INTRODUCTION: Hepatocellular carcinoma is a lethal disease worldwide and therefore the establishment of novel diagnostic biomarkers is imperative. In this study, it was hypothesized that an abnormal expression of the lysosomal-associated protein transmembrane 4 beta ( LAPTM4B) gene is crucial in the pathogenesis of hepatitis C virus-mediated hepatocellular carcinoma; hence we investigated the expression profile of LAPTM4B in hepatitis C virus-induced hepatocellular carcinoma.
METHODS: A group of 189 consecutive patients (hepatitis C virus-related hepatocellular carcinoma as tumor cases; n=93, hepatitis C virus-related cirrhotics as disease controls; n=96) opting for living donor liver transplantation as a therapeutic surgical regimen were recruited with informed consent. Additionally, paired adjacent non-tumorous tissues (n=93) obtained from cases were also included. Serum LAPTM4B protein concentrations were assessed by third-generation enzyme-linked immunosorbent assay and LAPTM4B mRNA, and protein expressions at tissue level were determined by quantitative real time reverse transcription-polymerase chain reaction (qRT-PCR) and immunohistochemistry techniques, respectively.
RESULTS: LAPTM4B protein concentrations in sera of patients were higher ( p<0.001) in tumor cases (1.25±0.25 ng/ml) compared to disease controls (0.53±0.28 ng/ml). Our study also depicts positive clinicopathological correlations between alpha-fetoprotein titers (b=0.65; p<0.001), quantitative hepatitis C virus RNA copies (b=0.33; p<0.001), and LAPTM4B protein concentrations, all in sera of patients. In addition, qRT-PCR and immunohistochemistry analyses revealed a significantly higher ( p<0.05) tissue LAPTM4B mRNA and protein expression, respectively, in tumor cases rather than in non-tumorous tissues and disease controls.
CONCLUSIONS: Together, our results illustrate the LAPTM4B gene as a diagnostic biomarker in patients with hepatocellular carcinoma having documented evidence of chronic hepatitis C virus infection.

PURPOSE: To determine the associations between lysosomal-associated transmembrane protein 4b (LAPTM4B) gene copy number and response to different chemotherapy regimens in hormone receptor negative (HR-) primary breast carcinomas.
PATIENTS AND METHODS: Two cohorts were analyzed: (1) 69 core biopsies from HR-breast carcinomas treated with neoadjuvant chemotherapy (anthracycline based in 72.5% of patients and non-anthracycline based in 27.5% of patients). (2) Tissue microarray (TMA) of 74 HR-breast carcinomas treated with adjuvant therapy (77.0% of the patients received anthracycline, 17.6% of the patients non-anthracycline-based therapy, and in 5.4% of the cases, no treatment data are available). Interphase FISH technique was applied on pretreatment core biopsies (cohort I) and on TMAs (cohort II) using custom-made dual-labelled FISH probes (LAPTM4B/CEN8q FISH probe Abnova Corp.).
RESULTS: In the neoadjuvant cohort in the anthracycline-treated group, we observed a significant difference (p = 0.029) of average LAPTM4B copy number between the non-responder and pathological complete responder groups (4.1 ± 1.1 vs. 2.6 ± 0.1). In the adjuvant setting, the anthracycline-treated group of metastatic breast carcinomas was characterized by higher LAPTM4B copy number comparing to the non-metastatic ones (p = 0.046). In contrast, in the non-anthracycline-treated group of patients, we did not find any LAPTM4B gene copy number differences between responder vs. non-responder groups or between metastatic vs. non-metastatic groups.
CONCLUSION: Our results confirm the possible role of the LAPTM4B gene in anthracycline resistance in HR- breast cancer. Analyzing LAPTM4B copy number pattern may support future treatment decision.

Lysosomal-associated protein transmembrane-4 beta (LAPTM4B) is a novel oncogene, whose overexpression is involved in cancer occurrence and progression. However, the mechanism of LAPTM4B transcriptional regulation remains unclear. In this study, the results of transcription factor (TF) profiling plate arrays indicated that AP4 was a potential transcription factor regulating LAPTM4B expression. LAPTM4B was positively correlated with AP4 and they were both associated with poor overall and disease-free survival. Luciferase and electrophoretic mobility shift assay assays confirmed that AP4 directly bound to the polymorphism region of LAPTM4B promoter and modulated its transcription. Functionally, AP4 promoted cell proliferation, migration, invasion, and assisted drug resistance in part through upregulation of LAPTM4B. Taken together, these findings identify LAPTM4B as a direct AP4 target gene and the interaction of AP4 and LAPTM4B plays an important role in breast cancer progression.

