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Serge Hardy, Elie Kostantin, Teri Hatzihristidis, Yevgen Zolotarov, Noriko Uetani, Michel L Tremblay
The human Phosphatase of Regenerative Liver (PRL) family comprises three members (PRL-1, -2, -3; gene name PTP4A1, PTP4A2, PTP4A3) that are highly expressed in a majority of cancers. This review summarizes our current understanding of PRL biology, including an overview of their evolutionary relationships and the regulatory mechanisms controlling their expression. We provide an updated view on our current knowledge on the PRL functions in solid tumors, hematological cancer and normal physiology, particularly emphasizing on the use of in vivo mouse models...
May 16, 2018: FEBS Journal
Kelley E McQueeney, Joseph M Salamoun, Jennifer G Ahn, Paula Pekic, Isabella K Blanco, Heather L Struckman, Elizabeth R Sharlow, Peter Wipf, John S Lazo
Dysregulation of the tightly controlled protein phosphorylation networks that govern cellular behavior causes cancer. The membrane-associated, intracellular protein tyrosine phosphatase PTP4A3 is overexpressed in human colorectal cancer and contributes to cell migration and invasion. To interrogate further the role of PTP4A3 in colorectal cancer cell migration and invasion, we deleted the Ptp4a3 gene from murine colorectal tumor cells. The resulting PTP4A3-/- cells exhibited impaired colony formation, spheroid formation, migration, and adherence compared with the paired PTP4A3fl/fl cells...
May 10, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Kelley E McQueeney, Joseph M Salamoun, James C Burnett, Nektarios Barabutis, Paula Pekic, Sophie L Lewandowski, Danielle C Llaneza, Robert Cornelison, Yunpeng Bai, Zhong-Yin Zhang, John D Catravas, Charles N Landen, Peter Wipf, John S Lazo, Elizabeth R Sharlow
Overexpression of protein tyrosine phosphatase PTP4A oncoproteins is common in many human cancers and is associated with poor patient prognosis and survival. We observed elevated levels of PTP4A3 phosphatase in 79% of human ovarian tumor samples, with significant overexpression in tumor endothelium and pericytes. Furthermore, PTP4A phosphatases appear to regulate several key malignant processes, such as invasion, migration, and angiogenesis, suggesting a pivotal regulatory role in cancer and endothelial signaling pathways...
February 2, 2018: Oncotarget
Magnus A Hjort, Pegah Abdollahi, Esten N Vandsemb, Mona H Fenstad, Bendik Lund, Tobias S Slørdahl, Magne Børset, Torstein B Rø
Phosphatase of regenerating liver-3 (PRL-3/PTP4A3) is upregulated in multiple cancers, including BCR-ABL1- and ETV6-RUNX-positive acute lymphoblastic leukemia (ALL). With this study, we aim to characterize the biological role of PRL-3 in B cell ALL (B-ALL). Here, we demonstrate that PRL-3 expression at mRNA and protein level was higher in B-ALL cells than in normal cells, as measured by qRT-PCR or flow cytometry. Further, we demonstrate that inhibition of PRL-3 using shRNA or a small molecular inhibitor reduced cell migration towards an SDF-1α gradient in the preB-ALL cell lines Reh and MHH-CALL-4...
January 9, 2018: Oncotarget
Malika Foy, Océane Anézo, Simon Saule, Nathalie Planque
In a previous transcriptomic analysis of 63 ocular melanomas of the uvea, we found that expression of the PRL-3/PTP4A3 gene, encoding a phosphatase that is anchored to the plasma membrane, was associated with the risk of metastasis, and a poor prognosis. We also showed that PRL-3 overexpression in OCM-1 ocular melanoma cells significantly increased cell migration in vitro and invasiveness in vivo, suggesting a direct role for PRL-3 in the metastatic spreading of uveal melanoma. Here, we aimed to identify PRL-3 substrates at the plasma membrane involved in adhesion to the extracellular matrix...
