The GPI-linked Ly-6 Antigen E48 Regulates Expression Levels of the FX Enzyme and of E-selectin Ligands on Head and Neck Squamous Carcinoma Cells

Eshel, Rinat; Zanin, Alexandra; Sagi‐Assif, Orit; Meshel, Tzipi; Smorodinsky, Nechama I.; Dwir, Oren; Alon, Ronen; Brakenhoff, Ruud H.; Dongen, Guus A.M.S. van; Witz, Isaac P.

doi:10.1074/jbc.275.17.12833

Cited by 30 publications

(41 citation statements)

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“…Several reports have suggested an association of E48 antigen expression with increased tumor progression (28)(29)(30)(31). The E48 antigen is highly expressed in locally invasive squamous cell carcinomas of the head and neck and constitutes a marker of disseminated tumor cells both in lymph nodes and bone marrow (32).…”

Section: Invasiveness and Tumor Cell Dissemination Requires Regulatiomentioning

confidence: 99%

“…Recently, the presence of micrometastatic cells in bone marrow of patients with squamous cell carcinomas of the head and neck with two or more lymph node metastases has been correlated with a poor metastasis-free survival (33). It has been hypothesized that E48 is a signal transduction protein that plays a role in cell-cell communication, and recent reports suggest involvement in mediating selectin-dependent binding of premetastatic tumor cells to the endothelium (28). Nevertheless, the signal transduction pathway and the adhesion system activated by E48 was unknown.…”

Section: Invasiveness and Tumor Cell Dissemination Requires Regulatiomentioning

confidence: 99%

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Genetic reprogramming of tumor cells by zinc finger transcription factors

Blancafort

Chen

González

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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Cancer arises by the accumulation of genetic alterations in DNA leading to aberrant gene transcription. Expression-profiling studies have correlated genomewide expression signatures with malignancy. However, functional analysis elucidating the contribution and synergy of genes in specific cancer cell phenotypes remains a formidable obstacle. Herein, we describe an alternative genetic approach for identification of genes involved in tumor progression by using a library of zinc finger artificial transcription factors (ATFs) and functional screening of tumor cells as a source of genetic plasticity and clonal selection. We isolated a six-zinc finger transcriptional activator (TF 20-VP, TF 20 containing the VP64 activator domain) that acts to reprogram a drug-sensitive, poorly invasive, and nonmetastatic cell line into a cell line with a drugresistant, highly invasive, and metastatic phenotype. Differential expression profiles of cells expressing TF 20-VP followed by functional studies, both in vitro and in animal models, revealed that invasion and metastasis requires coregulation of multiple target genes. Significantly, the E48 antigen, associated with poor metastasis-free survival in head and neck cancer, was identified as one specific target of TF 20-VP. We have shown phenotypic modulation of tumor cell behavior by E48 expression, including enhanced cell migration in vitro and tumor cell dissemination in vivo. This study demonstrates the use of ATFs to identify the group of genes that cooperate during tumor progression. By coregulating multiple targets, ATFs can be used as master genetic switches to reprogram and modulate complex neoplastic phenotypes. drug resistance ͉ metastasis ͉ invasion ͉ transcriptional regulation ͉ RNA inteference

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Section: Invasiveness and Tumor Cell Dissemination Requires Regulatiomentioning

confidence: 99%

Section: Invasiveness and Tumor Cell Dissemination Requires Regulatiomentioning

confidence: 99%

Genetic reprogramming of tumor cells by zinc finger transcription factors

Blancafort

Chen

González

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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“…Standard activation procedures (Wagers et al, 1998) were utilized. Briefly, T cells were activated by incubating these cells in 24-well plates precoated overnight at 41C with anti-CD3 and anti-CD28 mAbs (Ancell, Co., Bayport, MN, USA) (Eshel et al, 2000).…”

Section: Isolation and Activation Of Normal Human T Cellsmentioning

confidence: 99%

“…HUVEC were isolated from umbilical cord veins according to the method of Jaffe et al (1973) as previously described (Eshel et al, 2000). Primary cultures were serially passaged, and passages two and three were taken for experiments.…”

Section: Isolation and Activation Of Human Umbilical Cord Vein Endothmentioning

confidence: 99%

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Dual-specificity phosphatase Pyst2-L is constitutively highly expressed in myeloid leukemia and other malignant cells

