LAPTM4B

Gene Summary

Gene:LAPTM4B; lysosomal protein transmembrane 4 beta
Aliases: LC27, LAPTM4beta
Location:8q22.1
Summary:-
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:lysosomal-associated transmembrane protein 4B
Source:NCBIAccessed: 15 March, 2017

Ontology:

What does this gene/protein do?
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Cancer Overview

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Publications Per Year (1992-2017)
Graph generated 15 March 2017 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 15 March, 2017 using data from PubMed, MeSH and CancerIndex

Latest Publications: LAPTM4B (cancer-related)

Meng F, Tan S, Liu T, et al.
Predictive significance of combined LAPTM4B and VEGF expression in patients with cervical cancer.
Tumour Biol. 2016; 37(4):4849-55 [PubMed] Related Publications
Lysosome-associated protein transmembrane 4ß-35 (LAPTM4B-35) is overexpressed in several solid malignancies. This study determines the expression level of LAPTM4B-35 in the cervical cancer during tumor development and progression. The present study investigated the clinicopathological significance of the coexpression of LAPTM4B-35 and VEGF in patients with cervical cancer. Immunohistochemistry was used to evaluate the expression of LAPTM4B-35 and VEGF in 62 cervical intraepithelial neoplasia (CIN) and 226 cervical carcinoma in comparison with 45 normal cervical specimens. The correlation of combined LAPTM4B-35 and VEGF with clinicopathologic characteristics was analyzed using a chi-squared test. Patient survival was determined using Kaplan-Meier method and log-rank test. A Cox regression analysis was performed to determine the prognostic significance of the factors. Combined LAPTM4B-35 and VEGF expression was significantly associated with FIGO stage (P = 0.014), tumor histologic grade (P = 0.033), lymph node metastasis (P = 0.045), and recurrence (P = 0.010). Kaplan-Meier survival analysis showed that patients with cervical cancer expressing both LAPTM4B-35 and VEGF exhibited both poor overall survival (OS) and disease-free survival (DFS) (P = 0.015 and P = 0.016, respectively). Cox analysis demonstrated that combined LAPTM4B-35 and VEGF expression was an independent factor for both OS and DFS (P = 0.015 and P = 0.016, respectively). Overexpression of LAPTM4B-35combined with positive VEGF expression may serve as a new biological marker to predict the prognosis of cervical carcinoma patients.

Maki Y, Fujimoto J, Lang W, et al.
LAPTM4B is associated with poor prognosis in NSCLC and promotes the NRF2-mediated stress response pathway in lung cancer cells.
Sci Rep. 2015; 5:13846 [PubMed] Free Access to Full Article Related Publications
We recently demonstrated that lysosomal protein transmembrane 4 beta (LAPTM4B) is elevated in non-small cell lung cancers (NSCLCs) and in the surrounding premalignant airway field of cancerization. In the present study, we sought to begin to understand the relevance of LAPTM4B expression and signaling to NSCLC pathogenesis. In situ hybridization analysis of LAPTM4B transcript in tissue microarrays comprised of 368 NSCLCs demonstrated that LAPTM4B expression was significantly increased in smoker compared to non-smoker lung adenocarcinoma tumors (P < 0.001) and was significantly associated with poor overall survival (P < 0.05) in adenocarcinoma patients. Knockdown of LAPTM4B expression inhibited cell growth, induced cellular apoptosis and decreased cellular autophagy in serum starved lung cancer cells. Expression profiling coupled with pathways analysis revealed decreased activation of the nuclear factor erythroid 2-like 2 (NRF2) stress response pathway following LAPTM4B knockdown. Further analysis demonstrated that LAPTM4B augmented the expression and nuclear translocation of the NRF2 transcription factor following serum deprivation as well as increased the expression of NRF2 target genes such as heme oxygenase 1/HMOX1). Our study points to the relevance of LAPTM4B expression to NSCLC pathogenesis as well as to the probable role of LAPTM4B/NRF2 signaling in promoting lung cancer cell survival.

Meng F, Chen X, Song H, et al.
Lentivirus-mediated RNA Interference Targeting LAPTM4B Inhibits Human Ovarian Cancer Cell Invasion In Vitro.
Chem Biol Drug Des. 2016; 87(1):121-30 [PubMed] Related Publications
LAPTM4B (lysosome-associated protein transmembrane 4 beta) play an important role in several human carcinomas. We examines the effects of RNA interference mediated downregulation of human lysosomal-associated protein transmembrane 4 beta expression on the biological behavior of the human serous adenocarcinoma cell line NIH:OVCAR3. This study investigated the expression level of lysosomal-associated protein transmembrane 4 beta in several ovarian cancer cell lines. RNA interference mediated by recombinant lentiviral vectors expressing an artificial lysosomal-associated protein transmembrane 4 beta miRNA was used to induce long-lasting downregulation of lysosomal-associated protein transmembrane 4 beta gene expression in NIH:OVCAR3 cells. Lysosomal-associated protein transmembrane 4 beta expression as well as the motility, migration potential, and proliferation of the tumor cells was measured by flow cytometry, real-time polymerase chain reaction, Western blot analysis, transwell migration assays, wound healing assays, and cell counting kit-8 assays. In addition, the cell cycle analysis utilized fluorescence-activated cell sorting. Four recombinant plasmid expression vectors encoding premiRNAs against lysosomal-associated protein transmembrane 4 beta (pcDNA-LAPTM4B-miR-1, -2, -3, and-4) were constructed and transfected into 293T cells, which overexpress lysosomal-associated protein transmembrane 4 beta. The recombinant lentiviral vector for lysosomal-associated protein transmembrane 4 beta RNA interference was packaged with pcDNA-LAPTM4B-miR-3, which had the highest interfering efficiency, thereby successfully generating stable transfectants. Compared with the control cells, the LAPTM4B-miRNA-transfected NIH:OVCAR3 cells exhibited significant decreases in cell motility and invasion. Furthermore, LAPTM4B depletion resulted in a significant decrease in proliferating cell nuclear antigen, vascular endothelial growth factor, MMP2, MMP9, and CDK12 expression. We propose that lysosomal-associated protein transmembrane 4 beta expression may be an oncogene-inducing feature of invasive ovarian cancer cells and may be a potential therapeutic target for ovarian cancer treatment.

