LAPTM4B: an Oncogene in Various Solid Tumors and Its Functions
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Lysosomal Transmembrane Protein LAPTM4B Promotes Autophagy and Tolerance to Metabolic Stress in Cancer Cells
Author Manuscript Published OnlineFirst on October 28, 2011; DOI: 10.1158/0008-5472.CAN-11-0940 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Lysosomal transmembrane protein LAPTM4B promotes autophagy and tolerance to metabolic stress in cancer cells Yang Li1, Qing Zhang1, Ruiyang Tian1, Qi Wang1, Jean J. Zhao1, J. Dirk Iglehart1, 2, Zhigang Charles Wang1, Andrea L. Richardson1, 2 1 Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115 USA 2 Brigham and Women’s Hospital, Harvard Medical School, Boston MA 02115 USA Correspondence: [email protected] or [email protected] Running Title: LAPTM4B promotes autophagy and cell tolerance to stress Precis: Overexpression of a lysosomal protein implicated in chemoresistance and breast cancer is shown to promote autophagy and inhibit lysosome-mediated death pathways. Key Words: breast cancer, autophagy, lysosome-mediated death, metabolic stress This work supported by Susan G. Komen For the Cure (AR, ZW, YL, RT), Breast Cancer Research Foundation (JDI, AR, ZW), Terri Brodeur Breast Cancer Foundation (YL), and Friends of DFCI (YL). The authors have no conflicts of interest to disclose. Word count: 4997; Figures: 6 1 Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 2011 American Association for Cancer Research. Author Manuscript Published OnlineFirst on October 28, 2011; DOI: 10.1158/0008-5472.CAN-11-0940 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Abstract 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 Promotes the Progression of Nasopharyngeal Cancer
BJBMS RESEARCH ARTICLE MOLECULAR BIOLOGY LAPTM4B promotes the progression of nasopharyngeal cancer Qun Su, Hongtao Luo, Ming Zhang, Liying Gao, Fengju Zhao* ABSTRACT Lysosomal protein transmembrane 4 beta (LAPTM4B) is a protein that contains four transmembrane domains. The impact of LAPTM4B on the malignancy of nasopharyngeal carcinoma (NPC) remains unclear. In the present study, we aimed to investigate the role of LAPTM4B in NPC. NPC tissue samples were used to evaluate the expression of LAPTM4B and its relationship with patient prognosis. Furthermore, we inhibited the expression of LAPTM4B in NPC cell lines and examined the effects of LAPTM4B on NPC cell proliferation, migration, and invasion. We found that LAPTM4B protein was mainly localized in the cytoplasm and intracellular membranes of NPC cells. LAPTM4B protein was upregulated in NPC tissues and cell lines. High LAPTM4B expression was closely related to pathological subtypes and disease stages in NPC patients. NPC patients with high LAPTM4B expression had a worse prognosis. LAPTM4B knockdown inhibited the proliferation, migration, and invasion ability of NPC cells. LAPTM4B plays a cancer-promoting role in the progression of NPC and may be a potential target for NPC therapy. KEYWORDS: NPC; LAPTM4B; prognosis; proliferation; migration; invasion INTRODUCTION molecular regulatory mechanisms of NPC metastasis and find effective therapeutic targets. Nasopharyngeal carcinoma (NPC) is a malignant tumor Similar to other malignant solid tumors, the development originating from nasopharyngeal mucosal epithelial cells, of NPC is a complex process involving activation of onco- which usually occurs in the pharyngeal recess. Compared genes and inactivation of tumor suppressor genes. Lysosomal with other malignant solid tumors, NPC shows lower mor- protein transmembrane 4 beta (LAPTM4B) is a protein that bidity and mortality rates. -
Lysosomal Transmembrane Protein LAPTM4B Promotes Autophagy and Tolerance to Metabolic Stress in Cancer Cells