April 15, 2017: Experimental Cell Research
Toni Grönroos, Susanna Teppo, Juha Mehtonen, Saara Laukkanen, Thomas Liuksiala, Matti Nykter, Merja Heinäniemi, Olli Lohi
Cell signalling, which is often derailed in cancer, is a network of multiple interconnected pathways with numerous feedback mechanisms. Dynamics of cell signalling is intimately regulated by addition and removal of phosphate groups by kinases and phosphatases. We examined expression of members of the PTP4A family of phosphatases across acute leukemias. While expression of PTP4A1 and PTP4A2 remained relatively unchanged across diseases, PTP4A3 showed marked overexpression in ETV6-RUNX1 and BCR-ABL1 subtypes of precursor B cell acute lymphoblastic leukemia...
March 2017: Leukemia Research
Jianbiao Zhou, Zit-Liang Chan, Chonglei Bi, Xiao Lu, Phyllis S Y Chong, Jing-Yuan Chooi, Lip-Lee Cheong, Shaw-Cheng Liu, Ying Qing Ching, Yafeng Zhou, Motomi Osato, Tuan Zea Tan, Chin Hin Ng, Siok-Bian Ng, Shi Wang, Qi Zeng, Wee-Joo Chng
PRL-3 (PTP4A3), a metastasis-associated phosphatase, is also upregulated in patients with acute myeloid leukemia (AML) and is associated with poor prognosis, but the underlying molecular mechanism is unknown. Here, constitutive expression of PRL-3 in human AML cells sustains leukemogenesis in vitro and in vivo Furthermore, PRL-3 phosphatase activity dependently upregulates LIN28B, a stem cell reprogramming factor, which in turn represses the let-7 mRNA family, inducing a stem cell-like transcriptional program...
March 2017: Molecular Cancer Research: MCR
Javier Mariscal, Marta Alonso-Nocelo, Laura Muinelo-Romay, Jorge Barbazan, Maria Vieito, Alicia Abalo, Antonio Gomez-Tato, Casares de Cal Maria de Los Angeles, Tomas Garcia-Caballero, Carmela Rodriguez, Elena Brozos, Francisco Baron, Rafael Lopez-Lopez, Miguel Abal
Knowledge on the molecular mechanisms underlying metastasis colonization in Non-Small Cell Lung Cancer (NSCLC) remains incomplete. A complete overview integrating driver mutations, primary tumour heterogeneity and overt metastasis lacks the dynamic contribution of disseminating metastatic cells due to the inaccessibility to the molecular profiling of Circulating Tumour Cells (CTCs). By combining immunoisolation and whole genome amplification, we performed a global gene expression analysis of EpCAM positive CTCs from advanced NSCLC patients...
November 30, 2016: Scientific Reports
Fatemeh Kaveh, Lars O Baumbusch, Daniel Nebdal, Anne-Lise Børresen-Dale, Ole Christian Lingjærde, Hege Edvardsen, Vessela N Kristensen, Hiroko K Solvang
BACKGROUND: Detection and localization of genomic alterations and breakpoints are crucial in cancer research. The purpose of this study was to investigate, in a methodological and biological perspective, different female, hormone-dependent cancers to identify common and diverse DNA aberrations, genes, and pathways. METHODS: In this work, we analyzed tissue samples from patients with breast (n = 112), ovarian (n = 74), endometrial (n = 84), or cervical (n = 76) cancer...
November 22, 2016: BMC Cancer
Pegah Abdollahi, Esten N Vandsemb, Magnus A Hjort, Kristine Misund, Toril Holien, Anne-Marit Sponaas, Torstein B Rø, Tobias S Slørdahl, Magne Børset
Phosphatase of regenerating liver-3 (PTP4A3/PRL-3) is a dual-specificity phosphatase that is upregulated in various types of cancers and is related to poor prognosis and aggressive tumor behavior. The expression level of PRL-3 is elevated in response to several antiapoptotic cytokines, including IL6, in cancer cells from patients with multiple myeloma (MM) and can promote survival and migration. Here, it is demonstrated that PRL-3 activates Src kinase in the IL6-dependent MM cell line INA-6. Inhibition of PRL-3 by a small-molecule inhibitor of PRL-3 or by shRNA resulted in inactivation of Src...