Lebovitz CB, Robertson AG, Goya R, et al.
Cross-cancer profiling of molecular alterations within the human autophagy interaction network.
Autophagy. 2015; 11(9):1668-87 [PubMed] Free Access to Full Article Related Publications
Aberrant activation or disruption of autophagy promotes tumorigenesis in various preclinical models of cancer, but whether the autophagy pathway is a target for recurrent molecular alteration in human cancer patient samples is unknown. To address this outstanding question, we surveyed 211 human autophagy-associated genes for tumor-related alterations to DNA sequence and RNA expression levels and examined their association with patient survival outcomes in multiple cancer types with sequence data from The Cancer Genome Atlas consortium. We found 3 (RB1CC1/FIP200, ULK4, WDR45/WIPI4) and one (ATG7) core autophagy genes to be under positive selection for somatic mutations in endometrial carcinoma and clear cell renal carcinoma, respectively, while 29 autophagy regulators and pathway interactors, including previously identified KEAP1, NFE2L2, and MTOR, were significantly mutated in 6 of the 11 cancer types examined. Gene expression analyses revealed that GABARAPL1 and MAP1LC3C/LC3C transcripts were less abundant in breast cancer and non-small cell lung cancers than in matched normal tissue controls; ATG4D transcripts were increased in lung squamous cell carcinoma, as were ATG16L2 transcripts in kidney cancer. Unsupervised clustering of autophagy-associated mRNA levels in tumors stratified patient overall survival in 3 of 9 cancer types (acute myeloid leukemia, clear cell renal carcinoma, and head and neck cancer). These analyses provide the first comprehensive resource of recurrently altered autophagy-associated genes in human tumors, and highlight cancer types and subtypes where perturbed autophagy may be relevant to patient overall survival.

Cheng X, Zheng Z, Bu Z, et al.
LAPTM4B-35, a cancer-related gene, is associated with poor prognosis in TNM stages I-III gastric cancer patients.
PLoS One. 2015; 10(4):e0121559 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Lysosome-associated transmembrane protein 4β-35 (LAPTM4B-35), a member of the mammalian 4-tetratransmembrane spanning protein superfamily, has been reported to be overexpressed in several cancers. However the expression of LAPTM4B-35 and its role in the progression of gastric cancer (GC) remains unknown. The aim of this study was to investigate LAPTM4B-35 expression in GC, its potential relevance to clinicopathologic parameters and role of LAPTM4B-35 during gastric carcinogenesis.
METHODS: In the present study, paraffin-embedded specimens with GC (n = 240, including 180 paired specimens) and 24 paired fresh frozen tissues were analyzed. qRT-PCR and immunohistochemistry (IHC) were used to analyze the expression of LAPTM4B-35 in GC. The effects of LAPTM4B-35 on GC cell proliferation, migration and invasion were determined by overexpression and knockdown assays.
RESULTS: IHC showed that LAPTM4B-35 was expressed in 68.3% (123/180) of GC tissues, while in 16.1% (29/180) of their paired adjacent noncancerous gastric tissues (P = 0.000). LAPTM4B-35 mRNA levels in GC tissues were also significantly elevated when compared with their paired adjacent noncancerous tissues (P = 0.017). Overexpression of LAPTM4B-35 was significantly associated with degree of differentiation, depth of invasion, lymphovascular invasion and lymph node metastasis (P<0.05). Kaplan-Meier survival curves revealed that patients with LAPTM4B-35 expression had a significant decrease in overall survival (OS) in stages I-III GC patients (P = 0.006). Multivariate analysis showed high expression of LAPTM4B-35 was an independent prognostic factor for OS in stage I-III GC patients (P = 0.025).
CONCLUSION: These findings indicate that LAPTM4B-35 overexpression may be related to GC progression and poor prognosis, and thus may serve as a new prediction marker of prognosis in GC patients.

Liu L, Xu X, Jing L, et al.
Lysosomal-associated protein transmembrane 4 Beta-35 overexpression is a novel independent prognostic marker for gastric carcinoma.
PLoS One. 2015; 10(2):e0118026 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: The purpose of this work was to analyze the relationships between the expression status of Lysosomal-associated protein transmembrane-4 beta 35 (LAPTM4B-35) in cancerous tissues and clinicopathological characteristics and prognosis of the patients with gastric carcinoma (GC).
METHODS: The GC samples from 157 patients in a discovery cohort and 148 patients in a testing cohort with follow-up data were used to validate the feasibility of expression of LAPTM4B-35 protein in predicting GC prognosis. Immunohistochemical staining was used to determine the expression of LAPTM4B-35 protein in precancerous gastric lesions and gastric carcinomas. The correlation between the expression of LAPTM4B-35 and clinicopathologic characteristics of patients with gastric carcinoma was analyzed using chi-square test. Univariate and multivariate analyses were performed to determine the association between LAPTM4B-35 expression and prognosis.
RESULTS: LAPTM4B-35 expression was increased steadily in sequential stages of precancerous gastric lesions. Positive LAPTM4B-35 expression was more frequently detected in patients with distant metastasis (P = 0.023) and III+IV TNM stages (P = 0.042) in the discovery cohort. Kaplan-Meier survival curves and univariate analysis showed that expression of LAPTM4B-35 had a significant impact on overall survival of patients with gastric carcinoma in discovery cohort (P<0.001) and testing cohort (P = 0.001). LAPTM4B-35 expression was an independent prognostic indicator for the overall survival of patients with gastric carcinoma in both cohorts.
CONCLUSIONS: The present research demonstrated that LAPTM4B-35 over-expression was an independent factor in gastric carcinoma prognosis. LAPTM4B gene may be a useful target of interventions slowing the progression of precancerous gastric lesions and a new therapy method to improve the prognosis of gastric carcinoma.

