LIV-1 Promotes Prostate Cancer Epithelial-to-Mesenchymal Transition and Metastasis through HB-EGF Shedding and EGFR-Mediated ERK Signaling

Lue, Hui Wen; Yang, Xinggang; Wang, Ruoxiang; Qian, Weiping; Xu, Roy Z H; Lyles, Robert H.; Osunkoya, Adeboye O.; Zhou, Binhua P.; Vessella, Robert L.; Zayzafoon, Majd; Liu, Zhi Ren; Zhau, Haiyen E.; Chung, Leland W.K.

doi:10.1371/journal.pone.0027720

Cited by 98 publications

(89 citation statements)

References 332 publications

(75 reference statements)

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“…Circulating soluble 2-m has been identified by our laboratory as a crucial autocrine and paracrine growth-stimulating factor that allows cancer cells to metastasize, or gain access to bone and colonize the skeleton. This action of 2-m is mainly due to its ability to stimulate the expression of RANKL or LIV-1, which was confirmed by the overexpression or knockdown of these genes in human prostate cancer cell lines, with either increased or decreased prostate cancer bone metastasis, respectively [77,78]. We have reported that 2-m activates PKA signaling, mediated by CREB with increased expression of CREB target genes, including OC and BSP, in prostate cancer [30].…”

Section: Roles Of 2-m In Interaction Between Cancer Cells and Bone MIsupporting

confidence: 56%

Test Article

2014

ScienceOpen Research

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2-microglobulin ( 2-m) has become the focus of intense scrutiny since the discovery of its undesirable roles promoting osteomimicry and cancer progression. 2-m is a well-known housekeeping protein that forms complexes with the heavy chain of major histocompatibility complex class I molecules, which are heterodimeric cell surface proteins that present antigenic peptides to cytotoxic T cells. On recognition of foreign peptide antigens on cell surfaces, T cells actively bind and lyse antigen-presenting cancer cells. In addition to its roles in tumor immunity, 2-m has two different functions in cancer cells, either tumor promoting or tumor suppressing, in cancer cell context-dependent manner. Our studies have demonstrated that 2-m is involved extensively in the functional regulation of growth, survival, apoptosis, and even metastasis of cancer cells. We found that 2-m is a soluble growth factor and a pleiotropic signaling molecule which interacts with its receptor, hemochromatosis protein, to modulate epithelial-to-mesenchymal transition (EMT) through iron-responsive pathways. Specific antibodies against 2-m have remarkable tumoricidal activity in cancer, through 2-m action on iron flux, alterations of intracellular reactive oxygen species, DNA damage and repair enzyme activities, -catenin activation and cadherin switching, and tumor responsiveness to hypoxia. These novel functions of 2-m and 2-m signaling may be common to several solid tumors including human lung, breast, renal, and prostate cancers. Our experimental results could lead to the development of a novel class of antibody-based pharmaceutical agents for cancer growth control. In this review, we briefly summarize the recent data regarding 2-m as a promising new cancer therapeutic target and discuss antagonizing this therapeutic target with antibody therapy for the treatment of localized and disseminated cancers.Keywords: Anti-2-m antibody, apoptosis, 2-microglobulin ( 2-m), osteomimicry. INTRODUCTION2-microglobulin ( 2-m), a well-known housekeeping gene, is a nonglycosylated protein with a low molecular weight of 12-kDa. This 99-amino acid residue protein is synthesized by all nucleated cells. It has been identified as a major structural component of amyloid fibrils deposited in dialysis-related amyloidosis, a common and serious complication in patients receiving hemodialysis for more than 10 years [1, 2]. 2-m forms a small invariable light chain subunit of the major histocompatibility complex (MHC) class I antigen, also known as human leukocyte antigen (HLA), on the cell surface of nucleated cells. 2-m is an important structural protein in the regulation of host immune recognition of self and non-self antigens by CD8 + T lymphocytes and for immunoglobulin transport and iron metabolism [3][4][5][6]. Some animal studies have reported that even when no MHC class I antigens could be detected on cells and the animals were grossly deficient in CD4 -CD8 + T cells, which normally mediate cytotoxic T cell function, the homozygotes appeared normal [7,8]....