January 2017: Molecular Cancer Research: MCR
Shenyi Lian, Lin Meng, Xiaofang Xing, Yongyong Yang, Like Qu, Chengchao Shou
Phosphatase of regenerating liver-3 (PRL-3), also termed PTP4A3, is a metastasis-related protein tyrosine phosphatase. Its expression levels are significantly correlated with the progression and survival of a wide range of malignant tumors. However, the mechanism by which PRL-3 promotes tumor invasion and metastasis is not clear. In the present study, the functions of PRL-3 were systemically analyzed in the key events of metastasis including, motility and adhesion. A cell wounding assay, cell spread assay and cell-matrix adhesion assay were carried out to analyze the cell movement and cell adhesion ability of colon cancer, immunoprecipitation and immunofluorescence assay was confirmed the interaction of PRL-3 and JAM2...
September 2016: Oncology Letters
Liling Wang, Jianxun Liu, Zhiqiang Zhong, Xuhai Gong, Wei Liu, Lei Shi, Xuesong Li
Glioblastoma multiforme (GBM) is one of the most common primary malignant adult brain tumors. It is characterized by aggressive progression and poor prognosis. There is significant need to understand the mechanism of GBM malignancy and develop improved therapeutic options for GBM patients. We systematically studied the function of PTP4A3 in the malignancy of GBM. We found that PTP4A3 was upregulated in GBM tissues and cells. Knockdown of PTP4A3 expression in GBM cells inhibited cell proliferation, migration, and invasion...
September 1, 2016: Brain Research
Joseph M Salamoun, Kelley E McQueeney, Kalyani Patil, Steven J Geib, Elizabeth R Sharlow, John S Lazo, Peter Wipf
The phosphatase PTP4A3 is an attractive anticancer target, but knowledge of its exact role in cells remains incomplete. A potent, structurally novel inhibitor of the PTP4A family was obtained by photooxygenation of a less active, electron-rich thienopyridone (1). Iminothienopyridinedione 13 displays increased solution stability and is readily obtained by two new synthetic routes that converge in the preparation of 1. The late-stage photooxygenation of 1 to give 13 in high yield highlights the potential of this reaction to modify the structure and properties of a biological lead compound and generate value for expanding the scope of an SAR investigation...
July 6, 2016: Organic & Biomolecular Chemistry
Selma Maacha, Océane Anezo, Malika Foy, Géraldine Liot, Laurence Mery, Cécile Laurent, Xavier Sastre-Garau, Sophie Piperno-Neumann, Nathalie Cassoux, Nathalie Planque, Simon Saule
PURPOSE: To study PTP4A3 phosphatase and MMP14 metalloprotease synergy in uveal melanoma aggressiveness. METHODS: Cell membrane localization of matrix metalloprotease 14 (MMP14) in uveal melanoma cells expressing protein tyrosine phosphatase A3 (PTP4A3) was assessed by flow cytometry or immunohistochemistry. The vesicular trafficking of MMP14 in the presence of PTP4A3 was evaluated in OCM-1 cells expressing either the wild-type or mutated phosphatase. Finally, MMP14 localization at the cell membrane of OCM-1 cells was impaired using RNA interference, and the PTP4A3-related migration in vitro and invasiveness in vivo of the treated cells were evaluated...
April 1, 2016: Investigative Ophthalmology & Visual Science
Petra den Hollander, Kathryn Rawls, Anna Tsimelzon, Jonathan Shepherd, Abhijit Mazumdar, Jamal Hill, Suzanne A W Fuqua, Jenny C Chang, C Kent Osborne, Susan G Hilsenbeck, Gordon B Mills, Powel H Brown
Triple-negative breast cancer (TNBC) has the worst prognosis of all breast cancers, and women diagnosed with TNBC currently lack targeted treatment options. To identify novel targets for TNBC, we evaluated phosphatase expression in breast tumors and characterized their contributions to in vitro and in vivo growth of TNBC. Using Affymetrix microarray analysis of 102 breast cancers, we identified 146 phosphatases that were significantly differentially expressed in TNBC compared with estrogen receptor (ER)-positive tumors...
