Lysosome-associated Protein Transmembrane 4 Beta Research Articles

LAPTM4B promotes AML progression through regulating RPS9/STAT3 axis

Acute myeloid leukemia (AML) is a heterogeneous disorder with high morbidity and mortality under the existing treatment strategy. Here, we found that lysosome-associated protein transmembrane 4 beta (LAPTM4B) was frequently upregulated in AML, and high LAPTM4B was associated with poor outcome. Moreover, LAPTM4B promoted leukemia progression in vitro and in vivo. Mechanically, LAPTM4B interacted with RPS9, and positively regulated RPS9 protein stability, which enhanced leukemia cell progression via activating STAT3. Our findings indicate for the first time that LAPTM4B contributes to leukemia progression in a RPS9/STAT3-dependent manner, suggesting that LAPTM4B may serve as a promising target for treatment of AML.

Serum LAPTM4B as a Potential Diagnostic and Prognostic Biomarker for Breast Cancer.

Lysosome-associated protein transmembrane-4 beta (LAPTM4B) is an integral membrane protein overexpressed in various cancers and may function as a prognostic tumor marker. The present study is aimed at understanding the clinical significance of serum LAPTM4B in breast cancer (BC). Serum LAPTM4B level was evaluated in 426 BC patients, 40 benign breast disease, and 80 healthy controls by ELISA. We used the receiver operator characteristic (ROC) curve to assess the diagnostic significance. 46 BC patients were recruited to monitor the dynamic change of serum LAPTM4B during adjuvant therapy (AT). In addition, sera from a subset of 330 patients undergoing AT, including anti-HER2 treatment, were collected to evaluate the association between LAPTM4B levels and AT efficacy. Descriptive and explorative statistical analyses were used to assess LAPTM4 B's potential as a diagnostic and prognostic marker in BC. Serum LAPTM4B level was significantly increased in BC patients than benign group and controls. It could well discriminate BC from healthy controls with diagnostic accuracy with an AUC of 0.912, a sensitivity of 85.9%, and a specificity of 83.8%. Compared with pre-AT, serum LAPTM4B concentration remarkably decreased after AT. In addition, patients in the invalid response group (PD + SD) showed higher LAPTM4B levels than the valid response group (PR + CR). Our results proposed that serum LAPTM4B had a high diagnostic and prognostic impact as a circulating biomarker in BC.

Integrative Genome-Wide DNA Methylome and Transcriptome Analysis of Ovaries from Hu Sheep with High and Low Prolific.

DNA methylation plays an important role in biological processes by affecting gene expression. However, how DNA methylation regulates phenotypic variation in Hu sheep remains unclear. Therefore, we generated genome-wide DNA methylation and transcriptomic profiles in the ovaries of Hu sheep with different prolificacies and genotypes (FecBB and FecB+). Results showed that ovary DNA methylome and transcriptome were significantly different between high prolificacy and low prolificacy Hu sheep. Comparative methylome analyses identified 10,644, 9,594, and 12,214 differentially methylated regions and 87, 1,121, and 2,375 genes, respectively, showing differential expression levels in three different comparison groups. Female reproduction-associated differentially methylated regions-related genes and differentially expressed genes were enriched, thereby the respective interaction networks were constructed. Furthermore, systematical integrative analyses revealed a negative correlation between DNA methylation around the transcriptional start site and gene expression levels, which was confirmed by testing the expression of integrin β2 subunit (ITGB2) and lysosome-associated protein transmembrane-4 beta (LAPTM4B) in vivo and in vitro. These findings demonstrated that DNA methylation influences the propensity for prolificacy by affecting gene expression in the ovaries, which may contribute to a greater understanding of the epigenome and transcriptome that will be useful for animal breeding.

Induction of Lysosome-associated Protein Transmembrane 4 Beta via Sulfatase 2 Enhances Autophagic Flux in Liver Cancer Cells.

