Over-expression of lipocalin 2 promotes cell migration and invasion through activating ERK signaling to increase SLUG expression in prostate cancer

Ding, Guanxiong; Fang, Jie; Tong, Shijun; Liu, Qu; Jiang, Haowen; Ding, Qiang; Li, Jun

doi:10.1002/pros.22978

Cited by 70 publications

(69 citation statements)

References 49 publications

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“…NGAL is predictive of a poor prognosis in some cancers [73,91,105,134]. Ectopic NGAL expression enhanced positively the ability of prostate cancer cells to form colonies in soft agar; likewise, suppression of NGAL dramatically inhibited colony formation [91,105,134].…”

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confidence: 97%

“…NGAL is considered by some scientists to have properties of an oncogene, or in some cases, a tumor suppressor gene [9,10,73,89,96,[127][128][129][130][131][132][133][134]. Increased levels of NGAL have been detected in the urine and plasma of patients with various types of cancer (i.e.…”

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confidence: 99%

“…brain, breast, colon, ovarian, pancreatic and prostate). Novel non-invasive urine-based tests could prove useful for the detection and/or prognosis of many cancer types [3,9,10,73,96,[131][132][133][134][135][136]. Certain cytokines involved in inflammation such as IL-17 can regulate NGAL expression [135].…”

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confidence: 99%

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Roles of NGAL and MMP-9 in the tumor microenvironment and sensitivity to targeted therapy

Candido

Abrams

Steelman

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Various, diverse molecules contribute to the tumor microenvironment and influence invasion and metastasis. In this review, the roles of neutrophil gelatinase-associated lipocalin (NGAL) and matrix metalloproteinase-9 (MMP-9) in the tumor microenvironment and sensitivity to therapy will be discussed. The lipocalin family of proteins has many important functions. For example when NGAL forms a complex with MMP-9 it increases its stability which is important in cancer metastasis. Small hydrophobic molecules are bound by NGAL which can alter their entry into and efflux from cells. Iron transport and storage are also influenced by NGAL activity. Regulation of iron levels is important for survival in the tumor microenvironment as well as metastasis. Innate immunity is also regulated by NGAL as it can have bacteriostatic properties. NGAL and MMP-9 expression may also affect the sensitivity of cancer cells to chemotherapy as well as targeted therapy. Thus NGAL and MMP-9 play important roles in key processes involved in metastasis as well as response to therapy. This article is part of a Special Issue entitled: Tumor Microenvironment Regulation of Cancer Cell Survival, Metastasis, Inflammation, and Immune Surveillance edited by Peter Ruvolo and Gregg L. Semenza.

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confidence: 97%

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confidence: 99%

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Roles of NGAL and MMP-9 in the tumor microenvironment and sensitivity to targeted therapy

Candido

Abrams

Steelman

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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“…60 LCN2 plays an important role in promoting cell migration and invasion in cooperation with MMP-9 and by inducing EMT through the ERK/SLUG axis. 61 Growth differentiation factor 15 (GDF-15/MIC-1) belongs to the TGF-b superfamily and regulates inflammatory and apoptotic pathways in inflammation, cancer and obesity and was associated with aberrant growth and a poor prognosis. 62,63 Incubation of blood monocytederived macrophages with CM of an esophageal squamous cell carcinomas cell line induced M2 polarization and overexpression of GDF-15 as well as IL-6 and IL-8.…”

