Complex expression patterns of Eph receptor tyrosine kinases and their ephrin ligands in colorectal carcinogenesis

Aberrant expression of Eph and ephrin proteins in human cancers is extensively documented. However, data are frequently limited to one gene and therefore incomplete and in some instances conflicting. We analysed expression of all Eph and ephrin genes in colorectal cancer (CRC) cell lines and 153 clinical specimens, providing for the first time a comprehensive analysis of this system in CRC. Eph/ephrin mRNA expression was assessed by quantitative real-time PCR and correlated with protein expression (flow cytometry, Western blotting and immunocytochemistry). These data show that EphA1, EphA2, EphB2 and EphB4 were significantly over expressed in CRC. In all cases, at least one Eph gene was found in normal colon (EphA1, EphA2, EphB2, EphB4), where expression was observed at high levels in most CRCs. However, other Eph gene expression was lost in individual CRCs compared to the corresponding normal, EphA7 being a striking example. Loss of expression was more common in advanced disease and thus correlated with poor survival. This is consistent with the redundant functionality of Eph receptors, such that expression of a single Eph gene is sufficient for effector function. Overall, the data suggest a progressive loss of expression of individual Eph genes suggesting that individual CRCs need to be phenotyped to determine which Eph genes are highly expressed. Targeted therapies could then be selected from a group of specific antibodies, such as those developed for EphA1.     

Expression of Ephb2 and Ephb4 in breast carcinoma

Eph receptor tyrosine kinases and their cell-surfacebound ligands, the ephrins, play key roles in diverse biological processes. Eph receptors comprise the largest family of receptor tyrosine kinases consisting of eight EphA receptors (with five corresponding ephrinA ligands) and six EphB receptors (with three corresponding transmembrane ephrinB ligands). Originally identified as neuronal pathfinding molecules, EphB receptors and ephrinB ligands are later proved to be crucial regulators of vasculogenesis and embryogenesis. More studies indicate that Eph receptors are involved in angiogenesis and tumorigenesis. This study aimed to investigate the expression of EphB2 and EphB4 in breast carcinomas. Semiquantitative RT-PCR and immunohistochemistry were used to examine the expression patterns of EphB2 and EphB4. Clinicopathological and survival correlations were statistically analyzed in a series of 94 breast carcinomas, 9 normal specimens and 4 breast carcinoma cell lines. 1(1%), 16(17%), 29(31%), 48(51%) of the 94 tumors were negative, weak, moderate and strong EphB2 protein expression, respectively. 6(6%), 27(29%), 28(30%), 33(35%) of the tumors were negative, weak, moderate and strong EphB4 expression, respectively. Both EphB2 and EphB4 RT-PCR products could be detected in all specimens. Increased EphB2 protein expression was negatively associated with overall survival, and there was a trend that increased EphB2 protein expression was correlated with shorter disease free survival, while EphB4 protein expression was associated with histological grade and stage. EphB4 membrane staining was increased with S phase fraction and associated with DNA aneuploidy. These findings indicate that both EphB2 and EphB4 are involved in the development of breast cancer and that both molecules could be potential predictive markers.     

Lymphocyte response to pokeweed mitogen in chronic lymphocytic leukemia

The response of lymphocyte subpopulations to pokeweed mitogen (PWM) was studied in normal volunteers and patients with B-cell chronic lymphocytic leukemia (CLL). Since unfractionated peripheral blood mononuclear (PBM) cells from CLL patients consist of a markedly increased proportion of B-lymphocytes and a decreased proportion of T-lymphocytes, enriched fractions of CLL B-cells and CLL T-cells were cultured in 1:1 proportions in autologous and allogeneic combinations with normal B-cell and T-cell-enriched fractions. Cultures containing normal B-cells with either autologous or allogeneic normal T-cells responded well to PWM. CLL T-cells were capable of providing a helper function for both proliferation and differentiation of normal B-cells, which was not significantly different from that provided by allogeneic normal T-cells. CLL B-lymphocytes were unresponsive to PWM when cultured in the presence of either autologous CLL T-lymphocytes or allogeneic normal T-lymphocytes. The responsiveness of CLL B-cells was not restored by the addition of normal peripheral blood monocytes to the cultures. These experiments indicate that there is an intrinsic B-cell defect which prevents CLL B-lymphocytes from responding to PWM.     