Polymorphisms of the lysosomal-associated protein transmembrane-4 beta (LAPTM4B) gene are related to various forms of tumour susceptibility, which led us to hypothesize that some unique transcription factors targeting this polymorphism region may affect the biological function of LAPTM4B in tumour progression. In this study, we found that the transcription factor AP4 directly binds to the polymorphism region of the LAPTM4B gene promoter and induces its transcription. In addition, we demonstrated that AP4 promotes hepatocellular carcinoma (HCC) cell proliferation and metastasis and depresses chemotherapy sensitivity via LAPTM4B by activating the PI3K/AKT signalling pathway and caspase-dependent pathway. Interestingly, we found that AP4 could not only regulate LAPTM4B by directly binding to the promoter, but also be regulated via a positive feedback mechanism involving LAPTM4B acting on c-myc. Finally, we showed that AP4 and LAPTM4B are highly coexpressed in HCC tissues, and their coexpression may be a marker of poor prognosis. These findings provide evidence of the expression and functional coupling between AP4 and LAPTM4B and shed light on the regulation of LAPTM4B and its function in liver cancer.

Hepatocellular carcinoma (HCC) is one of the most common and rapidly fatal malignancies, for which hepatitis B virus (HBV) chronic infection constitutes a major risk factor. The lysosome-associated protein transmembrane-4 β gene (LAPTM4B) is a recently identified gene that was found to be overexpressed in several types of cancer. However, the role of LAPTM4B in HCC tumorigenesis and progression has not been clearly determined. The present study demonstrated that the mRNA as well as the protein levels of LAPTM4B were significantly upregulated in HCC specimens. Patients with higher levels of LAPTM4B mRNA in their HCC tissues tended to be of a younger age, HBsAg+, with an advanced Barcelona Clinic Liver Cancer stage. Moreover, LAPTM4B mRNA expression was positively associated with serum α -fetoprotein levels. We also observed that LAPTM4B was able to promote HCC cell proliferation, migration and invasion in vitro. In conclusion, our results indicated that LAPTM4B plays an important role in the promotion of hepatocarcinogenesis and cancer progression and may serve as a biomarker for the diagnosis and monitoring of HCC.

Pancreatic carcinoma is an aggressive malignancy with particularly low 5-year survival rate. In order to improve the dismal survival rate, identification of new potential susceptibility risk factors for the prevention and early detection of pancreatic carcinoma is of utmost importance. Lysosomal protein transmembrane 4 beta has two alleles designated as LAPTM4B*1 and LAPTM4B*2. The aim of this study was to investigate the association between lysosomal protein transmembrane 4 beta gene polymorphism and the risk of pancreatic carcinoma in China. A population-based case-control analysis was performed in 233 patients with pancreatic carcinoma and 842 control subjects. The genotypes of lysosomal protein transmembrane 4 beta were determined by utilizing polymerase chain reaction based on specific primers. The χ

Beclin1 is an essential autophagy regulator and a haploinsufficient tumor-suppressor. Reduced Berclin1 expression has been associated with many types of human malignancies including gastric cancer. However, the mechanism of how Beclin1 represses tumorigenesis of gastric cancer remains elusive. In recent proteomics study, we found that Beclin1 is associated with Lysosome-associated transmembrane protein 4β (LAPTM4B). LAPTM4B plays an important role in promoting the growth and proliferation of tumor cells, it is overexpressed in a variety of solid tumors and serves as a biomarker for tumor therapy. Further analysis showed that Beclin1 interacts with both the N- and C-termini of LAPTM4B and this interaction is independent of Vps34 complex. We demonstrated that Beclin1 competes with Epidermal growth factor receptor (EGFR) for LAPTM4B binding and Beclin1 can repress the LAPTM4B mediated EGFR activation and gastric cancer cell growth. Taken together, our study proposes a role of Beclin1 in repressing gastric cancer through disrupting the oncogenic promoting function of LAPTM4B.