Author Manuscript Published OnlineFirst on October 28, 2011; DOI: 10.1158/0008-5472.CAN-11-0940 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Lysosomal transmembrane protein LAPTM4B promotes autophagy and tolerance to metabolic stress in cancer cells Yang Li1, Qing Zhang1, Ruiyang Tian1, Qi Wang1, Jean J. Zhao1, J. Dirk Iglehart1, 2, Zhigang Charles Wang1, Andrea L. Richardson1, 2 1 Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115 USA 2 Brigham and Women’s Hospital, Harvard Medical School, Boston MA 02115 USA Correspondence: [email protected] or [email protected] Running Title: LAPTM4B promotes autophagy and cell tolerance to stress Precis: Overexpression of a lysosomal protein implicated in chemoresistance and breast cancer is shown to promote autophagy and inhibit lysosome-mediated death pathways. Key Words: breast cancer, autophagy, lysosome-mediated death, metabolic stress This work supported by Susan G. Komen For the Cure (AR, ZW, YL, RT), Breast Cancer Research Foundation (JDI, AR, ZW), Terri Brodeur Breast Cancer Foundation (YL), and Friends of DFCI (YL). The authors have no conflicts of interest to disclose. Word count: 4997; Figures: 6 1 Downloaded from cancerres.aacrjournals.org on September 26, 2021. © 2011 American Association for Cancer Research. Author Manuscript Published OnlineFirst on October 28, 2011; DOI: 10.1158/0008-5472.CAN-11-0940 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Abstract 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. -
Integrative Bulk and Single-Cell Profiling of Premanufacture T-Cell Populations Reveals Factors Mediating Long-Term Persistence of CAR T-Cell Therapy
Published OnlineFirst April 5, 2021; DOI: 10.1158/2159-8290.CD-20-1677 RESEARCH ARTICLE Integrative Bulk and Single-Cell Profiling of Premanufacture T-cell Populations Reveals Factors Mediating Long-Term Persistence of CAR T-cell Therapy Gregory M. Chen1, Changya Chen2,3, Rajat K. Das2, Peng Gao2, Chia-Hui Chen2, Shovik Bandyopadhyay4, Yang-Yang Ding2,5, Yasin Uzun2,3, Wenbao Yu2, Qin Zhu1, Regina M. Myers2, Stephan A. Grupp2,5, David M. Barrett2,5, and Kai Tan2,3,5 Downloaded from cancerdiscovery.aacrjournals.org on October 1, 2021. © 2021 American Association for Cancer Research. Published OnlineFirst April 5, 2021; DOI: 10.1158/2159-8290.CD-20-1677 ABSTRACT The adoptive transfer of chimeric antigen receptor (CAR) T cells represents a breakthrough in clinical oncology, yet both between- and within-patient differences in autologously derived T cells are a major contributor to therapy failure. To interrogate the molecular determinants of clinical CAR T-cell persistence, we extensively characterized the premanufacture T cells of 71 patients with B-cell malignancies on trial to receive anti-CD19 CAR T-cell therapy. We performed RNA-sequencing analysis on sorted T-cell subsets from all 71 patients, followed by paired Cellular Indexing of Transcriptomes and Epitopes (CITE) sequencing and single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) on T cells from six of these patients. We found that chronic IFN signaling regulated by IRF7 was associated with poor CAR T-cell persistence across T-cell subsets, and that the TCF7 regulon not only associates with the favorable naïve T-cell state, but is maintained in effector T cells among patients with long-term CAR T-cell persistence. -
Molecular Cloning and Characterization of LAPTM4B, a Novel Gene Upregulated in Hepatocellular Carcinoma
Oncogene (2003) 22, 5060–5069 & 2003 Nature Publishing Group All rights reserved 0950-9232/03 $25.00 www.nature.com/onc Molecular cloning and characterization of LAPTM4B, a novel gene upregulated in hepatocellular carcinoma Gen-Ze Shao1, Rou-Li Zhou*,1, Qing-Yun Zhang1, Ye Zhang1, Jun-Jian Liu1, Jing-An Rui2, Xue Wei2 and Da-Xiong Ye2 1Department of Cell Biology & Genetics, School of Basic Medical Sciences, Peking University, Beijing 100083, China; 2Department of Basic Surgery, Peking Union Medical College Hospital, Beijing 100032, China Lysosomal-associated protein transmembrane-4 beta mortality rates. A recent statistic (Nakakuya et al., (LAPTM4B), a novel gene upregulated in hepatocellular 2000) showed that 89% of the HCC cases around the carcinoma (HCC), was cloned using fluorescence differ- world occurred in developing countries, especially in ential display, RACE, and RT–PCR. It contains seven Southeast Asia and South Africa. In many countries, exons and encodes a 35-kDa protein with four putative including the United States, a definite increase in the transmembrane regions. Both the N- and C-termini of the incidence of HCC was also noticed in the report (El- protein are proline-rich, and may serve as potential Serag, 2002). As estimated by IARC, the total incidence ligands for the SH3 domain. Immunohistochemical in 2000 was 564 000 and the mortality was up to 549 000. analysis localized the protein predominantly to intracel- The major risk factors for this cancer have been lular membranes. Northern blot showed that the identified as chronic infections with hepatitis B (HBV) LAPTM4B mRNAs were remarkably upregulated in or hepatitis C (HCV) viruses, and dietary exposure to HCC (87.3%) and correlated inversely with differentia- aflatoxins. -