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Section: Roles Of 2-m In Interaction Between Cancer Cells and Bone MIsupporting

confidence: 56%

Test Article

2014

ScienceOpen Research

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“…According to these authors, an increase in the expression of transporters of this mineral occurs in cells with malignant tumors, including metallothionein, Zip5, Zip6, Zip7, Zip8, and Zip10, producing an influx of zinc into the neoplastic cells, suggesting that its accumulation inside the breast tumor induces processes dependent on this mineral, for example, the activation of MMPs. 39 Lue et al 40 demonstrated that zinc transporter protein denominated LIV-1 belonging to the Zip transporter family was associated with increased MMP-2 and MMP-9 activity in prostate tumor cells. This protein may play a role in both cell growth, by acting as a zinc transporter, as well as the induction of metastasis, by association with matrix metalloproteinases.…”

Section: Author(s) Study Design Resultsmentioning

confidence: 99%

Zinc and metalloproteinases 2 and 9: What is their relation with breast cancer?

Holanda

Oliveira²,

Cruz³

et al. 2017

Rev. Assoc. Med. Bras.

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Zinc is the catalytic component of proteins that regulate responses to DNA damage, intracellular signaling enzymes, and matrix metalloproteinases, which are important proteins in carcinogenesis. The objective of this review is to bring current information on the participation of zinc and matrix metalloproteinases types 2 and 9 in mechanisms involved in the pathogenesis of breast cancer. We conducted a literature review, in consultation with the PubMed, Lilacs, and Scielo databases. The zinc and cysteine residues are structural elements shared by all members of the family of matrix metalloproteinases, and these proteins appear to be involved in the propagation of various types of neoplasms, including breast cancer. Moreover, transported zinc is likely to be used for the metalation of the catalytic domain of the newly synthesized metalloproteinases before the latter are secreted. Accordingly, increase in zinc concentrations in cellular compartments and the reduction of this trace element in the blood of patients with breast cancer appear to alter the activity of metalloproteinases 2 and 9, contributing to the occurrence of malignancy. Thus, it is necessary to carry out further studies with a view to clarify the role of zinc and metalloproteinases 2 and 9 in the pathogenesis of breast cancer.

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“…ZIP6 can be a growth factorelicited signaling molecule through its zinc influx functions from the extracellular space, and thereby enhanced zinc influx mediated by altered ZIP6 expression has been shown to be closely associated with invasive and metastatic ability and cancer progression (374,462). Elevated expression of ZIP6 is involved in epithelial-mesenchymal transition (EMT) of breast cancer cells (159), in pancreatic carcinoma (418), and in prostate cancer cells (256). In particular, the intimate association of ZIP6 with breast cancer is supported by a number of studies.…”

Section: F Zip6 (Liv-1 Subfamily)mentioning

confidence: 99%

The Physiological, Biochemical, and Molecular Roles of Zinc Transporters in Zinc Homeostasis and Metabolism

Kambe

Tsuji

Hashimoto

et al. 2015

Physiological Reviews

838

797

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Zinc is involved in a variety of biological processes, as a structural, catalytic, and intracellular and intercellular signaling component. Thus zinc homeostasis is tightly controlled at the whole body, tissue, cellular, and subcellular levels by a number of proteins, with zinc transporters being particularly important. In metazoan, two zinc transporter families, Zn transporters (ZnT) and Zrt-, Irt-related proteins (ZIP) function in zinc mobilization of influx, efflux, and compartmentalization/ sequestration across biological membranes. During the last two decades, significant progress has been made in understanding the molecular properties, expression, regulation, and cellular and physiological roles of ZnT and ZIP transporters, which underpin the multifarious functions of zinc. Moreover, growing evidence indicates that malfunctioning zinc homeostasis due to zinc transporter dysfunction results in the onset and progression of a variety of diseases. This review summarizes current progress in our understanding of each ZnT and ZIP transporter from the perspective of zinc physiology and pathogenesis, discussing challenging issues in their structure and zinc transport mechanisms.

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LIV-1 Promotes Prostate Cancer Epithelial-to-Mesenchymal Transition and Metastasis through HB-EGF Shedding and EGFR-Mediated ERK Signaling

Cited by 98 publications

References 332 publications

Test Article

Test Article

Zinc and metalloproteinases 2 and 9: What is their relation with breast cancer?

The Physiological, Biochemical, and Molecular Roles of Zinc Transporters in Zinc Homeostasis and Metabolism

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