Autophagy has been shown to be a key cellular event controlling tumor growth in different neoplasms including hepatocellular carcinoma (HCC). Although this biological role of autophagy has been clearly established, the mechanism underlying its regulation remains elusive. Here, we demonstrate a role of sulfatase 2 (SULF2), a 6‐O‐endosulfatase modulating various growth factors and cytokine‐related signaling pathways controlling tumor cell proliferation and survival, in the regulation of autophagy in HCC cells. SULF2 increased autophagosome formation, shown by increased LC3B‐II protein and green fluorescent protein–LC3 puncta. Increased fusion between autophagosomes and lysosomes/lysosomal enzymes, higher expression of lysosomal membrane protein, and an increase in autolysosomes were also shown by western blot, immunofluorescence, and electron microscopy of SULF2‐expressing cells, indicating enhanced autophagic flux. In contrast, RNA‐interference silencing of SULF2 in Huh7 cells induced lysosomal membrane permeabilization with diffuse cytosolic staining of cathepsin D and punctate staining of galectin‐3. Analysis of the mechanism showed that inhibition of lysosome‐associated protein transmembrane 4 beta (LAPTM4B), a gene induced by SULF2, resulted in decreased autophagosome formation, decreased fusion between autophagosomes and lysosomes, and increased lysosomal membrane permeabilization. Interestingly, down‐regulation of LAPTM4B also phenocopies the knockdown of SULF2, significantly reducing cell viability and colony formation. Conclusion: Our results demonstrate a role for SULF2 in the regulation of autophagic flux that is mediated through LAPTM4B induction in HCC cells, and provide a foundation for future translational efforts targeting autophagy in liver malignancies.

In Vitro and In Vivo Study on the Effect of Lysosome-associated Protein Transmembrane 4 Beta on the Progression of Breast Cancer.

PurposeAlthough the effect of lysosome-associated protein transmembrane 4 beta (LAPTM4B) on the proliferation, migration, and invasion of breast cancer (BC) cells has already been studied, its specific role in BC progression is still elusive. Here, we evaluated the effect of different levels of LAPTM4B expression on the proliferation, invasion, adhesion, and tumor formation abilities of BC cells in vitro, as well as on breast tumor progression in vivo.MethodsWe investigated the influence of LAPTM4B expression on MCF-7 cell proliferation, invasion, adhesion, and tube formation abilities in vitro through its overexpression or knockdown and on breast tumor progression in vivo.ResultsCell growth curves and colony formation assays showed that LAPTM4B promoted the proliferation of breast tumor cells. Cell cycle analysis results revealed that LAPTM4B promoted the entry of cells from the G1 into the S phase. Transwell invasion and cell extracellular matrix adhesion assays showed that LAPTM4B overexpression increased the invasion and adhesion capabilities of MCF-7 cells. More branches were observed in MCF-7 cells overexpressing LAPTM4B under an electron microscope. In comparison with LAPTM4B overexpression, LAPTM4B knockdown decreased the expression of vascular endothelial growth factor-A and significantly inhibited the vasculogenic tube formation ability of tumors. These results were also verified with western blot analysis.ConclusionLAPTM4B promoted the proliferation of MCF-7 cells through the downregulation of p21 (WAF1/CIP1) and caspase-3, and induced cell invasion, adhesion, and angiogenesis through the upregulation of hypoxia-inducible factor 1 alpha, matrix metalloproteinase 2 (MMP2), and MMP9 expression. This specific role deems LAPTM4B as a potential therapeutic target for BC treatment.

LAPTM4B gene polymorphism augments the risk of cancer: Evidence from an updated meta-analysis.

Lysosome‐associated protein transmembrane‐4 beta (LAPTM4B) has two alleles named as LAPTM4B*1 and LAPTM4B*2 (GenBank No. AY219176 and AY219177). Allele *1 has a single copy of a 19‐bp sequence in the 5` untranslated region (5`UTR), but allele *2 contains tandem repeats of 19‐bp sequence.1 LAPTM4B gene is located on long chromosome 8 (8q22.1) and contains seven exons that encodes two isoforms of tetratransmembrane proteins, LAPTM4B‐24 and LAPTM4B‐35, with molecular weights of 25 kDa and 35 kDa respectively. The LAPTM4B‐35′s primary structure is formed by 317 amino acid residues, and LAPTM4B‐24 comprised 226 amino acids. LAPTM4B, an integral membrane protein, contains several lysosomal‐targeting motifs at the C terminus and colocalizes with late endosomal and lysosomal markers. LAPTM4B is a proto‐oncogene, which becomes up‐regulated in various cancers. Preceding studies have examined the possible link between LAPTM4B polymorphism and susceptibility to several cancers,1-26 but the findings are still inconsistent. Hence, the present meta‐analysis was designed to investigate the impact of LAPTM4B polymorphism on risk of cancer.

LAPTM4B-35 is a novel prognostic factor for glioblastoma.