Breast cancer 1 (BRCA1) and E2F transcription factor 1 (E2F1) are related to metabolism and cell cycle regulation. However, the corresponding mechanism is not clear in HCC. High BRCA1 direct pathway was constructed with 11 molecules from E2F1 feedback-interactive network in HCC by GRNInfer based on 39 Pearson mutual positive corelation CC ≥0.25 molecules with E2F1. Integration of GRNInfer with GO, KEGG, BioCarta, GNF_U133A, UNIGENE_EST, Disease, GenMAPP databases by DAVID and MAS 3.0, E2F1 feedback-interactive BRCA1 indirect mitochondrion to cytosol pathway was identified as upstream LAPTM4B activation, feedback UNG, downstream BCAT1-HIST1H2AD-TK1 reflecting protein, and DNA binding with enrichment of small molecule metabolism; The corresponding BRCA1 indirect membrane to cytosol pathway as upstream CCNB2-NUSAP1 activation, feedback TTK-HIST1H2BJ-CENPF, downstream MCM4-TK1 reflecting ATP, and microtubule binding with enrichment of CD4+T-related cell cycle regulation in HCC. Therefore, we propose that E2F1 interactive with BRCA1 pathway induces HCC two different small molecule metabolism or cell cycle regulation via mitochondrion or CD4+T to cytosol. Knowledge analysis demonstrates our E2F1 feedback-interactive BRCA1 pathway wide disease distribution and reflects a novel common one of tumor and cancer.

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.

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 (12.0 months, 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.

A modern biomedical research project can easily contain hundreds of analysis steps and lack of reproducibility of the analyses has been recognized as a severe issue. While thorough documentation enables reproducibility, the number of analysis programs used can be so large that in reality reproducibility cannot be easily achieved. Literate programming is an approach to present computer programs to human readers. The code is rearranged to follow the logic of the program, and to explain that logic in a natural language. The code executed by the computer is extracted from the literate source code. As such, literate programming is an ideal formalism for systematizing analysis steps in biomedical research. We have developed the reproducible computing tool Lir (literate, reproducible computing) that allows a tool-agnostic approach to biomedical data analysis. We demonstrate the utility of Lir by applying it to a case study. Our aim was to investigate the role of endosomal trafficking regulators to the progression of breast cancer. In this analysis, a variety of tools were combined to interpret the available data: a relational database, standard command-line tools, and a statistical computing environment. The analysis revealed that the lipid transport related genes LAPTM4B and NDRG1 are coamplified in breast cancer patients, and identified genes potentially cooperating with LAPTM4B in breast cancer progression. Our case study demonstrates that with Lir, an array of tools can be combined in the same data analysis to improve efficiency, reproducibility, and ease of understanding. Lir is an open-source software available at github.com/borisvassilev/lir.

Our previous studies demonstrated that LAPTM4B-35 is overexpressed in a variety of solid cancers including hepatocellular carcinoma (HCC), and is an independent factor for prognosis. LAPTM4B-35 overexpression causes carcinogenesis and enhances cancer growth, metastasis and multidrug resistance, and thus may be a candidate for therapeutic targeting. The present study shows ethylglyoxal bisthiosemicarbazon (ETS) has effective anticancer activity through LAPTM4B-35 targeting. Bel-7402 and HepG2 cell lines from human HCC were used as cell models in which LAPTM4B-35 is highly expressed, and a human fetal liver cell line was used as a control. The results showed ETS has a specific and pronounced lethal effect on HCC cells, but not on fetal liver cells in culture. ETS also attenuated growth and metastasis of human HCC xenograft in nude mice, and extended the life span of mice with HCC. ETS induced HCC cell apoptosis, and upregulated a large number of proapoptotic genes and downregulated antiapoptotic genes. When endogenous overexpression of LAPTM4B-35 was knocked down with RNAi, the killing effect of ETS on HepG2 cells was significantly attenuated. ETS also inhibited phosphorylation of LAPTM4B-35 Tyr285, which involves in activation of the PI3K/Akt signaling pathway induced by LAPTM4B-35 overexpression. In addition, the induction of alterations in quantity of c-Myc, Bcl-2, Bax, cyclinD1 and Akt-p molecules in HepG2 cells by LAPTM4B-35 overexpression could be reversed by ETS.
CONCLUSION: ETS is a promising candidate for treatment of HCC through LAPTM4B-35 protein targeting.