Mir-188-5P Inhibits Tumour Growth and Metastasis in Prostate Cancer by Repressing LAPTM4B Expression
www.impactjournals.com/oncotarget/ Oncotarget, Vol. 6, No.8 miR-188-5p inhibits tumour growth and metastasis in prostate cancer by repressing LAPTM4B expression Hongtuan Zhang1,2,3, Shiyong Qi1, Tao Zhang1, Andi Wang1, Ranlu Liu1, Jia Guo2, Yuzhuo Wang2,3 and Yong Xu1 1 Department of Urology, National Key Specialty of Urology, Second Hospital of Tianjin Medical University, Tianjin Key Institute of Urology, Tianjin Medical University, Tianjin, China 2 Vancouver Prostate Centre & Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada 3 Department of Experimental Therapeutics, British Columbia Cancer Agency, Vancouver, British Columbia, Canada Correspondence to: Yong Xu, email: [email protected] Keywords: miRNA, metastasis, miR-188-5p, prostate cancer, LAPTM4B Received: December 14, 2014 Accepted: January 03, 2015 Published: January 21, 2015 This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Elucidation of the molecular targets and pathways regulated by the tumour- suppressive miRNAs can shed light on the oncogenic and metastatic processes in prostate cancer (PCa). Using miRNA profiling analysis, we find that miR-188-5p was significantly down-regulated in metastatic PCa. Down-regulation of miR-188-5p is an independent prognostic factor for poor overall and biochemical recurrence- free survival. Restoration of miR-188-5p in PCa cells (PC-3 and LNCaP) significantly suppresses proliferation, migration and invasion in vitro and inhibits tumour growth and metastasis in vivo. We also find overexpression of miR-188-5p in PC-3 cells can significantly enhance the cells’ chemosensitivity to adriamycin. -
A Robust Twelve-Gene Signature for Prognosis Prediction Of
Ouyang et al. Cancer Cell Int (2020) 20:207 https://doi.org/10.1186/s12935-020-01294-9 Cancer Cell International PRIMARY RESEARCH Open Access A robust twelve-gene signature for prognosis prediction of hepatocellular carcinoma Guoqing Ouyang1, Bin Yi2, Guangdong Pan1 and Xiang Chen3* Abstract Background: The prognosis of hepatocellular carcinoma (HCC) patients remains poor. Identifying prognostic mark- ers to stratify HCC patients might help to improve their outcomes. Methods: Six gene expression profles (GSE121248, GSE84402, GSE65372, GSE51401, GSE45267 and GSE14520) were obtained for diferentially expressed genes (DEGs) analysis between HCC tissues and non-tumor tissues. To identify the prognostic genes and establish risk score model, univariable Cox regression survival analysis and Lasso-penalized Cox regression analysis were performed based on the integrated DEGs by robust rank aggregation method. Then Kaplan–Meier and time-dependent receiver operating characteristic (ROC) curves were generated to validate the prognostic performance of risk score in training datasets and validation datasets. Multivariable Cox regression analysis was used to identify independent prognostic factors in liver cancer. A prognostic nomogram was constructed based on The Cancer Genome Atlas (TCGA) dataset. Finally, the correlation between DNA methylation and prognosis-related genes was analyzed. Results: A twelve-gene signature including SPP1, KIF20A, HMMR, TPX2, LAPTM4B, TTK, MAGEA6, ANX10, LECT2, CYP2C9, RDH16 and LCAT was identifed, and risk score was calculated by corresponding coefcients. The risk score model showed a strong diagnosis performance to distinguish HCC from normal samples. The HCC patients were stratifed into high-risk and low-risk group based on the cutof value of risk score. -
Downloaded Per Proteome Cohort Via the Web- Site Links of Table 1, Also Providing Information on the Deposited Spectral Datasets
