AP-1-Mediated Invasion Requires Increased Expression of the Hyaluronan Receptor CD44

Lamb, Richard F.; Hennigan, Robert F.; Turnbull, Kathryn Jane; Katsanakis, Kostas D.; MacKenzie, Elaine D.; Birnie, G.D.; Ozanne, Brad

doi:10.1128/mcb.17.2.963

Cited by 154 publications

(153 citation statements)

References 69 publications

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“…Cell surface CD44 is the receptor for hyaluronate, a major glycosaminoglycan component of the cellular matrix, and may promote tumor invasion (22). Adhesion to the cellular matrix, a critical step in the metastatic process, has been found to be CD44-dependent in several malignancies (23,24). Expression of 15-PGDH in A549 cells appeared to cause down-regulation of CD44.…”

Section: -Pgdh Is a Tumor Suppressormentioning

confidence: 99%

15-Hydroxyprostaglandin dehydrogenase (15-PGDH) and lung cancer

Tai

Tang

Ding

2007

Prostaglandins & Other Lipid Mediators

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Abstract15-Hydroxyprostaglandin dehydrogenase (15-PGDH) catalyzes NAD + -linked oxidation of 15 (S)-hydroxyl group of prostaglandins and lipoxins and is the key enzyme responsible for the biological inactivation of these eicosanoids. The enzyme was found to be under-expressed as opposed to cyclooxygenase-2 (COX-2) being over-expressed in lung and other tumors. A549 human lung adenocarcinoma cells were used as a model system to study the role of 15-PGDH in lung tumorigenesis. Up-regulation of COX-2 expression by pro-inflammatory cytokines in A549 cells was accompanied by a down-regulation of 15-PGDH expression. Over-expression of COX-2 but not COX-1 by adenoviral-mediated approach also attenuated 15-PGDH expression. Similarly, overexpression of 15-PGDH by the same strategy inhibited IL-1β-induced COX-2 expression. It appears that the expression of COX-2 and 15-PGDH is regulated reciprocally. Adenoviral-mediated transient over-expression of 15-PGDH in A549 cells resulted in apoptosis. Xenograft studies in nude mice also showed tumor suppression with cells transiently over-expressing 15-PGDH. However, cells stably over-expressing 15-PGDH generated tumors faster than those control cells. Examination of different clones of A549 cells stably expressing different levels of 15-PGDH indicated that the levels of 15-PGDH expression correlated positively with those of mesenchymal markers, and negatively with those of epithelial markers. It appears that the stable expression of 15-PGDH induces epithelialmesenchymal transition (EMT) which may account for the tumor promotion in xenograft studies. A number of anti-cancer agents, such as transforming growth factor-β1 (TGF-β1), glucocorticoids and some histone deacetylase inhibitors were found to induce 15-PGDH expression. These results suggest that tumor suppressive action of these agents may, in part, be related to their ability to induce 15-PGDH expression.

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Section: -Pgdh Is a Tumor Suppressormentioning

confidence: 99%

15-Hydroxyprostaglandin dehydrogenase (15-PGDH) and lung cancer

Tai

Tang

Ding

2007

Prostaglandins & Other Lipid Mediators

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“…All of the CD44 variants (CD44v) contain insertions of various combinations of variant exons (1-10) located between exons 5 and 16 of the CD44 gene (Screaton et al, 1992(Screaton et al, , 1993. In contrast to merlin, which displays tumor-suppressor activity, CD44 promotes tumor invasion and metastasis (Gunthert et al, 1991;Sherman et al, 1994;Lamb et al, 1997;Yu et al, 1997;Stamenkovic, 1999, 2000).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of the hyaluronan-CD44 interaction by merlin contributes to the tumor-suppressor activity of merlin

Bai

et al. 2006

Oncogene

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Mutation or loss of expression of merlin is responsible for neurofibromatosis type 2 (NF2), which is characterized by the development of schwannomas and other tumors of the nervous system. Like the ERM (ezrin-radixin-moesin) proteins, merlin interacts with CD44, a cell-surface receptor for hyaluronan (HA) that promotes tumorigenesis. However, the relationship between merlin and CD44 and the mechanism by which merlin exerts its tumorsuppressor function have not been elucidated. In the present study, we show that increased expression of wildtype merlin in Tr6BC1 schwannoma cells inhibits HA binding to CD44. Furthermore, we demonstrate that the residues required for this inhibitory effect and the interaction between CD44 and merlin lie within the first 50 amino acids of merlin. Overexpression of merlin inhibited subcutaneous growth of Tr6BC1 cells in immunocompromised Rag1 mice. In contrast, knocking down expression of endogenous merlin promoted tumor cell growth, as did overexpression of a merlin deletion mutant (merlinDel-1) that lacks the first 50 amino acids but not of other NH 2 -terminal deletion mutants. Together, our results demonstrate that inhibition of the CD44-HA interaction contributes to the tumor-suppressor function of merlin, and they suggest that merlin inhibits tumor growth, at least in part, by negatively regulating CD44 function.

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“…AP-1 is a heterodimeric protein composed of various combinations of the Jun and Fos family proteins, and this¯exibility permits transactivation or transrepression of gene expression (Bushel et al, 1995;De Cesare et al, 1995;reviewed in Karin et al, 1997). Upon transformation of 208F cells with v-fos, the cells show extensive reorganization in their cytoskeleton and become invasive (Hennigan et al, 1994;Lamb et al, 1997a). These cytoskeletal rearrangments result in a striking change in the morphology of the cells: they change from being¯at with F-actin stress ®bres to being bipolar with long pseudopodia, which are lined with cortical F-actin cables that have dynamic actin-rich membrane ru e-like structures at their tips.…”

Section: Introductionmentioning

confidence: 99%

“…We have previously shown that AP-1 is essential for invasion of FBR cells and 208F cells treated with EGF (Hennigan et al, 1994;Lamb et al, 1997a). This was achieved using antisense oligonucleotides to c-jun, and the expression of a c-Jun dominant negative mutant (TAM-67) to inhibit invasion.…”

Section: Introductionmentioning

confidence: 99%

“…These searches have revealed genes which encode proteins that have previously been implicated in invasion, as well as numerous novel genes that may play a role in transformation. An example of the genes whose expression are up-regulated is that encoding the cell surface hyaluronan receptor CD44, which is localized at the tips of pseudopodia in v-fos and EGF transformed 208F cells (Lamb et al, 1997a). CD44 antisense oligonucleotides caused a reduction in invasiveness in both of these cells.…”

Section: Introductionmentioning

confidence: 99%

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Krp1, a novel kelch related protein that is involved in pseudopod elongation in transformed cells

et al. 2000

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AP-1-Mediated Invasion Requires Increased Expression of the Hyaluronan Receptor CD44

Abstract: Fibroblasts transformed by Fos oncogenes display increased expression of a number of genes implicated in

Cited by 154 publications

References 69 publications

15-Hydroxyprostaglandin dehydrogenase (15-PGDH) and lung cancer

15-Hydroxyprostaglandin dehydrogenase (15-PGDH) and lung cancer

Inhibition of the hyaluronan-CD44 interaction by merlin contributes to the tumor-suppressor activity of merlin

Krp1, a novel kelch related protein that is involved in pseudopod elongation in transformed cells

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