Uteroglobin (UG) Suppresses Extracellular Matrix Invasion by Normal and Cancer Cells That Express the High Affinity UG-binding Proteins

Kundu, Gopal C.; Mandal, A. K.; Zhang, Zhongjian; Mantile-Selvaggi, Giuditta; Mukherjee, Anil B.

doi:10.1074/jbc.273.35.22819

Cited by 42 publications

(49 citation statements)

References 64 publications

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“…Despite the rather low level of homology between uteroglobin and HIN-1, our data indicate that the two proteins seem to share quite similar functions. Both inhibit many features of the invasive phenotype, including anchorage-dependent and anchorageindependent growth, and invasion of extracellular matrix (12)(13)(14)(15). HIN-1 and uteroglobin ligand binding activity, suggesting putative receptor expression, exists on the same cell types that express these proteins, suggesting that they act in an autocrine manner.…”

Section: Discussionmentioning

confidence: 99%

“…Similar to HIN-1, the expression of uteroglobin is lost in the majority of lung and prostate cancers (11). Exogenous overexpression of uteroglobin in cancer cell lines results in reversion of many features of the transformed phenotype, including decreased anchorage-dependent and anchorage-independent growth as well as decreased ability to invade extracellular matrix (12)(13)(14)(15). Furthermore, mice with homologous deletion of the uteroglobin gene develop spontaneous tumors and show increased susceptibility to chemical carcinogen-induced lung cancer (16,17).…”

Section: Introductionmentioning

confidence: 99%

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HIN-1, an Inhibitor of Cell Growth, Invasion, and AKT Activation

et al. 2005

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The HIN-1 gene encoding a small, secreted protein is silenced due to methylation in a substantial fraction of breast, prostate, lung, and pancreatic carcinomas, suggesting a potential tumor suppressor function. The receptor of HIN-1 is unknown, but ligand-binding studies indicate the presence of high-affinity cell surface HIN-1 binding on epithelial cells. Here, we report that HIN-1 is a potent inhibitor of anchoragedependent and anchorage-independent cell growth, cell migration, and invasion. Expression of HIN-1 in synchronized cells inhibits cell cycle reentry and the phosphorylation of the retinoblastoma protein (Rb), whereas in exponentially growing cells, HIN-1 induces apoptosis without apparent cell cycle arrest and effect on Rb phosphorylation. Investigation of multiple signaling pathways revealed that mitogen-induced phosphorylation and activation of AKT are inhibited in HIN-1-expressing cells. In addition, expression of constitutively activate AKT abrogates HIN-1-mediated growth arrest. Taken together, these studies provide further evidence that HIN-1 possesses tumor suppressor functions, and that these activities may be mediated through the AKT signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

HIN-1, an Inhibitor of Cell Growth, Invasion, and AKT Activation

et al. 2005

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“…However, UG expression in both malignant lung tumors originating from lung epithelia as well as in the cell lines derived from these tumors is either drastically suppressed or totally undetectable (22,23). Further, we demonstrated that UG prevents migration and extracellular matrix invasion of cancer cells in vitro (24).…”

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confidence: 96%

Lack of an Endogenous Anti-inflammatory Protein in Mice Enhances Colonization of B16F10 Melanoma Cells in the Lungs