et al. 2003

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Northern blotting confirmed previous results indicating that the mitogen-activated protein kinase (MAPK) phosphatase Pyst2-L was highly expressed in leukocytes obtained from acute myeloid leukemia (AML) patients. High levels of Pyst2-L mRNA were expressed in bone marrow (BM) and peripheral leukocytes from nine AML and acute lymphoblastic leukemia (ALL) patients. BM from healthy individuals expressed very low levels of Pyst2-L. Whereas high levels of Pyst2-L mRNA and protein were detected in several leukemia cell lines, Pyst2-L mRNA was detected neither in 33/34 samples of normal peripheral blood mononuclear cells (PBMC) nor in leukocyte fractions enriched with CD34 þ cells. Certain solid tumor and lymphoblastoid cell lines expressed high levels of Pyst2-L mRNA. In view of the association of Pyst2-L to MAPK signaling cascades, we tested if cell activation, a process involving MAPK signaling, influences Pyst2-L expression. Indeed, activation of T cells and endothelial cells increased Pyst2-L in these cells. Furthermore, TPA, a known MAPK activator, induces the expression of both Pyst2-L mRNA as well as the Pyst2-L protein in leukemia cells. This induction was partially inhibited by PD098059, an Mek1/2-specific inhibitor. Based on the results of this and previous studies, we hypothesize that the high levels of Pyst2-L detected in the active state of AML and ALL diseases and in other types of cancer reflect an altered MAPK signaling pathway in such malignant processes. This alteration may be the result of a failed attempt to counter the constitutive activation of MAPK in transformed cells or alternatively, may represent the activated state of such cells.

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Human Ly‐6 antigen E48 (Ly‐6D) regulates important interaction parameters between endothelial cells and head‐and‐neck squamous carcinoma cells

Eshel

Zanin

Kapon

et al. 2002

Intl Journal of Cancer

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Selectin ligands are crucial components in the interaction between endothelial cells and extravasating cancer cells and, thus, play an important role in metastasis formation. Headand-neck squamous cell carcinoma (HNSCC) variants expressing high levels of E48, a human Ly-6 protein (E48 hi ), expressed higher levels of the fucose-generating FX enzyme and of the fucosylated E-selectin ligand sLe a than cells expressing low levels of E48 (E48 lo ). Signaling through E48 upregulated expression levels of these molecules in HNSCC. Head-and-neck squamous cell carcinoma (HNSCC) is a major health problem. About 500,000 new cases are diagnosed annually worldwide. 1,2 Despite advances made in the diagnosis and treatment of HNSCC during the last decades, the treatment efficay and associated morbidity as well as the 5-year survival rate have only marginally improved. 3,4 However, the type of relapse is gradually shifting from locoregional recurrence to distant metastasis. 1 It is therefore critically important to develop novel treatment modalities. Advancement in the development of new forms of therapy depends to a large extent on the availability of additional information on and a profound understanding of the molecular and cellular mechanisms involved in HNSCC carcinogenesis and progression. There is already ample information on the genetic alterations in HNSCC, including mutation of p53, 5 amplification of PRAD-1 (chromosome 11q13) 6 and frequent LOH on 9p, 3p, 17p, 8p, 13q and 18q. 7 These alterations characterize specific histopathologic stages of HNSCC. However, the molecular mechanisms involved in lymphogenic and hematogenic metastasis formation remain unknown. These parameters obviously determine the prognosis of the disease.MAb E48 was 1 of several developed to detect and treat minimal residual HNSCC following primary treatment. 8 It recognizes an outer membrane antigen, expressed by HNSCC. This antigen was characterized by cDNA cloning 9 and proved to be a GPIanchored membrane protein expressed by squamous cells. E48 is highly (nearly 70%) homologous to the murine ThB protein, a member of the Ly-6 gene family. 9 -11 E48 maps on human chromosome 8q24, 9 the syntenic locus of mouse chromosome 15E, to which the mouse Ly-6 gene family has been mapped. 11 Whereas both E48 and ThB are expressed on keratinocytes of squamous epithelia, 9 they differ in lymphocyte expression. ThB is expressed by mouse lymphocytes, whereas E48 is not expressed by human lymphocytes. 12 The function of E48 on keratinocytes of squamous epithelia remains unclear, though it might be involved in cellular adhesion. 9 Shortly after the cloning of cDNA encoding the E48 antigen, several additional human Ly-6 genes were cloned. [13][14][15][16][17] Our laboratory reported previously on a linkage between the overexpression of certain Ly-6 proteins on mouse tumor cells and a high-malignancy phenotype of such cells. 18 -20 In view of the association of Ly-6 with a high-malignancy phenotype of mouse tumors, it was of interest to study the role, if any, pla...

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The GPI-linked Ly-6 Antigen E48 Regulates Expression Levels of the FX Enzyme and of E-selectin Ligands on Head and Neck Squamous Carcinoma Cells

Cited by 30 publications

References 35 publications

Genetic reprogramming of tumor cells by zinc finger transcription factors

Genetic reprogramming of tumor cells by zinc finger transcription factors

Dual-specificity phosphatase Pyst2-L is constitutively highly expressed in myeloid leukemia and other malignant cells

Human Ly‐6 antigen E48 (Ly‐6D) regulates important interaction parameters between endothelial cells and head‐and‐neck squamous carcinoma cells

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