April 1, 2016: Cancer Research
Hsin-Chih Yeh, Chun-Nung Huang, Ching-Chia Li, Lin-Li Chang, Hui-Hui Lin, Hung-Lung Ke, A-Mei Huang, Peir-In Liang, Chien-Feng Li, Wen-Jeng Wu
PURPOSE: Bladder cancer (BC) is the most common malignancy in urinary system. The prognosis of metastatic BC is poor, but there remains no reliable marker to early detect metastasis. Dysregulated prenylated protein tyrosine phosphatases (PTPs) are commonly associated with cancer metastasis. From a published BC transcriptome, we identified that PTP IVA3 (PTP4A3) was the most significantly upregulated gene implicated in tumor progression among genes related to prenylated PTPs. We therefore analyzed PTP4A3 expression in our well-characterized cohort of BC...
June 2016: World Journal of Urology
Duanzheng Zhao, Libin Guo, Henrique Neves, Hiu-Fung Yuen, Shu-Dong Zhang, Cian M McCrudden, Qing Wen, Jin Zhang, Qi Zeng, Hang Fai Kwok, Yao Lin
Although PTP4A3 has been shown to be a very important factor in promoting cancer progression, the role of its close family member PTP4A2 is still largely unknown. Recent reports have shown contradicting results on the role of PTP4A2 in breast cancer progression. Considering this, we aimed to investigate the prognostic value of PTP4A2 in five independent breast cancer data sets (minimum 198 patients per cohort, totaling 1,124 patients) in the Gene Expression Omnibus Database. We found that high expression of PTP4A2 was a favorable prognostic marker in all five independent breast cancer data sets, as well as in the combined cohort, with a hazard ratio of 0...
2015: OncoTargets and Therapy
Hsin-Chih Yeh, Ching-Chia Li, Chun-Nung Huang, Tzyh-Chyuan Hour, Bi-Wen Yeh, Wei-Ming Li, Peir-In Liang, Lin-Li Chang, Chien-Feng Li, Wen-Jeng Wu
PURPOSE: Increasing evidence has shown that protein tyrosine phosphatases have dominant roles in setting the levels of tyrosine phosphorylation and promoting oncogenic processes. PTP4A3 has been implicated in cancer metastasis but to our knowledge the role of PTP4A3 in upper tract urothelial carcinoma is unknown. The aim of this study was to investigate the association of PTP4A3 with disease characteristics, distant metastasis and prognosis of upper tract urothelial carcinoma. MATERIALS AND METHODS: The importance of PTP4A3 was initially examined in paired normal urothelium, noninvasive upper tract urothelial carcinoma, invasive upper tract urothelial carcinoma and nodal metastatic tissue...
November 2015: Journal of Urology
Yu-Han Huang, Abdul Qader O Al-Aidaroos, Hiu-Fung Yuen, Shu-Dong Zhang, Han-Ming Shen, Ewelina Rozycka, Cian M McCrudden, Vinay Tergaonkar, Abhishek Gupta, You Bin Lin, Jean Paul Thiery, James T Murray, Qi Zeng
Autophagy, a "self-eating" cellular process, has dual roles in promoting and suppressing tumor growth, depending on cellular context. PTP4A3/PRL-3, a plasma membrane and endosomal phosphatase, promotes multiple oncogenic processes including cell proliferation, invasion, and cancer metastasis. In this study, we demonstrate that PTP4A3 accumulates in autophagosomes upon inhibition of autophagic degradation. Expression of PTP4A3 enhances PIK3C3-BECN1-dependent autophagosome formation and accelerates LC3-I to LC3-II conversion in an ATG5-dependent manner...
October 1, 2014: Autophagy
Julie M Cramer, Mark W Zimmerman, Tim Thompson, Gregg E Homanics, John S Lazo, Eric Lagasse
The PTP4A3 gene is highly expressed in human colon cancer and often associates with enhanced metastatic potential. Genetic disruption of the mouse Ptp4a3 gene reduces the frequency of colon tumor formation in mice treated in a colitis-associated cancer model. In the current study, we have examined the role of Ptp4a3 in the tumor-initiating cell population of mouse colon tumors using an in vitro culture system. Tumors generated in vivo following AOM/DSS treatment were isolated, dissociated, and expanded on a feeder layer resulting in a CD133(+) cell population, which expressed high levels of Ptp4a3...
July 2014: Stem Cell Research
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