Saha

Lee

Zhang

et al. 2010

Journal of Biological Chemistry

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Emerging evidence indicates a link between inflammation and cancer metastasis, but the molecular mechanism(s) remains unclear. Uteroglobin (UG), a potent anti-inflammatory protein, is constitutively expressed in the lungs of virtually all mammals. UG-knock-out (UG-KO) mice, which are susceptible to pulmonary inflammation, and B16F10 melanoma cells, which preferentially metastasize to the lungs, provide the components of a model system to determine how inflammation and metastasis are linked. We report here that B16F10 cells, injected into the tail vein of UG-KO mice, form markedly elevated numbers of tumor colonies in the lungs compared with their wild type littermates. Remarkably, UG-KO mouse lungs overexpress two calcium-binding proteins, S100A8 and S100A9, whereas B16F10 cells express the receptor for advanced glycation end products (RAGE), which is a known receptor for these proteins. Moreover, S100A8 and S100A9 are potent chemoattractants for RAGE-expressing B16F10 cells, and pretreatment of these cells with a blocking antibody to RAGE suppressed migration and invasion. Interestingly, in UG-KO mice S100A8/S100A9 concentrations in blood are lowest in tail vein and highest in the lungs, which most likely guide B16F10 cells to migrate to the lungs. Further, B16F10 cells treated with S100A8 or S100A9 overexpress matrix metalloproteinases, which are known to promote tumor invasion. Most notably, the metastasized B16F10 cells in UG-KO mouse lungs express MMP-2, MMP-9, and MMP-14 as well as furin, a pro-protein convertase that activates MMPs. Taken together, our results suggest that a lack of an anti-inflammatory protein leads to increased pulmonary colonization of melanoma cells and identify RAGE as a potential anti-metastatic drug target.It is estimated that more than 90% of human cancer deaths result from metastasis (1-8), a complex process in which the cells from a primary tumor successfully invade and colonize a distant organ (6 -9). It has long been suspected that a functional relationship exists between inflammation and cancer. Indeed, in 1863, Virchow observed that cancer develops at locations where chronic inflammation is present. This hypothesis is partly based on his assumption that some substances that cause tissue injury and inflammation also enhance cell proliferation (10). Although it is clear now that proliferation alone does not account for cancer, the cause and effect relationship between inflammation and cancer is widely accepted. Nonetheless, many aspects of the molecular and cellular mechanisms that link inflammation, migration, and establishment of tumor colonies in a distant organ remain unresolved (5). Recently, it has been reported that a tumor microenvironment actively contributes to cancer initiation, progression, and metastasis (11, 12). It has also been suggested that reductions in the rates of cancer morbidity and mortality may be achieved by gaining greater understanding of the molecular mechanism(s) of tumor cell migration, invasion, and establishment of colonies (13). In this regard...

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“…Accordingly, lymphoblast cells were transfected with IIS antisense oligonucleotides and used for chemotaxis assay. Conditioned medium from fibroblast cell culture was used as the chemoattractant, and cell migration and invasion assays were conducted as previously reported (32,33). The results show that chemotactic migration of antisense oligo-transfected cells was markedly inhibited compared with that of the control and sense oligonucleotide-transfected cells (Fig.…”

Section: Inhibition Of Iis Expression Prevents Lymphoblast Cell Migramentioning

confidence: 94%

“…The founding member of this protein family, UG, which is induced by IFN-␥, is also a secreted protein, and recently, we have demonstrated that UG binds to as-yet-unidentified cell surface binding protein(s) with high affinity and specificity and regulates cellular migration and invasion (32,33,43). Consistent with these findings, we find that IIS is also induced by IFN-␥, and the suppression of IIS expression by antisense oligonucleotide treatment of the cells inhibits chemotactic migration and invasion.…”

Section: Discussionmentioning

confidence: 99%

IFN-γ Stimulates the Expression of a Novel Secretoglobin That Regulates Chemotactic Cell Migration and Invasion

Choi

Ray

Zhang

et al. 2004

The Journal of Immunology

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IFNs are a family of cytokines that alert the immune system against viral infections of host cells. The IFNs (IFN-α, IFN-β, and IFN-γ) interact with specific cellular receptors and stimulate the production of second messengers, leading to the expression of antiviral and immunomodulatory proteins. We report in this study that IFN-γ stimulates the expression of a novel gene that encodes a protein with 30% amino acid sequence identity with uteroglobin, the founding member of the newly formed Secretoglobin (SCGB) superfamily. We named this protein IFN-γ-inducible SCGB (IIS), because its expression in lymphoblast cells is augmented by IFN-γ treatment. IIS is expressed in virtually all tissues, and the highest level of expression is detectable in lymph nodes, tonsil, cultured lymphoblasts, and the ovary. Interestingly, although the expression of IIS mRNA is not significantly different in resting lymphoid cells, it is markedly elevated in activated CD8+ and CD19+ cells. Furthermore, treatment of lymphoblast cells with IIS antisense phosphorothioate (S)-oligonucleotides prevents chemotactic migration and invasion. Taken together, these results raise the possibility that this novel SCGB has immunological functions.

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Uteroglobin (UG) Suppresses Extracellular Matrix Invasion by Normal and Cancer Cells That Express the High Affinity UG-binding Proteins

Cited by 42 publications

References 64 publications

HIN-1, an Inhibitor of Cell Growth, Invasion, and AKT Activation

HIN-1, an Inhibitor of Cell Growth, Invasion, and AKT Activation

Lack of an Endogenous Anti-inflammatory Protein in Mice Enhances Colonization of B16F10 Melanoma Cells in the Lungs

IFN-γ Stimulates the Expression of a Novel Secretoglobin That Regulates Chemotactic Cell Migration and Invasion

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