www.nature.com/scientificreports OPEN Assessment of a complete and classifed platelet proteome from genome‑wide transcripts of human platelets and megakaryocytes covering platelet functions Jingnan Huang1,2*, Frauke Swieringa1,2,9, Fiorella A. Solari2,9, Isabella Provenzale1, Luigi Grassi3, Ilaria De Simone1, Constance C. F. M. J. Baaten1,4, Rachel Cavill5, Albert Sickmann2,6,7,9, Mattia Frontini3,8,9 & Johan W. M. Heemskerk1,9* Novel platelet and megakaryocyte transcriptome analysis allows prediction of the full or theoretical proteome of a representative human platelet. Here, we integrated the established platelet proteomes from six cohorts of healthy subjects, encompassing 5.2 k proteins, with two novel genome‑wide transcriptomes (57.8 k mRNAs). For 14.8 k protein‑coding transcripts, we assigned the proteins to 21 UniProt‑based classes, based on their preferential intracellular localization and presumed function. This classifed transcriptome‑proteome profle of platelets revealed: (i) Absence of 37.2 k genome‑ wide transcripts. (ii) High quantitative similarity of platelet and megakaryocyte transcriptomes (R = 0.75) for 14.8 k protein‑coding genes, but not for 3.8 k RNA genes or 1.9 k pseudogenes (R = 0.43–0.54), suggesting redistribution of mRNAs upon platelet shedding from megakaryocytes. (iii) Copy numbers of 3.5 k proteins that were restricted in size by the corresponding transcript levels (iv) Near complete coverage of identifed proteins in the relevant transcriptome (log2fpkm > 0.20) except for plasma‑derived secretory proteins, pointing to adhesion and uptake of such proteins. (v) Underrepresentation in the identifed proteome of nuclear‑related, membrane and signaling proteins, as well proteins with low‑level transcripts. -
Downloaded Package Was Applied to Remove Genes and Samples with Too from the Gene Expression Omnibus (GEO) Database of the Many Missing Values
fgene-12-668448 June 29, 2021 Time: 18:22 # 1 ORIGINAL RESEARCH published: 05 July 2021 doi: 10.3389/fgene.2021.668448 Integrated Analysis of lncRNAs, mRNAs, and TFs to Identify Regulatory Networks Underlying MAP Infection in Cattle Maryam Heidari1, Abbas Pakdel1*, Mohammad Reza Bakhtiarizadeh2 and Fariba Dehghanian3 1 Department of Animal Sciences, College of Agriculture, Isfahan University of Technology, Isfahan, Iran, 2 Department of Animal and Poultry Science, College of Aburaihan, University of Tehran, Tehran, Iran, 3 Department of Biology, University of Isfahan, Isfahan, Iran Johne’s disease is a chronic infection of ruminants that burdens dairy herds with a significant economic loss. The pathogenesis of the disease has not been revealed clearly due to its complex nature. In order to achieve deeper biological insights into molecular mechanisms involved in MAP infection resulting in Johne’s disease, a system biology approach was used. As far as is known, this is the first study that considers lncRNAs, Edited by: Natalia Polouliakh, TFs, and mRNAs, simultaneously, to construct an integrated gene regulatory network Sony Computer Science involved in MAP infection. Weighted gene coexpression network analysis (WGCNA) and Laboratories, Japan functional enrichment analysis were conducted to explore coexpression modules from Reviewed by: Shigetoshi Eda, which nonpreserved modules had altered connectivity patterns. After identification of The University of Tennessee, hub and hub-hub genes as well as TFs and lncRNAs in the nonpreserved modules, Knoxville, United States integrated networks of lncRNA-mRNA-TF were constructed, and cis and trans targets Hugo Tovar, Instituto Nacional de Medicina of lncRNAs were identified. Both cis and trans targets of lncRNAs were found in eight Genómica (INMEGEN), Mexico nonpreserved modules. -
The Relationship Between LAPTM4B Polymorphisms and Cancer Risk In
Xia et al. SpringerPlus (2015) 4:179 DOI 10.1186/s40064-015-0941-7 a SpringerOpen Journal RESEARCH Open Access The relationship between LAPTM4B polymorphisms and cancer risk in Chinese Han population: a meta-analysis Ling-Zi Xia1,2, Zhi-Hua Yin1,2, Yang-Wu Ren1,2, Li Shen1,2, Wei Wu1,2, Xue-Lian Li1,2, Peng Guan1,2 and Bao-Sen Zhou1,2* Abstract LAPTM4B is a newly cloned gene that shows an active role in many solid tumors progression in substantial researches, mainly through the autophage function. Accumulated studies have been conducted to determine the association of LAPTM4B polymorphism with cancer risk. While the results are inconsistent, we conducted the meta-analysis to determine the strength of the relationship. Results showed that allele*2 carriers exhibited a significantly increased risk of cancer development with comparison to allele*1 homozygote (for *1/2, OR = 1.55, 95% CI 1.367-1.758; for *2/2, OR = 2.093, 95%CI 1.666-2.629; for *1/2 + *2/2, OR = 1.806, 95%CI 1.527-2.137). We also observed a significant association between *2/2 homozygote and cancer risk with comparison to allele*1 containing genotypes (OR = 1.714, 95%CI 1.408-2.088). Allele*2 is a risk factor for cancer risk (OR = 1.487, 95%CI 1.339-1.651). Stratified analysis by tumor type exhibits the significant association of this genetic variants with various cancers. In conclusion, LAPTM4B polymorphism is associated with cancer risk and allele*2 is a risk factor. Keywords: LAPTM4B; Polymorphism; Meta-analysis; Cancer risk Background (Scarlatti et al. -