Lysosome-associated protein transmembrane-4 beta (LAPTM4B)-35, a newly identified cancer-associated gene, is overexpressed in a wide variety of malignant tumors. However, studies of its expression and role in glioma have not yet been reported. This study aimed to investigate the expression and the role of LAPTM4B-35 in glioma and to assess its value as a prognostic factor. Seventy-seven glioma cases (Grade II in 18 patients, Grade III in 16 and Grade IV in 43) were immunohistochemically examined for LAPTM4B-35, pAkt, factor VIII and Ki-67 expressions. The LAPTM4B-35 expression score of Grade II gliomas was lower than those of Grade III-IV gliomas (p < 0.05), while the difference between Grade III and IV gliomas was not statistically significant. Of the 43 patients with glioblastoma (GBM), 27 (62.8%) had high LAPTM4B-35 expression, which was associated with high tumor micro-vessel density and pAkt activation. The median progression-free survival (PFS) of GBM patients with high LAPTM4B-35 expression was 5.13 months, significantly shorter than that of those with low LAPTM4B-35 expression (12.0months, p < 0.0001). The median overall survival (OS) of GBM patients with high LAPTM4B-35 expression was 12.5 months, again significantly shorter than that of those with low LAPTM4B-35 expression (29.6 months, p < 0.0001). Multivariate analysis indicated LAPTM4B-35 to be an independent prognostic factor for PFS and OS of GBM patients. Our findings show LAPTM4B-35 to be strongly associated with tumor proliferation, tumor angiogenesis and poor outcomes of GBM patients, suggesting LAPTM4B-35 to potentially be applicable as a novel prognostic marker and even to possibly play a role in improving GBM treatment.

LAPTM4B Predicts Axillary Lymph Node Metastasis in Breast Cancer and Promotes Breast Cancer Cell Aggressiveness in Vitro

Purpose: Lysosome-associated protein transmembrane-4 beta (LAPTM4B) is associated with the prognosis of several human malignancies. In this study, the role of LAPTM4B in the metastatic potential of breast cancer (BC) and its underlying molecular mechanisms were investigated. Methods: The relationship between LAPTM4B expression and axillary lymph node metastasis was determined in 291 BC specimens by immunohistochemistry. The expression of LAPTM4B in paired BC cells was overexpressed and inhibited to analyse the role of LAPTM4B in the aggressiveness of BC. Cell proliferation, migration and invasion were assessed in vitro. Metastasis-related protein levels were detected through Western blot. Results: Immunohistochemical staining demonstrated that high expression level of LAPTM4B was independently associated with axillary lymph node metastasis (odds ratio=2.428; 95%CI=1.333- 4.425; P=0.004). The LAPTM4B inhibition in MCF-7 cells inhibited cell proliferation, migration, invasion, and resulted in simultaneous downregulation of phosphorylated N-cadherin, vimentin, and upregulation of E-cadherin. By contrast, the LAPTM4B overexpression promoted cell proliferation, migration, invasion, and led to simultaneous upregulation of N-cadherin, vimentin, and downregulation of E-cadherin in T47D cells. Conclusions: High expression level of LAPTM4B predicts tumor metastatic potential in patients with BC. Our results provide the first evidence of the role of LAPTM4B as an Epithelial-mesenchymal transition (EMT) inducer that promotes aggressiveness in BC cells.

Deregulation of microRNA-188-5p in prostate carcinoma and effects on proliferation and metastasis of prostate carcinoma cell lines