Zhang H, Tian B, Yu H, et al.
LAPTM4B-35 protein as a potential therapeutic target in gastric cancer.
Tumour Biol. 2014; 35(12):12737-42 [PubMed] Related Publications
The objective of this study is to investigate lysosome-associated protein transmembrane 4b-35 (LAPTM4B-35) protein expression in gastric cancer and its clinical implications. LAPTM4B-35 protein expression in 652 gastric cancer specimens and matched adjacent non-cancerous tissues was evaluated by immunohistochemical staining. Subsequently, the relationship between LAPTM4B-35 protein expression, clinical pathological parameters, and prognosis of gastric cancer was determined. LAPTM4B-35 protein expression was significantly higher in gastric cancer tissue compared to adjacent non-cancerous tissues (P = 0.001). In total, 417 (63.96 %) of the 652 gastric cancer cases demonstrated high LAPTM4B-35 protein expression. Multiple regression analysis was performed to identify the factors related to lymph node metastasis. As a result, age, tumor number, primary tumor category, histological type, histological growth pattern, and LAPTM4B-35 protein expression were found to be significantly related to lymph node metastasis (P = 0.010, 0.001, 0.032, 0.001, 0.001, and 0.001, respectively). Survival analysis identified that LAPTM4B-35 protein expression was also an independent prognostic factor (P = 0.001). LAPTM4B-35 was highly expressed in gastric cancer and may be a potential target for the management of gastric cancer.

Hashemi M, Amininia S, Ebrahimi M, et al.
Association between LAPTM4B gene polymorphism and breast cancer susceptibility in an Iranian population.
Med Oncol. 2014; 31(8):111 [PubMed] Related Publications
Lysosome associated protein transmembrane 4beta (LAPTM4B) contribute to the risk of numerous cancers. The present study focused on the possible association between LAPTM4B polymorphism and the risk of breast cancer (BC) in an Iranian population in southeast Iran. This case control study includes 311 BC patients and 225 healthy women. Genomic DNA was extracted from the whole blood by salting out method and LAPTM4B genotype was investigated using polymerase chain reaction. Our findings showed that LAPTM4B genotype was not associated with the risk of BC in any inheritance model tested. The minor allele frequency in case and control group was 0.297 and 0.278, respectively. The minor allele (LAPTM4B*2) was not associated with BC risk in comparison with LAPTM4B*1 allele (odds ratio 1.10, 95 % confidence intervals 0.84-1.44, p = 0.495). Moreover, LAPTM4B polymorphism was not associated with clinical and pathological characteristics in the patient group. In conclusion, the findings of our study suggested that the polymorphism of LAPTM4B gene was not associated with susceptibility to BC and clinicopathological characteristics in an Iranian population.

Mo C, Lu Y, Deng Y, et al.
LAPTM4B polymorphism increases susceptibility to multiple cancers in Chinese populations: a meta-analysis.
BMC Genet. 2014; 15:48 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Lysosome-associated protein transmembrane-4 beta (LAPTM4B) is a novel cancer-related gene. While recent studies have reported that the LAPTM4B polymorphism increased the susceptibility of several cancers, the results remain inconclusive. Therefore, we performed a meta-analysis to systematically summarize the possible association.
RESULTS: The meta-analysis was conducted based on 17 studies in Chinese populations, including 4160 cases and 4148 controls. The relevant studies were searched through electronic databases updated in November 2013. The strength of association between the LAPTM4B polymorphism and susceptibility to multiple cancers was assessed by odds ratio (OR) and 95% confidence interval (95% CI).The meta-analysis results suggested that the LAPTM4B polymorphism was significantly associated with overall susceptibility to multiple cancers in all genetic models (*2 vs. *1, OR = 1.53, 95% CI = 1.37-1.70; *2/2 vs. *1/1, OR = 2.18, 95% CI = 1.72-2.75; *2/1 vs.*1/1, OR = 1.62, 95% CI = 1.41-1.86; *2/1 + *2/2 vs. *1/1, OR = 1.70, 95% CI = 1.47-1.97; *2/2 vs. *2/1 + *1/1, OR = 1.76, 95% CI = 1.50-2.05). Further subgroup analysis revealed a significant association between the LAPTM4B polymorphism and cancer susceptibility in the subgroups stratified by control source, cancer type, histopathologic differentiation, and TNM stage.
CONCLUSIONS: This meta-analysis indicated that the LAPTM4B *2 allele was associated with increasing risk of multiple cancers, tumor initiation and development.

Tang H, Tian H, Yue W, et al.
LAPTM4B polymorphism is associated with non‑small cell lung cancer susceptibility and prognosis.
Oncol Rep. 2014; 31(5):2454-60 [PubMed] Related Publications
Lysosome-associated protein transmembrane-4β (LAPTM4B) is a novel cancer-related gene that is upregulated in many tumors, and which plays important roles in carcinogenesis. It has two alleles, LAPTM4B 1 and LAPTM4B 2. LAPTM4B 1 contains only one copy of a 19-bp sequence in the first exon, whereas LAPTM4B 2 contains two tight tandem segments. Previous studies have shown that LAPTM4B 2 is a risk factor for susceptibility and prognosis of many tumors. The present study investigated the relationship between LAPTM4B polymorphism and non-small cell lung cancer (NSCLC) susceptibility and prognosis. We identified LAPTM4B genotypes with polymerase chain reaction (PCR) in peripheral blood samples. In the adjusted multivariate logistic regression analysis, we found that LAPTM4B 1/2, LAPTM4B 2/2 exhibited 1.48-fold [95% confidence interval (CI), 1.076-2.037] and 2.855-fold (95%CI, 1.722-4.734) increases in the risk of developing NSCLC compared with non-LAPTM4B 2 carriers. Furthermore, our results showed that overall survival time and disease-free survival time of patients with LAPTM4B 2 were significantly shorter than in patients carrying LAPTM4B 1 (P=0.001 and P=0.001, respectively). In addition, multivariate Cox regression analysis revealed that LAPTM4B 2 was also an independent prognostic factor for NSCLC. These results suggest that LAPTM4B polymorphisms may be a prospective marker for evaluating the risk and prognosis of NSCLC.