Section: Secretory Phenotype Of Sclc Ctc-induced Macrophagesmentioning

confidence: 99%

Small cell lung cancer: Recruitment of macrophages by circulating tumor cells

et al. 2015

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Tumor-associated macrophages (TAMs) play an important role in tumor progression, suppression of antitumor immunity and dissemination. Blood monocytes infiltrate the tumor region and are primed by local microenvironmental conditions to promote tumor growth and invasion. Although many of the interacting cytokines and factors are known for the tumor-macrophage interactions, the putative contribution of circulating tumor cells (CTCs) is not known so far. These specialized cells are characterized by increased mobility, ability to degrade the extracellular matrix (ECM) and to enter the blood stream and generate secondary lesions which is a leading cause of death for the majority of tumor patients. The first establishment of two permanent CTC lines, namely BHGc7 and 10, from blood samples of advanced stage small cell lung cancer (SCLC) patients allowed us to investigate the CTC-immune cell interaction. Cocultures of peripheral blood mononuclear cells (PBMNCs) with CTCs or addition of CTC-conditioned medium (CTC-CM) in vitro resulted in monocyte-macrophage differentiation and appearance of CD14 C , CD163 weak and CD68 C macrophages expressing markers of TAMs. Furthermore, we screened the supernatants of CTC-primed macrophages for presence of approximately 100 cytokines and compared the expression with those induced by the local metastatic SCLC26A cell line. Macrophages recruited by SCLC26A-CM showed expression of osteopontin (OPN), monocyte chemoattractant protein-1 (MCP-1), IL-8, chitinase3-like 1 (CHI3L1), platelet factor (Pf4), IL-1ra and matrix metalloproteinase-9 (MMP-9) among other minor cytokines/chemokines. In contrast, BHGc7-CM induced marked overexpression of complement factor D (CFD)/adipsin and vitamin D-BP (VDBP), as well as increased secretion of OPN, lipocalin-2 (LCN2), CHI3L1, uPAR, MIP-1 and GDF-15/MIC-1. BHGc10, derived independently from relapsed SCLC, revealed an almost identical pattern with added expression of ENA-78/CXCL5. CMs of the non-tumor HEK293 cell line revealed no induction of macrophages, whereas incubation of PBMNCs with recombinant CHI3L1 gave positive results. Thus, the specific contributions of CTCs in SCLC affect CFD/adipsin, possibly involved in immunity/cachexia, VDBP which gives rise to group-specific component protein-derived macrophage-activating factor (GcMAF), GDF-15/MIC-1 which enhances the malignant phenotype of tumor cells and ENA-78/CXCL5 which attracts angiogenic neutrophils. In conclusion, CTCs are competent to specifically manipulate TAMs to increase invasiveness, angiogenesis, immunosuppression and possibly lipid catabolism.

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“…Interestingly, proteins encoded by all three Nudt3 target mRNAs have been implicated in increased tumor cell invasion and metastatic potential. The expression of LCN2 is elevated in numerous human epithelial cancers, including breast (Lim et al 2007), and shown to promote cell migration and invasion (Fougere et al 2010;Ding et al 2015). Whether the function of Nudt3 in modulating cell motility is a contributing factor in cellular invasion and metastasis remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

Nudt3 is an mRNA decapping enzyme that modulates cell migration

Grudzien-Nogalska

Jiao

Song

et al. 2016

RNA

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Removal of the 5′ -end 7-methylguanosine cap structure is a critical step in the highly regulated process of mRNA decay. The Nudix hydrolase, Dcp2, was identified as a first decapping enzyme and subsequently shown to preferentially modulate stability of only a subset of mRNAs. This observation led to the hypothesis that mammalian cells possess multiple decapping enzymes that may function in distinct pathways. Here we report Nudt3 is a Nudix protein that possesses mRNA decapping activity in cells and is a modulator of MCF-7 breast cancer cell migration. Reduction of Nudt3 protein levels in MCF-7 cells promotes increased cell migration and corresponding enhanced filopodia extensions. Importantly, this phenotype was reversed by complementation with wild type, but not catalytically inactive Nudt3 protein indicating Nudt3 decapping activity normally functions to control cell migration. Genome-wide analysis of Nudt3 compromised cells identified elevated levels of transcripts involved in cell motility including integrin β6, lipocalin-2, and fibronectin. The observed increase in mRNA abundance was dependent on Nudt3 decapping activity where integrin β6 and lipocalin-2 were modulated directly through mRNA stability, while fibronectin was indirectly controlled. Moreover, increased cell migration observed in Nudt3 knockdown cells was mediated through the extracellular integrin β6 and fibronectin protein nexus. We conclude that Nudt3 is an mRNA decapping enzyme that orchestrates expression of a subset of mRNAs to modulate cell migration and further substantiates the existence of multiple decapping enzymes functioning in distinct cellular pathways in mammals.

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Over-expression of lipocalin 2 promotes cell migration and invasion through activating ERK signaling to increase SLUG expression in prostate cancer

Abstract: LCN2 plays an important role in promoting cell migration and invasion of prostate cancer by inducing EMT through the ERK/SLUG axis. Therefore, targeted inhibition of LCN2 may represent a therapeutic strategy to prevent the metastasis of prostate cancer.

Cited by 70 publications

References 49 publications

Roles of NGAL and MMP-9 in the tumor microenvironment and sensitivity to targeted therapy

Roles of NGAL and MMP-9 in the tumor microenvironment and sensitivity to targeted therapy

Small cell lung cancer: Recruitment of macrophages by circulating tumor cells

Nudt3 is an mRNA decapping enzyme that modulates cell migration

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