Objective To measure the expression level of microRNA (miRNA, miR)-188-5p in prostate carcinoma (PCa) and investigate its biological functions on prostate carcinoma cell lines. Methods In 30 PCa and 40 benign prostatic hyperplasia (BPH) samples, quantificational real-time reverse transcriptase-polymerase chain reaction (RT-qPCR) was used to detect the expression of miR-188-5p in prostate tissues. In different prostate cell lines, miR-188-5p expression was also detected using RT-qPCR. The miR-188-5p mimic was re-introduced into PC-3 and LNCaP cells by Lipfectamine 2000. The function of miR-188-5p on PCa cells was explored by colony formation assays, Transwell migration and invasion assays. The candidate targets for miR-188-5p were investigated using prediction algorithm provided by miRanda. Luciferase activity was measured using the dual luciferase reporter assay system. Results The expression level of miR-188-5p was significantly lower in PCa tissues than in pericarcinous and BPH tissues (0.996±0.024, 0.990±0.094, 0.385±0.031; P 0.05). It was also found that miR-188-5p was significantly down-regulated in PCa cell lines as compared with that in RWPE-1 (0.409±0.034, 0.358±0.024, 0.255±0.018, 1.022±0.012; P<0.01). The colony formation assays showed that ectopic miR-188-5p expression significantly inhibited colony formation compared to control PC-3 and LNCaP cells (21±5, 47±3; 25±4, 51±5; P<0.01). We next found ectopic miR-188-5p expression significantly reduced the cell invasion and migration compared to control PC-3 and LNCaP cells (P<0.05). Through computational analysis, the binding site for miR-188-5p at 3’-untranslated region (3’-UTR) of lysosome-associated protein transmembrane 4 beta (LAPTM4B) was depicted. The luciferase-based assay validated LAPTM4B was regulated by miR-188-5p. Conclusion The miR-188-5p was significantly down-regulated in PCa. Restoration of miR-188-5p in PCa cells significantly suppresses proliferation, migration and invasion in vitro. The miR-188-5p can negatively regulate LAPTM4B expression by directly binding to its 3’-UTR. Key words: MicroRNA-188-5p; Lysosome-associated protein transmembrane 4 beta; Prostate carcinoma

Lentivirus-mediated RNA Interference Targeting LAPTM4B Inhibits Human Ovarian Cancer Cell Invasion In Vitro.

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.

Differential expression of lysosome-associated protein transmembrane-4 beta (LAPTM4B) in granulosa cells of ovarian follicles and in other bovine tissues.

BackgroundLAPTM4B is a member of the lysosome-associated transmembrane protein superfamily that is differentially expressed in normal human tissues and upregulated in various types of carcinomas. These proteins are thought to be involved in the regulation of cell proliferation and survival. The objective of this study was to investigate the expression of bovine LAPTM4B during ovarian follicular development and in various bovine tissues.Methods and resultsNorthern blot analysis revealed a 1.8 kb transcript, with highly variable steady state levels among tissues. RT-PCR analysis showed that LAPTM4B mRNA transcripts were low in granulosa cells of small antral follicles, increased in large dominant follicles, and decreased in ovulatory follicles following injection of human chorionic gonadotropin (hCG; P < 0.003). Ovulatory follicles collected at various times after hCG injection revealed a significant reduction of LAPTM4B mRNA starting at 18 h post-hCG (P < 0.029). Immunobloting analysis using antibodies generated against bovine LAPTM4B recognized proteins of 26.3 and 31.5 kDa in granulosa cells of developing follicles and corpus luteum. Further analyses of affinity-purified His-tag LAPTM4B overexpressed in HEK cells showed that the 31.5 kDa protein represented the ubiquinated isoform of the 26.3 kDa native protein. The 26.3 kDa protein was differentially expressed showing highest amounts in dominant follicles and lowest amounts in ovulatory follicles 24 h post-hCG. Immunohistochemical analyses of LAPTM4B showed marked heterogeneity of labeling signal among tissues, with LAPTM4B mainly localized to perinuclear vesicles, in keeping with its putative lysosomal membrane localization.ConclusionThis study reports for the first time that bovine LAPTM4B in granulosa cells is present in both unubiquinated and ubiquinated forms, and is differentially expressed in developing ovarian follicles, suggesting a possible role in terminal follicular growth.

LAPTM4B Down Regulation Inhibits the Proliferation, Invasion and Angiogenesis of HeLa Cells In Vitro

Background/Aims: LAPTM4B (lysosome-associated protein transmembrane 4 beta) is a novel oncogene with important functions in aggressive human carcinomas, including cervical cancer. However, the specific functions and internal molecular mechanisms associated with this gene in the context of cervical cancer remain unclear. Methods: In this study, we explored the effects and mechanisms of LAPTM4B on tumor growth, metastasis and angiogenesis in vitro by depletion of LAPTM4B in Hela cell. RNA interference was used to induce down regulation of LAPTM4B gene expression in Hela cells. The motility, migration potential, and proliferation of the Hela cells were measured by flow cytometry, Transwell migration assays, wound healing assays, and Cell Counting Kit-8 assays. In addition, the cell cycle analysis utilized fluorescence-activated cell sorting. Results: In this study, RNAi-mediated LAPTM4B knockdown inhibited cell growth and angiogenesis. In vitro, HeLa cells with down regulated LAPTM4B also exhibited decreased migration and invasion activity as well as significantly reduced CDK12, HIF-1α, MMP-2, MMP-9 and VEGF expression. LAPTM4B blockade significantly decreased cord lengths and branch points in a tube formation assay. Conclusions: These results suggested that LAPTM4B inactivation could be a novel therapeutic target for cervical cancer.