Kadara H, Fujimoto J, Yoo SY, et al.
Transcriptomic architecture of the adjacent airway field cancerization in non-small cell lung cancer.
J Natl Cancer Inst. 2014; 106(3):dju004 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Earlier work identified specific tumor-promoting abnormalities that are shared between lung cancers and adjacent normal bronchial epithelia. We sought to characterize the yet unknown global molecular and adjacent airway field cancerization (FC) in early-stage non-small cell lung cancer (NSCLC).
METHODS: Whole-transcriptome expression profiling of resected early-stage (I-IIIA) NSCLC specimens (n = 20) with matched tumors, multiple cytologically controlled normal airways with varying distances from tumors, and uninvolved normal lung tissues (n = 194 samples) was performed using the Affymetrix Human Gene 1.0 ST platform. Mixed-effects models were used to identify differentially expressed genes among groups. Ordinal regression analysis was performed to characterize site-dependent airway expression profiles. All statistical tests were two-sided, except where noted.
RESULTS: We identified differentially expressed gene features (n = 1661) between NSCLCs and airways compared with normal lung tissues, a subset of which (n = 299), after gene set enrichment analysis, statistically significantly (P < .001) distinguished large airways in lung cancer patients from airways in cancer-free smokers. In addition, we identified genes (n = 422) statistically significantly and progressively differentially expressed in airways by distance from tumors that were found to be congruently modulated between NSCLCs and normal lung tissues. Furthermore, LAPTM4B, with statistically significantly increased expression (P < .05) in airways with shorter distance from tumors, was upregulated in human immortalized cells compared with normal bronchial epithelial cells (P < .001) and promoted anchorage-dependent and -independent lung cancer cell growth.
CONCLUSIONS: The adjacent airway FC comprises both site-independent profiles as well as gradient and localized airway expression patterns. Profiling of the airway FC may provide new insights into NSCLC oncogenesis and molecular tools for detection of the disease.

Zhang M, Xu JJ, Zhou RL, Zhang QY
cAMP responsive element binding protein-1 is a transcription factor of lysosomal-associated protein transmembrane-4 Beta in human breast cancer cells.
PLoS One. 2013; 8(2):e57520 [PubMed] Free Access to Full Article Related Publications
Lysosomal-associated protein transmembrane-4 beta (LAPTM4B) is a potential proto-oncogene, whose overexpression is involved in cancer occurrence and progression. Its transcript is up-regulated in various types of solid tumors including breast cancer. However, its transcriptional regulation mechanism is still unclear. To investigate the mechanism of transcriptional regulation of LAPTM4B in human breast cancer cells, a series of luciferase reporter constructs and construct with mutated binding site for cAMP responsive element binding protein-1 (CREB1) were generated by PCR amplification and transiently transfected into breast cancer cells to determine the transcriptional activities of different promoter regions. The +10+292 promoter region was possessed the highest transcriptional activity. The ability of CREB1 to bind the LAPMT4B promoter was confirmed by electrophoretic mobility shift assay, super-shift and RNA interference experiments. Our study identified the core promoter region responsible for constitutive expression of LAPTM4B and clarified that CREB1 played an important role in LAPTM4B transcriptional regulation in human breast cancer cells.

Wang B, Xu J, Zhou R, Zhang Q
Association of LAPTM4B gene polymorphism with nasopharyngeal carcinoma susceptibility in a Chinese population.
Med Oncol. 2013; 30(1):470 [PubMed] Related Publications
Lysosome-associated protein transmembrane-4 beta (LAPTM4B) is a novel cancer-related gene. It has two alleles designated LAPTM4B 1 and LAPTM4B 2. Previous studies have revealed that LAPTM4B polymorphisms contribute to the risk of many cancers. The aim of this study was to investigate the association between different LAPTM4B alleles and the risk of nasopharyngeal carcinoma (NPC), one of the most common cancers in southern China. Using polymerase chain reaction (PCR) in a case-control study, we detected the LAPTM4B genotype in peripheral blood samples from 134 patients with NPC and 327 control subjects. The chi-square test was used to analyze differences of categorical variables and Hardy-Weinberg equilibrium. Odds ratios and 95 % CI were computed using an unconditional logistic regression model. The frequency of allele 2 was 26.87 % in the NPC group, which was not significantly different from that of the control group (27.98 %, P = 0.867). Using the LAPTM4B 1/1 genotype as a reference, we found that the 1/2, 2/2 and 1/2 + 2/2 genotype were also not associated with the risk of NPC. No association was observed between LAPTM4B gene polymorphisms and the risk of NPC adjusted by gender and age. The results of our study indicated that the polymorphism of LAPTM4B gene did not influence the susceptibility of NPC in the Chinese population. Large-scale studies are needed to confirm our findings.

Meng F, Li H, Zhou R, et al.
LAPTM4B gene polymorphism and endometrial carcinoma risk and prognosis.
Biomarkers. 2013; 18(2):136-43 [PubMed] Related Publications
A novel gene called LAPTM4B (lysosome-associated protein transmembrane 4 beta) plays several crucial roles in carcinogenesis. In this case-control study, we investigated the relationship between LAPTM4B gene polymorphism and susceptibility to endometrial carcinoma (EC). In an adjusted multivariate logistic regression analyses, subjects with the LAPTM4B*1/2 and *2/2 genotypes respectively exhibited 1.572-fold (95% confidence interval (CI) = 1.041-2.375) and 2.335-fold (95% CI = 1.365-3.995) increases in the risk of developing EC relative to those carrying LAPTM4B*1/1. Patients with LAPTM4B *2 had both significantly shorter overall survival (OS) and shorter disease-free survival (DFS) (both p < 0.001). Multivariate analysis showed that LAPTM4B genotype is an independent prognostic factor for OS and DFS (both p < 0.001). These results suggest that LAPTM4B polymorphisms might play an important role in the aetiology of EC.