BACKGROUND: The expression levels and clinical significances of Lysosomal-associated protein transmembrane-4β-35 (LAPTM4B-35) protein are unknown in the non-small-cell lung cancer (NSCLC). This study aimed to explore the expression and prognostic value of LAPTM4B-35 in NSCLC patients.
METHODS: The clinicopathological and survival data of 107 NSCLC patients who received radical surgery from 2007 and 2011 were reviewed. The LAPTM4B-35 expression of the paired tumors and adjacent normal specimens were detected, and the association between LAPTM4B-35 and clinical variables was explored. Kaplan-Meier analysis and Cox regression (Proportional hazard model) were performed to investigate the prognostic significance for NSCLC.
RESULTS: LAPTM4B-35 was over expressed in NSCLC tissues. The elevated LAPTM4B-35 expression was associated with cancer recurrence (P = 0.031). The 5-year median OS and PFS were significantly worse in the LAPTM4B-35 overexpressed group. Multivariate Cox analysis showed that LAPTM4B-35 over-expression was an independent factor for OS and PFS in NSCLC(P = 0.018, P = 0.026, respectively).
CONCLUSIONS: The overexpressed LAPTM4B-35 was an independent prognostic biomarker for NSCLC, which could predict cancer recurrence and poor over survival. And that may be applied as potential target for NSCLC treatment.

BACKGROUND: Lysosome-associated transmembrane-4 beta (LAPTM4B) is an oncogene that participates tumorgenesis in a variety of human solid tumors, and it has two alleles named as LAPTM4B*1 and *2. The present study aimed to identify the association of LAPTM4B genotype with clinicopathological features and prognosis in colorectal and esophageal cancer patients.
METHOD: Genotypes of LAPTM4B were determined by PCR in 167 colon cancer cases (72 patients in a discovery cohort and 95 patients in a testing cohort), 160 rectal cancer cases and 164 esophageal cancer cases. Association between the LAPTM4B gene polymorphism and clinicopathological variables was calculated by Chi-square test or Fisher's exact test. Patient survival differences were calculated by the Kaplan-Meier method. Prognostic factors were determined with Log-rank test and Cox regression model.
RESULTS: LAPTM4B *1/1 was more frequently detected in colon cancer patients with lymph node metastasis and TNM III+IV stages in total colon cancer (discovery + testing cohorts). LAPTM4B *2/2 decreased in recurrent patients in total colon cancer patients (P = 0.045). Kaplan-Meier survival curves and Log-rank test showed that LAPTM4B*1 was correlated with shorter overall survival (OS) in discovery and testing cohorts of colon cancer (P = 0.0254 and 0.0292, respectively), but not in rectal and esophageal cancer cases (P = 0.7669 and 0.9356, respectively). Multivariate analysis showed that LAPTM4B genotype was an independent prognostic factor for OS in total colon cancer [P = 0.004, hazard ratio (HR) = 0.432; 95% confidence interval (CI) = 0.243-0.768], but not in rectal and esophageal cancers (P = 0.791, HR = 1.073, 95% CI = 0.638-1.804 and 0.998, HR = 1.000, 95% CI = 0.663-1.530, respectively).
CONCLUSION: These findings suggested that LAPTM4B allele *1 was a risk factor associated with poor prognosis in patients with colon cancer, but not in patients with rectal or esophageal cancers. LAPTM4B genotype status might be a useful prognostic indicator for patients that need surgical operation in colon cancer.

The oncogene Lysosome-associated protein transmembrane-4β (LAPTM4B) gene was identified, and the polymorphism region in the 5'-UTR of this gene was certified to be associated with tumor susceptibility. LAPTM4B-35 protein was found to be highly expressed in various solid tumors and could be a poor prognosis marker. The functions of LAPTM4B in solid tumors were also explored. It is suggested that LAPTM4B could promote the proliferation of tumor cells, boost invasion and metastasis, resist apoptosis, initiate autophagy and assist drug resistance.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.