Molecular Targeting and Enhancing Anticancer Efficacy of Oncolytic HSV-1 to Midkine Expressing Tumors
University of Cincinnati Date: 12/20/2010 I, Arturo R Maldonado , hereby submit this original work as part of the requirements for the degree of Doctor of Philosophy in Developmental Biology. It is entitled: Molecular Targeting and Enhancing Anticancer Efficacy of Oncolytic HSV-1 to Midkine Expressing Tumors Student's name: Arturo R Maldonado This work and its defense approved by: Committee chair: Jeffrey Whitsett Committee member: Timothy Crombleholme, MD Committee member: Dan Wiginton, PhD Committee member: Rhonda Cardin, PhD Committee member: Tim Cripe 1297 Last Printed:1/11/2011 Document Of Defense Form Molecular Targeting and Enhancing Anticancer Efficacy of Oncolytic HSV-1 to Midkine Expressing Tumors A dissertation submitted to the Graduate School of the University of Cincinnati College of Medicine in partial fulfillment of the requirements for the degree of DOCTORATE OF PHILOSOPHY (PH.D.) in the Division of Molecular & Developmental Biology 2010 By Arturo Rafael Maldonado B.A., University of Miami, Coral Gables, Florida June 1993 M.D., New Jersey Medical School, Newark, New Jersey June 1999 Committee Chair: Jeffrey A. Whitsett, M.D. Advisor: Timothy M. Crombleholme, M.D. Timothy P. Cripe, M.D. Ph.D. Dan Wiginton, Ph.D. Rhonda D. Cardin, Ph.D. ABSTRACT Since 1999, cancer has surpassed heart disease as the number one cause of death in the US for people under the age of 85. Malignant Peripheral Nerve Sheath Tumor (MPNST), a common malignancy in patients with Neurofibromatosis, and colorectal cancer are midkine- producing tumors with high mortality rates. In vitro and preclinical xenograft models of MPNST were utilized in this dissertation to study the role of midkine (MDK), a tumor-specific gene over- expressed in these tumors and to test the efficacy of a MDK-transcriptionally targeted oncolytic HSV-1 (oHSV). -
Clinical Impact of Circulating LAPTM4B-35 in Pancreatic Ductal Adenocarcinoma
Journal of Cancer Research and Clinical Oncology (2019) 145:1165–1178 https://doi.org/10.1007/s00432-019-02863-w ORIGINAL ARTICLE – CANCER RESEARCH Clinical impact of circulating LAPTM4B-35 in pancreatic ductal adenocarcinoma Zixuan Yang1 · Norbert Senninger1 · Isabelle Flammang1 · Qifa Ye2 · Sameer A. Dhayat1 Received: 14 December 2018 / Accepted: 12 February 2019 / Published online: 18 February 2019 © Springer-Verlag GmbH Germany, part of Springer Nature 2019 Abstract Purpose LAPTM4B is upregulated in a wide range of cancers associated with poor prognosis. However, the clinical impact of LAPTM4B as diagnostic and prognostic marker in pancreatic ductal adenocarcinoma (PDAC) remains unknown. Thus, the aim of the present study was to investigate the expression of LAPTM4B as circulating marker in PDAC. Methods Expression analysis of LAPTM4B-35 in pancreatic tissue and preoperative blood serum samples of 169 patients with PDAC UICC Stages I–IV (n = 98), chronic pancreatitis (n = 41), and healthy controls (n = 30) by immunohistochem- istry, Western blot, and ELISA. Descriptive and explorative statistical analyses of LAPTM4B-35’s potential as diagnostic and prognostic marker in PDAC. Results Expression of LAPTM4B-35 was significantly increased in tumor tissue and corresponding blood serum samples of patients with PDAC (each p < 0.001) and it could well discriminate PDAC from healthy controls and chronic pancreatitis (p < 0.001; p = 0.0037). LAPTM4B-35 in combination with CA.19-9 outperforms the diagnostic accuracy with an AUC of 0.903 (p < 0.001), sensitivity of 82%, and specificity of 92%. Kaplan–Meier survival analysis revealed an improved overall survival in PDAC UICC I–IV with low expression of circulating LAPTM4B-35 (17 versus 10 months, p = 0.039) as well as an improved relapse-free survival in curatively treated PDAC UICC I–III (16 versus 10 months; p = 0.037).