de Ronde JJ, Lips EH, Mulder L, et al.
SERPINA6, BEX1, AGTR1, SLC26A3, and LAPTM4B are markers of resistance to neoadjuvant chemotherapy in HER2-negative breast cancer.
Breast Cancer Res Treat. 2013; 137(1):213-23 [PubMed] Related Publications
Response rates to chemotherapy remain highly variable in breast cancer patients. We set out to identify genes associated with chemotherapy resistance. We analyzed what is currently the largest single-institute set of gene expression profiles derived from breast cancers prior to a single neoadjuvant chemotherapy regimen (dose-dense doxorubicin and cyclophosphamide). We collected, gene expression-profiled, and analyzed 178 HER2-negative breast tumor biopsies ("NKI dataset"). We employed a recently developed approach for detecting imbalanced differential signal (DIDS) to identify markers of resistance to treatment. In contrast to traditional methods, DIDS is able to identify markers that show aberrant expression in only a small subgroup of the non-responder samples. We found a number of markers of resistance to anthracycline-based chemotherapy. We validated our findings in three external datasets, totaling 456 HER2-negative samples. Since these external sets included patients who received differing treatment regimens, the validated markers represent markers of general chemotherapy resistance. There was a highly significant overlap in the markers identified in the NKI dataset and the other three datasets. Five resistance markers, SERPINA6, BEX1, AGTR1, SLC26A3, and LAPTM4B, were identified in three of the four datasets (p value overlap < 1 × 10(-6)). These five genes identified resistant tumors that could not have been identified by merely taking ER status or proliferation into account. The identification of these genes might lead to a better understanding of the mechanisms involved in (clinically) observed chemotherapy resistance and could possibly assist in the recognition of breast cancers in which chemotherapy does not contribute to response or survival.

Larysz D, Zebracka-Gala J, Rudnik A, et al.
Expression of genes FOLR1, BAG1 and LAPTM4B in functioning and non-functioning pituitary adenomas.
Folia Neuropathol. 2012; 50(3):277-86 [PubMed] Related Publications
INTRODUCTION: The mechanism of pathogenesis of adenomas pituitary is still unknown; differences between pituitary cells of different origin are observed. Identification of genes specific to pituitary adenomas should give better understanding of differences in their response to therapy, especially to radiotherapy. The aim of our study was to independently validate differences in the expression of FOLR1, BAG1, LAPTM4B between functioning (FA) and non-functioning (NFA) pituitary adenomas reported by microarray-based studies.
MATERIAL AND METHODS: Analysis of gene expression was performed by real-time quantitative PCR (QPCR) in 76 pituitary adenomas, 25 functioning and 51 non-functioning ones. The expression of the examined genes was normalized to the reference index, obtained by calculation of the geometric mean of reference genes expression: GUS-B, B2M, ACTB, EIF3S10, UBE2D2 and ATP6V1E.
RESULTS: Two genes showed significant differences in expression between non-functioning adenomas and functioning ones (FA) (FOLR1 32.4 x greater p = 0.022, BAG1 2.2 x lower p = 0.0002). The expression of LAPTM4B (1.1 x lower) was only insignificantly changed. The expression of FOLR1 in all tumours (functioning and non-functioning) was higher in older patients (over 50 years of age) (p = 0.018). Expression of BAG1 was significantly lower in older patients (p = 0.015). In a subgroup of pure non-functioning adenomas there was a higher expression of FOLR1 in older patients (p = 0.006). Analysis of expression profiles and invasiveness of tumours did not reveal any significant differences both in non-functioning and functioning tumours.
CONCLUSIONS: Among pituitary adenomas, the highest level of expression FOLR1 is seen in NFA which are negative by immunohistochemistry to all pituitary hormones while GH-producing adenomas are the only class of pituitary tumours where FOLR1 expression is virtually absent. For BAG1 we confirm a significantly higher expression in functioning (both PRL and GH producing) adenomas than non-functioning ones, while LAPTM4B does not exhibit any expression changes between different classes of pituitary tumours.

Zhai G, Yan K, Ji X, et al.
LAPTM4B allele *2 is a marker of poor prognosis for gallbladder carcinoma.
PLoS One. 2012; 7(9):e45290 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Lysosomal protein transmembrane 4 beta (LAPTM4B) is a novel cancer-related gene which has two alleles designated LAPTM4B*1 and LAPTM4B*2. In this study we investigated the correlation of LAPTM4B genotype with prognosis and clinicopathologic features in patients who had undergone curative resection for gallbladder carcinoma (GBC).
METHODOLOGY/PRINCIPAL FINDINGS: PCR assay was performed to determine the LAPTM4B genotype in 85 patients. The correlation of LAPTM4B genotype with clinicopathologic parameters was assessed with the Chi-squared test. Differences in patient survival were determined by the Kaplan-Meier method. Multivariate analysis of prognostic factors was carried out with Cox regression analysis. Patients with LAPTM4B *2 had both significantly shorter overall survival (OS) and shorter disease-free survival (DFS) (both P<0.001). Multivariate analysis showed that LAPTM4B genotype is a prognostic factor for OS and DFS (both P<0.001).
CONCLUSIONS/SIGNIFICANCE: LAPTM4B allele *2 is a risk factor associated with poor prognosis in patients with resected GBC, and LAPTM4B status may be therefore be useful preoperatively as an adjunct in evaluation of the operability of GBC.

Huang L, Zhou K, Yang Y, et al.
FLT3-ITD-associated gene-expression signatures in NPM1-mutated cytogenetically normal acute myeloid leukemia.
Int J Hematol. 2012; 96(2):234-40 [PubMed] Related Publications
Concomitance of the FLT3-ITD mutation is associated with poor prognosis in NPM1-mutated cytogenetically normal acute myeloid leukemia (CN-AML) patients, and precise studies on its role in leukemogenesis are needed; these may be elucidated at the molecular level by gene express profiling. In the present study, we built a gene-expression-based classifier using prediction analysis of microarray to characterize the FLT3-ITD signature in NPM1-mutated CN-AML patients, which comprised 10 annotated genes, and demonstrated an overall accuracy of 83.8 % in cross-validation. To characterize the signature in another way, differential expression was revealed for 34 genes by class comparison, and the up-regulation of LAPTM4B and MIR155HG was validated by quantitative RT-PCR in our small cohort of NPM1-mutated CN-AML samples, which appeared to be associated with this specific subtype. The 10-gene classifier and differentially expressed genes identified in this study indicate a potential utility for risk-assessed treatment stratification, and suggest new therapeutic targets for these high-risk AML patients.

