between loss of expression and methylation in 20 breast cancer cell lines for the three genes (85-95%) were statistically significant. Nonmalignant breast tissues (n = 30) had very low frequencies of methylation (0-7%). In 74 breast tumors, methylation frequencies LAMA3, LAMB3, and LAMC2 were 44, 4, and 20%, respectively. The differences in methylation frequencies between cell lines and tumors were not statistically significant for all of the three genes. The methylation frequencies of LAMA3 and mean chain methylation index in cell lines and tumors were significantly different from methylation frequencies in nonmalignant tissues, and they were significantly higher in high stage and large size tumors as compared with low-stage and small size tumors. LAMA3 promoter methylation frequency in breast tumors was associated with increased tumor stage (P < 0.001) and tumor size (P < 0.001).CONCLUSIONS:
Our results demonstrate epigenetic inactivation of LN5-encoding genes in breast cancers and association of LAMA3 promoter methylation with increased tumor stage and tumor size. Our findings are of biological interest and potentially of clinical importance.Related: Breast Cancer
Manda R, Kohno T, Niki T, et al.Differential expression of the LAMB3 and LAMC2 genes between small cell and non-small cell lung carcinomas.
Biochem Biophys Res Commun. 2000; 275(2):440-5 [PubMed
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To identify genes differentially expressed between small cell lung carcinoma (SCLC) cells and non-SCLC cells, mRNA differential display was applied to 3 SCLC cell lines and 6 non-SCLC cell lines. The LAMB3 gene was identified as being expressed only in non-SCLC cells and not in SCLC cells. The LAMB3 gene encodes the laminin beta3 chain, which is a unique component of laminin-5. Laminin-5 is a heterotrimer protein consisting of the alpha3, beta3, and gamma2 chains, and another unique component of laminin-5 is the gamma2 chain encoded by the LAMC2 gene. RT-PCR analysis of the LAMB3 and LAMC2 genes in 45 lung cancer cell lines revealed that both the LAMB3 and LAMC2 genes were co-expressed in 21 of 32 non-SCLC cell lines (66%) but only in one of 13 SCLC cell lines (8%). Coexpression of the LAMB3 and LAMC2 genes was also observed in all 4 cases of primary non-SCLC cells examined but not in the corresponding non-cancerous lung cells. Since alpha6beta4 integrin, the specific laminin-5 binding receptor, is known to be expressed only in non-SCLC cells and not in SCLC cells, it was indicated that laminin-5 is a critical microenvironmental factor for the growth of non-SCLC cells but not of SCLC cells. The differences in the expression of integrins and laminins would be critical factors to distinguish SCLC and non-SCLC cells, and such differences might be associated with the unique biological properties of SCLC cells, including metastatic potential and drug sensitivity.Related: Non-Small Cell Lung Cancer Lung Cancer
Van der Woude syndrome (VWS) is a common form of syndromic cleft lip and palate and accounts for approximately 2% of all cleft lip and palate cases. Distinguishing characteristics include cleft lip with or without cleft palate, isolated cleft palate, bilateral lip pits, hypodontia, normal intelligence, and an autosomal-dominant mode of transmission with a high degree of penetrance. Previously, the VWS locus was mapped to a 1.6-cM region in 1q32-q41 between D1S491 and D1S205, and a 4.4-Mb contig of YAC clones of this region was constructed. In the current investigation, gene-based and anonymous STSs were developed from the existing physical map and were then used to construct a contig of sequence-ready bacterial clones across the entire VWS critical region. All STSs and BAC clones were shared with the Sanger Centre, which developed a contig of PAC clones over the same region. A subset of 11 clones from both contigs was selected for high-throughput sequence analysis across the approximately 1.1-Mb region; all but two of these clones have been sequenced completely. Over 900 kb of genomic sequence, including the 350-kb VWS critical region, were analyzed and revealed novel polymorphisms, including an 8-kb deletion/insertion, and revealed 4 known genes, 11 novel genes, 9 putative genes, and 3 psuedogenes. The positional candidates LAMB3, G0S2, HIRF6, and HSD11 were excluded as the VWS gene by mutation analysis. A preliminary gene map for the VWS critical region is as follows: [see text] 41-TEL. The data provided here will help lead to the identification of the VWS gene, and this study provides a model for how laboratories that have a regional interest in the human genome can contribute to the sequencing efforts of the entire human genome.Related: Chromosome 1 Polymorphisms
Swensson O, Christophers EGeneralized atrophic benign epidermolysis bullosa in 2 siblings complicated by multiple squamous cell carcinomas.
Arch Dermatol. 1998; 134(2):199-203 [PubMed
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Generalized atrophic benign epidermolysis bullosa is a form of junctional epidermolysis bullosa characterized by skin fragility; atrophic alopecia; sparse eyebrows, eyelashes, and axillary and pubic hair; dystrophic fingernails and toenails; and enamel defects in decidual and permanent teeth. Substantial progress was recently made elucidating the genetic defects underlying this disorder. In affected persons, pathogenetic mutations were identified in the genes encoding the beta 3 chain of laminin 5 (LAMB3) or the 180-kd bullous pemphigoid antigen (BPAG2/COL17A1).OBSERVATIONS:
Two brothers, aged 39 and 32 years, had characteristic clinical features of generalized atrophic benign epidermolysis bullosa. By electron microscopy, dermoepidermal separation was seen at the level of the lamina lucida, establishing a diagnosis of junctional epidermolysis bullosa. Lesional and clinically unaffected skin showed basal keratinocytes with hypoplastic hemidesmosomes, possibly indicating a defect of hemidesmosomal or associated proteins. Both patients presented with multiple fungating tumors on atrophic and scarred skin on their lower legs; 2 tumors in the older sibling and 4 tumors in the younger sibling were diagnosed as well-differentiated squamous cell carcinomas. Tumor staging elicited no evidence of regional lymph node involvement or systemic disease. Treatment was by microscopically controlled surgery. All wounds were allowed to heal by secondary intention. In both patients, wound healing was markedly delayed and characterized by the formation of abundant granulation tissue and poor re-epithelialization.CONCLUSIONS:
In the absence of other apparent risk factors for the development of squamous cell carcinomas, chronic wounding resulting from recurrent skin blistering probably provided an important prerequisite for tumor promotion in these patients. The 2 cases presented herein provide evidence that the development of malignant skin tumors in patients with epidermolysis bullosa is not confined to the dystrophic forms but also may occur in some variants of junctional epidermolysis bullosa, such as generalized atrophic benign epidermolysis bullosa.Related: Cancer Treatments and Hair Loss Squamous Cell Carcinoma - Skin Cancer Skin Cancer