Association between LAPTM4B gene polymorphism and breast cancer susceptibility in an Iranian population.

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.

Overexpression of LAPTM4B is correlated with tumor angiogenesis and poor prognosis in non-small cell lung cancer.

Lysosome-associated protein transmembrane-4 beta (LAPTM4B) is a novel oncogene, which has been indicated to be dramatically overexpressed in various malignant tumors. The aims of this study were to detect LAPTM4B protein expression in patients with non-small cell lung cancer (NSCLC) and then analyze the relationships of LAPTM4B protein with clinicopathologic factors, tumor angiogenesis and prognosis with SPSS statistical software. Immunohistochemistry was used to examine the expression of LAPTM4B and CD34 proteins in NSCLC tissues, and its results showed that LAPTM4B protein expression in NSCLC tissues was significantly higher than that in normal lung tissues (P < 0.001). Of the186 NSCLC cases, 129 (69.35 %) had strong expression of LAPTM4B protein, which was associated with histopathologic differentiation (P = 0.017), lymph node metastasis (P = 0.001) and TNM stage (P = 0.046), as well as the microvessel density (MVD) (P = 0.019). Kaplan-Meier survival analysis revealed that patients with strong LAPM4B protein expression and high MVD might have poor overall survival (OS; P = 0.001, P = 0.002, respectively) and disease-free survival (DFS; P = 0.002, P = 0.038, respectively). Multivariate analysis demonstrated that LAPTM4B protein was an independent prognostic marker for OS and DFS of NSCLC patients (P = 0.037, P = 0.046, respectively). These findings illustrated that LAPTM4B protein was closely associated with NSCLC progression, angiogenesis and poor prognosis, suggesting that LAPTM4B protein could be applied not only in predicting patient's outcome, but also in antiangiogenic therapy as a possible novel target molecule.

LAPTM4B polymorphism increases susceptibility to multiple cancers in Chinese populations: a meta-analysis.

BackgroundLysosome-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.ResultsThe 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.ConclusionsThis meta-analysis indicated that the LAPTM4B *2 allele was associated with increasing risk of multiple cancers, tumor initiation and development.

Abstract 2367: Transcriptomic architecture of the airway field cancerization in early-stage non-small cell lung cancer .

Abstract Earlier work has identified in lung cancer a field cancerization (FC) phenomenon in which tumors and adjacent normal appearing tissues share specific molecular abnormalities (e.g., loss of heterozygosity) that may be highly pertinent to cancer pathogenesis. We sought to characterize the global molecular airway FC adjacent to early-stage non-small cell lung cancer (NSCLC) in an attempt to unravel profiles that may help to explain the development of the disease. We performed whole-transcript expression profiling of a set of resected early-stage NSCLC specimens (n=20 patients) with matched histologically normal airways of varying distance from the tumor and paired uninvolved normal lung tissue (n=194 samples). Using linear mixed-effects models, we derived FC profiles signifying genes concordantly differentially expressed between tumors and airways compared to normal lung tissues. Gene set enrichment analysis demonstrated that a subset of the genes (n=299) was significantly and congruently modulated between large airways of smokers with and without lung cancer. We then questioned whether the airway FC exhibits site from tumor-dependent expression patterns. Ordinal regression analysis identified airway profiles (n=422 genes) that were significantly progressively expressed by distance from tumors and topologically organized into canonical cancer-associated pathways, such as eukaryotic initiation factor, p70S6K kinase, polo-like kinase and mammalian target of rapamycin signaling (all p&amp;lt;0.001). In addition, the site-dependent airway profiles recapitulated NSCLC expression patterns and were concordantly modulated between tumors and uninvolved normal lung tissues pinpointing their probable roles in lung cancer pathogenesis. Quantitative real-time PCR (QRTPCR) analysis confirmed the differential expression of FC markers selected by both pathways analysis and statistical criteria. Notably, lysosome associated protein transmembrane 4 beta (LAPTM4B), a putative oncogene with no known role in lung carcinogenesis, was among the top 5 site-dependent FC markers and was significantly elevated in NSCLC and immortalized bronchial epithelial cell lines compared to normal cells. Furthermore, transient or stable knockdown of LAPTM4B by RNA interference decreased NSCLC cell growth as well as anchorage-dependent and -independent colony formation. In conclusion, our efforts in understanding the adjacent molecular FC in NSCLC unraveled airway profiles that 1) are, in part, relevant to lung cancer detection; 2) are modulated by distance from corresponding tumors; 3) recapitulate NSCLC expression patterns and 4) harbor markers engaged in mediating the lung malignant phenotype. Profiling the adjacent airway FC in conjunction with tumors, may provide additional insights into the molecular pathology of NSCLC. Funded in part by Department of Defense award W81XWH-10-1-1007. Citation Format: Yuho Maki, Junya Fujimoto, Suk-Young Yoo, Adam Gower, Li Shen, Melinda M. Garcia, Mohamed Kabbout, Chi-Wan Chow, Waun Ki Hong, Neda Kalhor, Jing Wang, Cesar Moran, Avrum Spira, Kevin R. Coombes, Ignacio I. Wistuba, Humam Kadara. Transcriptomic architecture of the airway field cancerization in early-stage non-small cell lung cancer . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2367. doi:10.1158/1538-7445.AM2013-2367