Yang H, Zhai G, Ji X, et al.
LAPTM4B allele *2 is a marker of poor prognosis following hepatic tumor resection for hepatocellular carcinoma.
PLoS One. 2012; 7(4):e34984 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Lysosomal protein transmembrane 4 beta (LAPTM4B) is a gene related to hepatocellular carcinoma that has two alleles designated LAPTM4B*1 and LAPTM4B*2. This study aimed to investigate the correlation of LAPTM4B genotype with prognosis and clinicopathologic features in patients who have undergone resection for hepatocellular carcinoma (HCC).
METHODOLOGY/PRINCIPAL FINDINGS: The LAPTM4B genotype was analyzed by PCR in 68 patients who had undergone curative hepatic resection for hepatocellular carcinoma. The correlation of LAPTM4B genotype with clinicopathologic parameters was assessed with the Chi-squared test. Differences in patient survival were determined by the Kaplan-Meier method. Multivariate analysis of prognostic factors was carried out with Cox regression analysis. Patients with LAPTM4B *2 had both significantly shorter overall survival (OS) and shorter disease-free survival (DFS) (both P<0.001). Multivariate analysis showed that LAPTM4B genotype is an independent prognostic factor for OS and DFS (both P<0.001).
CONCLUSIONS/SIGNIFICANCE: Allele *2 of LAPTM4B is a risk factor associated with poor prognosis in patients with resected HCC. LAPTM4B status may be useful preoperatively as an adjunct in evaluation of the operability of HCC.

Xu Y, Liu Y, Zhou R, et al.
LAPTM4B polymorphisms is associated with ovarian cancer susceptibility and its prognosis.
Jpn J Clin Oncol. 2012; 42(5):413-9 [PubMed] Related Publications
OBJECTIVE: Lysosome-associated protein transmembrane 4 beta (LAPTM4B) is an important novel gene associated with the proliferation and differentiation of cells. Recent studies have shown that it was overexpressed in many cancer tissues. This study investigated the association between different LAPTM4B polymorphisms and the susceptibility and prognosis of ovarian cancer.
METHODS: A case-control study was performed in 282 patients with ovarian cancer and 365 control subjects. Genomic DNA was extracted from peripheral blood lymphocytes in all participants. LAPTM4B genotypes were determined using polymerase chain reaction.
RESULTS: There was a significantly higher LAPTM4B 2 allele frequency in ovarian cancer cases than controls (P < 0.05). Using the LAPTM4B 1/1 genotype as the reference, we found that the LAPTM4B 1/2 and LAPTM4B 2/2 genotypes were positively associated with ovarian cancer. Additionally, we found a negative correlation between the tumor grade and LAPTM4B allele genotype, which indicates strongly that LAPTM4B 2 could affect the survival of patients.
CONCLUSIONS: These findings indicate that the LAPTM4B 2 allele may be a risk factor for ovarian cancer and may play an important role in genetic susceptibility to ovarian cancer.

Yang H, Zhai G, Ji X, et al.
Correlation of LAPTM4B polymorphisms with gallbladder carcinoma susceptibility in Chinese patients.
Med Oncol. 2012; 29(4):2809-13 [PubMed] Related Publications
Gallbladder carcinoma (GBC) is a malignancy with an extremely poor prognosis. In order to improve the survival rate, identification of new susceptibility risk factors is of importance. Here, we report findings on the novel cancer-related gene lysosomal protein transmembrane 4 beta (LAPTM4B) that has two alleles designated LAPTM4B*1 and LAPTM4B*2. Allele *1 differs from allele *2 in that it contains one copy of a 19-bp sequence, whereas this sequence is duplicated in exon 1 of allele *2. This study aimed to investigate the relationship of LAPTM4B allelic variation and GBC susceptibility. LAPTM4B genotype was analyzed in 155 healthy individuals and 91 GBC patients by PCR, and the genotypic distribution of LAPTM4B was analyzed with the chi-squared test. The frequency of allele *2 was 37.9 and 24.8% in the GBC and the control groups, respectively, representing a significant difference between these two groups (P<0.001). LAPTM4B allele *2 may be a risk factor associated with genetic susceptibility to GBC.

Li Y, Iglehart JD, Richardson AL, Wang ZC
The amplified cancer gene LAPTM4B promotes tumor growth and tolerance to stress through the induction of autophagy.
Autophagy. 2012; 8(2):273-4 [PubMed] Free Access to Full Article Related Publications
Autophagy is a fundamental salvage pathway that encapsulates damaged cellular components and delivers them to the lysosome for degradation and recycling. This pathway usually conducts a protective cellular response to nutrient deprivation and various stresses. Tumor cells live with metabolic stress and use autophagy for their survival during tumor progression and metastasis. Genomic instability in tumor cells may result in amplification of crucial gene(s) for autophagy and upregulate the autophagic pathway. We demonstrate that a cancer-associated gene, LAPTM4B, plays an important role in lysosomal functions and is critical for autophagic maturation. Its amplification and overexpression promote autophagy, which renders tumor cells resistant to metabolic and genotoxic stress and results in more rapid tumor growth.

Fan M, Liu Y, Zhou R, Zhang Q
Association of LAPTM4B gene polymorphism with breast cancer susceptibility.
Cancer Epidemiol. 2012; 36(4):364-8 [PubMed] Related Publications
BACKGROUND: Lysosome associated protein transmembrane 4 beta (LAPTM4B) was a cancer-associated gene that is mapped to chromosome 8q22 with seven exons and six introns. LAPTM4B gene polymorphism has been reported to be significantly associated with susceptibility of several solid tumors.
METHODS: We performed a case-control study was to investigate the association between LAPTM4B polymorphism and the risk of breast cancer in 732 breast cancer patients and 649 controls.
RESULTS: A significant difference in the frequency of LAPTM4B*2 was observed between the patients and the controls (P < 0.01). Using the LAPTM4B*1/1 genotype as a reference, we found that LAPTM4B allelic variation was significantly associated with breast cancer occurrence, with adjusted odds ratios of 1.387 (95%CI = 1.111-1.730) for LAPTM4B*1/2 and 1.592 (95% CI = 1.043-2.430) for LAPTM4B*2/2 genotype.
CONCLUSION: Our results suggested that LAPTM4B*2 is associated with an increased risk of breast cancer in the Chinese women population and may be a risk factor of breast cancer.

Zhai G, Yang H, Ji X, et al.
Correlation of LAPTM4B polymorphisms with hepatocellular carcinoma in Chinese patients.
Med Oncol. 2012; 29(4):2744-9 [PubMed] Related Publications
Hepatocellular carcinoma (HCC) is the leading cause of cancer mortality in many countries. Evaluation of new susceptibility risk factors is therefore warranted in order to explore means to improve the survival rate. Here, we report on a novel HCC-related gene known as lysosomal protein transmembrane 4 beta (LAPTM4B) that has two alleles designated LAPTM4B*1 and LAPTM4B*2. Allele *1 differs from allele *2 in that it contains one copy of a 19-bp sequence, whereas this sequence is duplicated in allele *2 in exon 1 of LAPTM4B. In this study, we aimed to investigate the relationship between LAPTM4B allelic variation and HCC susceptibility. The LAPTM4B genotype was analyzed in the blood samples from 102 HCC patients and 135 healthy individuals by PCR. The genotypic distribution of LAPTM4B was analyzed using the chi-squared test. The frequencies of allele *2 were 38.24 and 24.07% in the HCC group and control group, respectively, representing a significant difference between these two groups (P<0.001). Thus, allele *2 of LAPTM4B appears to be associated with genetic susceptibility of HCC and may therefore be considered as a risk factor.

Yin M, Lou C, Zhang W, et al.
LAPTM4B overexpression is a novel independent prognostic marker for metastatic ovarian tumors.
Int J Gynecol Cancer. 2012; 22(1):54-62 [PubMed] Related Publications
OBJECTIVE: Metastatic ovarian tumors are a series of lethal carcinomas that almost always have bad prognosis. Their prognoses, however, vary depending on the primary tumor malignancies of each. It has been reported that LAPTM4B, a novel tumor-associated gene, might indicate a worse prognosis when it was overexpressed in other carcinomas. Therefore, the authors expected to investigate whether LAPTM4B overexpression is an independent prognostic marker in metastatic ovarian tumors.
METHODS: Immunohistochemistry was used to assess LAPTM4B expression in metastatic ovarian tumors from 102 patients. Subsequently, univariate and multivariate survival analyses with Cox regression were performed to determine the association between LAPTM4B expression and prognosis. To identify any differences in prognosis between the 2 groups of patients with differing primary malignancies, the log-rank test was used.
RESULTS: The median overall and progression-free survival rates of patients with tumors of gastrointestinal tract origin were 0.97 and 0.51 years, respectively, and both were statistically significantly lower than those of patients with tumors of breast origin (P < 0.0001), which were 2.68 and 1.96 years, accordingly. Of 102 patients, 77 were classified as having a high expression of LAPTM4B, and LAPTM4B expression had a significant association with the prognosis of metastatic ovarian tumors (P < 0.01); no statistically significant interaction between LAPTM4B expression and primary malignancies was detected (P > 0.1). On the other hand, medians of overall survival and progression-free survival of patients with tumors of gastrointestinal tract origin were significantly lower than those of patients with tumors of breast origin (P < 0.0001).
CONCLUSIONS: Patients with metastatic ovarian tumors of breast origin had significantly better prognosis than those with the disease from gastrointestinal tract primary malignancies. LAPTM4B overexpression might be an independent prognostic marker of metastatic ovarian tumors.

Wang S, Zhang QY, Zhou RL
Relationship between LAPTM4B gene polymorphism and susceptibility of primary liver cancer.
Ann Oncol. 2012; 23(7):1864-9 [PubMed] Related Publications
BACKGROUND: Lysosome associated protein transmembrane 4 beta (LAPTM4B) was identified first as a novel gene overexpressed in human hepatocellular carcinoma. LAPTM4B*1 and LAPTM4B*2 are two alleles of the gene; they are differentiated at 5'UTR in the first exon. Allele *1 contains only one copy of a 19-bp sequence in the 5'UTR. However, allele *2 contains another identical 19-bp sequence following the first one tightly. In this case-control study, we aimed to identify the relationship between LAPTM4B gene polymorphism and the susceptibility of primary liver cancer.
MATERIALS AND METHODS: The case-control study was conducted in China, including 303 primary liver cancer cases and 515 controls. LAPTM4B gene polymorphism was determined by PCR. Statistical analysis includes odds ratio (OR) and 95% confidence interval (CI) calculations using unconditional logistic regression.
RESULTS: We found a significant difference in the frequency of LAPTM4B*2 between cases and controls (P<0.05). Our study showed that LAPTM4B*1/2 and *2/2 were associated with a significantly increased risk of primary liver cancer compared with LAPTM4B*1/1 (OR=1.898, 95% CI=1.387-2.598 and OR=2.483, 95% CI=1.480-4.168, respectively). The genotypes of LAPTM4B in this study have negative correlation with the clinicopathologicals observed.
CONCLUSION: The evidences suggest that gene polymorphism of LAPTM4B may influence the individuals' susceptibility to primary liver cancer and allele *2 being considered as a potential risk factor.