Association of LAPTM4B gene polymorphism with nasopharyngeal carcinoma susceptibility in a Chinese population

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.

LAPTM4B gene polymorphism and endometrial carcinoma risk and prognosis

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.

Overexpression of LAPTM4B: an independent prognostic marker in breast cancer

Lysosome-associated protein transmembrane 4 beta (LAPTM4B), a novel oncoprotein, has been shown to be overexpressed in several human malignancies. Our purpose was to evaluate the expression of LAPTM4B in breast carcinoma and its significance, which was not previously studied by others. Through immunohistochemistry, LAPTM4B expression was evaluated in 35 benign breast tumor specimens and 194 breast cancer specimens. The correlation of LAPTM4B expression with clinicopathological parameters was assessed using χ(2) analysis. The survival status of patients was analyzed using the Kaplan-Meier and log-rank tests. Cox regression was used for the multivariate analysis of prognostic factors. The immunohistochemistry results showed that the expression level of LAPTM4B in breast cancer cases was significantly higher than that in benign breast tumor tissues (P < 0.001). Moreover, statistical analysis also showed that high LAPTM4B expression was positively related to TNM stage, lymph node metastasis, and recurrence. Furthermore, it was also shown that patients with high LAPTM4B expression had significantly poorer overall survival and disease-free survival compared with patients with low expression of LAPTM4B (P = 0.019 and P = 0.005, respectively). Multivariate Cox regression analysis revealed that high LAPTM4B expression level was an independent prognostic factor for both overall survival and disease-free survival of patients with breast cancer (P = 0.041 and P = 0.023, respectively). Overexpression of LAPTM4B may contribute to the tumor progression and poor prognosis of breast cancer, thus testing the expression of LAPTM4B will be helpful for predicting prognosis in breast cancer.

LAPTM4B Allele *2 Is Associated with Breast Cancer Susceptibility and Prognosis

BackgroundLysosome-associated protein transmembrane 4 beta (LAPTM4B) has two alleles named LAPTM4B*1 and LAPTM4B*2. Allele *1 contains only one copy of a 19-bp sequence at the 5′UTR in the first exon, whereas this sequence of allele*2 is duplicated and arrayed as a tandem repeat. Previous studies revealed that LAPTM4B polymorphisms contribute to the risk of certain types of cancers. This study aimed to investigate the polymorphism of LAPTM4B in breast cancer by analysis the correlation of LAPTM4B genotype with breast cancer susceptibility, clinicopathologic features and prognosis.MethodsGenotyping of the LAPTM4B polymorphism was determined by PCR method. The expression levels of LAPTM4B in breast cancer tissues and breast cancer cell lines were determined by quantitative reverse-transcription PCR (qRT-PCR) analysis. The correlation of LAPTM4B genotype with clinicopathologic parameters and prognosis were assessed statistically.ResultsThe results of qRT-PCR analysis indicated that LAPTM4B*2 was associated with the higher level of LAPTM4B expression compared with the LAPTM4B*1 in both breast cancer cell lines and breast cancer tissues. We found that LAPTM4B*2 was associated with an increased risk for breast cancer. LAPTM4B*2 was significantly associated with higher histopathologic grade, lymph node metastasis and poor prognosis.ConclusionLAPTM4B*2 is a risk factor associated with breast cancer susceptibility and poor prognosis. LAPTM4B*2 may be a potential predicative marker for the susceptibility, progression and metastasis of breast cancer.