Li Y, Zhang Q, Tian R, et al.
Lysosomal transmembrane protein LAPTM4B promotes autophagy and tolerance to metabolic stress in cancer cells.
Cancer Res. 2011; 71(24):7481-9 [PubMed] Free Access to Full Article Related Publications
Amplification of chromosome 8q22, which includes the gene for lysosomal associated transmembrane protein LAPTM4B, has been linked to de novo anthracycline resistance in primary breast cancers with poor prognosis. LAPTM4B overexpression can induce cytosolic retention of anthracyclines and decrease drug-induced DNA damage. In this study, we tested the hypothesis that LAPTM4B may contribute to tumor cell growth or survival in the absence of a chemotherapeutic exposure. In mammary cells, LAPTM4B protein was localized in lysosomes where its depletion increased membrane permeability, pH, cathepsin release, and cellular apoptosis. Loss of LAPTM4B also inhibited later stages of autophagy by blocking maturation of the autophagosome, thereby rendering cells more sensitive to nutrient deprivation or hypoxia. Conversely, enforced overexpression of LAPTM4B promoted autophagic flux and cell survival during in vitro starvation and stimulated more rapid tumor growth in vivo. Together, our results indicate that LAPTM4B is required for lysosome homeostasis, acidification, and function, and that LAPTM4B renders tumor cells resistant to lysosome-mediated cell death triggered by environmental and genotoxic stresses.

Li L, Shan Y, Yang H, et al.
Upregulation of LAPTM4B-35 promotes malignant transformation and tumorigenesis in L02 human liver cell line.
Anat Rec (Hoboken). 2011; 294(7):1135-42 [PubMed] Related Publications
Hepatocellular carcinoma (HCC) is one of the most frequent malignant neoplasms worldwide and is the second leading cause of cancer death in China. We have previously demonstrated that LAPTM4B-35, encoded by lysosomal protein transmembrane 4 beta gene, is overexpressed in over 80% of HCCs and is a novel-independent prognostic factor for metastasis, recurrence, and postoperative survival in HCC. In this study, we investigated the role of LAPTM4B-35 in malignant transformation and tumorigenesis using L02 cells, a cell line originated from human normal liver cells. Our data show that replication-deficient adenovirus vector-mediated upregulation of LAPTM4B-35 promotes anchorage-independent proliferation and resistance to adriamycin-induced apoptosis. Study of the underlying mechanisms demonstrated alterations of molecular events involved in these processes, which included the activation of phosphoinositide 3-kinases (PI3K)/serine/threonine protein kinase B (PKB/AKT)/bcl-xL/bcl-2-associated death promoter homolog (Bad) signaling pathway, inhibition of caspase-3 activation, upregulation of Bcl-2, and downregulation of Bax. In addition, upregulation of LAPTM4B-35 in L02 cells resulted in tumorigenesis in 100% (6/6) of inoculated nude mice and accelerated the death of mice with xenografts in vivo. In conclusion, LAPTM4B-35 promotes malignant transformation and tumorigenesis in human liver L02 cell line through promotion of deregulated proliferation and inhibition of apoptosis. These findings suggest that overexpression of LAPTM4B-35 may play a critical role in hepatocarcinogenesis and therefore, may be a therapeutic target for HCC.

Zhou L, He XD, Yu JC, et al.
Overexpression of LAPTM4B-35 attenuates epirubucin-induced apoptosis of gallbladder carcinoma GBC-SD cells.
Surgery. 2011; 150(1):25-31 [PubMed] Related Publications
BACKGROUND: It was shown previously that LAPTM4B promoted growth of gallbladder carcinoma (GBC) cells and predicted poor prognosis in GBC; however, its roles and relative mechanisms in apoptosis of GBC cells remain unknown.
METHODS: The plasmids, pcDNA3-AE, containing the complete open reading frame of LAPTM4B and Mock (pcDNA3), were transfected transiently into GBC-SD cells, followed by induction of apoptosis by epirubicin. Cell apoptosis was determined by Hoechst 33258 staining, propidium iodide (PI) staining, and Annexin V/PI double staining flow cytometry. Protein expression was detected by immunoblotting.
RESULTS: Overexpression of LAPTM4B-35 was observed in cells transfected with pcDNA3-AE. These cells possessed significantly less apoptosis ratios compared with cells transfected with the Mock plasmid, although the values were still greater than those in parent cells. Of the apoptosis-related molecules, expression of Bcl-2 and Bcl-xL was up-regulated in cells transfected with pcDNA3-AE, whereas expressions of Bax, Bid, and cleaved caspase-9 and -3 were down-regulated compared with their expression in other kinds of cells.
CONCLUSION: Our data show that LAPTM4B-35 attenuated epirubicin-induced apoptosis of GBC-SD cells in vitro through a mitochondria-dependent pathway. Therefore, the protein LAPTM4B-35 might be associated with the chemoresistance of GBC.

Yin M, Xu Y, Lou G, et al.
LAPTM4B overexpression is a novel predictor of epithelial ovarian carcinoma metastasis.
Int J Cancer. 2011; 129(3):629-35 [PubMed] Related Publications
LAPTM4B is a novel tumor-associated gene. To date, there have been no published data regarding the role of LAPTM4B expression in epithelial ovarian carcinoma metastasis. Therefore, this study was performed to determine whether LAPTM4B overexpression is a new predictor of epithelial ovarian carcinoma metastasis. LAPTM4B expression was evaluated in 22 normal ovarian specimens and 139 ovarian carcinomas by western blotting analyses and immunohistochemistry. Univariate and multivariate analyses were used to determine the association between LAPTM4B expression and epithelial ovarian carcinoma metastasis. Western blotting analysis demonstrated that LAPTM4B was overexpressed in metastatic tissues from patients with ovarian cancers, and immunohistochemistry results revealed that among 59 patients with LAPTM4B overexpression, 57 (96.6%) presented intraperitoneal metastasis and 31 (52.5%) had lymph node metastasis. The results of the univariate and multivariate analyses demonstrated that LAPTM4B overexpression correlated with metastasis. The odds ratio of high-to-low expression for intraperitoneal metastasis was 11.410 (95% CI: 2.357, 55.239) and that for lymph node metastasis was 6.332 (95% CI: 2.533, 15.831). For intraperitoneal metastasis, the sensitivity and specificity of LAPTM4B overexpression were 48.7% and 90.9%; for lymph node metastasis, they were 73.8%% and 71.1%, respectively. LAPTM4B overexpression is a new predictor of epithelial ovarian carcinoma metastasis and an important potential biomarker for the early diagnosis of ovarian carcinoma.

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Cite this page: Cotterill SJ. LAPTM4B, Cancer Genetics Web: http://www.cancer-genetics.org/LAPTM4B.htm Accessed:

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