Kinetics of protein a activation of mononuclear cells from patients with chronic lymphocytic leukemia — I. CLL B-cells are not intrinsically unresponsive to staphylococcal protein A

The response of lymphocyte subpopulations to staphylococcal Protein A (SPA) was studied in patients with B-cell chronic lymphocytic leukemia (CLL) and normal volunteers. The kinetics of the proliferative response, optimal dose and sera requirements were determined. Of 92 experiments conducted in 60 patients, SPA induced peripheral blood mononuclear cells (PBMC) proliferation in 81.5% of cases studied. The mean proliferative response of CLL PBMC was significantly lower than normal PBMC, 5823 vs. 30,364 cpm. However, enriched CLL B-cells failed to respond to SPA compared to normal enriched B-cells, with mean cpm 444 vs. 6438 respectively. As PBMC from CLL consist of increased proportions of B-cells and decreased proportions of T-cells, enriched CLL B-cells were cultured at 1 : 1 ratio with autologous or allogeneic normal T-cell enriched fractions. CLL B-lymphocytes were stimulated by SPA when cultured in the presence of T-lymphocytes, indicating a T-helper defect in the B-CLL proliferative response to SPA, rather than an intrinsic inability of CLL B-cells to proliferate. These observations are of import for further studies of CLL B-lymphocyte function, cytogenetics, and establishment of CLL B-cell lines in culture.     

EphB2 activity plays a pivotal role in pediatric medulloblastoma cell adhesion and invasion

Eph/ephrin signaling has been implicated in various types of key cancer-enhancing processes, like migration, proliferation, and angiogenesis. In medulloblastoma, invading tumor cells characteristically lead to early recurrence and a decreased prognosis. Based on kinase-activity profiling data published recently, we hypothesized a key role for the Eph/ephrin signaling system in medulloblastoma invasion. In primary medulloblastoma samples, a significantly higher expression of EphB2 and the ligand ephrin-B1 was observed compared with normal cerebellum. Furthermore, medulloblastoma cell lines showed high expression of EphA2, EphB2, and EphB4. Stimulation of medulloblastoma cells with ephrin-B1 resulted in a marked decrease in in vitro cell adhesion and an increase in the invasion capacity of cells expressing high levels of EphB2. The cell lines that showed an ephrin-B1-induced phenotype possessed increased levels of phosphorylated EphB2 and, to a lesser extent, EphB4 after stimulation. Knockdown of EphB2 expression by short hairpin RNA completely abolished ephrin ligand-induced effects on adhesion and migration. Analysis of signal transduction identified p38, Erk, and mTOR as downstream signaling mediators potentially inducing the ephrin-B1 phenotype. In conclusion, the observed deregulation of Eph/ephrin expression in medulloblastoma enhances the invasive phenotype, suggesting a potential role in local tumor cell invasion and the formation of metastases.     

Expression of adhesion molecules in B-cell chronic lymphocytic leukaemia: an analysis in lymphoid compartments--peripheral blood, bone marrow and lymph node

The trafficking or homing of different lymphoid subsets to particular microenvironment is mediated by specific cell adhesion molecules (CAMs) expressed on lymphocytes and endothelial cells. B-cell chronic lymphocytic leukaemia (B-CLL) or Non-Hodgkin's lymphoma of small lymphocytic, B-cell type are monoclonal expansions of mature lymphocytes. The relative distribution of the tumor lymphocytes among various lymphoid compartments vary from patient to patient. Very few studies underlying this issue are available. To this effect, we have analysed the expression of LFA-1; VLA-4, ICAM-1; CD44H and CD44v6 (haematopoietic and variant form respectively) on freshly isolated lymphocytes obtained from bone marrow (BM), peripheral blood (PB) and lymph node (LN) by flow cytometry. Overall, we find strong expression of CD44H, low to moderate expression of LFA-1, negative to low expression of VLA-4 and lack of expression of CD44v6. ICAM-1 expression was observed only in patients with prominent lymphadenopathy. Higher expression of CD44H in PB lymphoid cells relative to that of BM lymphoid cells correlated with higher PB lymphocytosis (p < 0.001). Proliferating cell nuclear antigen expression in LN sections correlated inversely with VLA-4 expression on BM and PB lymphoid cells (p < 0.05). There was no significant correlation between expression of CAMs and bcl-2 protein.     

Erythropoietin-producing hepatocyte B6 variant-derived peptides with the ability to induce glioma-reactive cytotoxic T lymphocytes in human leukocyte antigen-A2+ glioma patients

We recently cloned a variant form of erythropoietin-producing hepatocyte (Eph)B6, a member of the Eph receptor tyrosine kinase family. In the present study, we examined the expression of the EphB6 variant (EphB6v) in a panel of brain tumor cell lines and glioblastoma tissues and we found that EphB6v was preferentially expressed in malignant brain tumors, such as glioblastomas and anaplastic astrocytomas. The EphB6v has a unique 54 amino acid sequence at the C-terminal that is not found in normal EphB6. Therefore, we attempted to identify antigenic peptides unique to EphB6v for immunotherapy. The two EphB6v-derived peptides exhibited the ability to bind to human leukocyte antigen (HLA)-A0201 molecules, and each of them was able to induce cytotoxic T lymphocytes in vitro in the peripheral blood mononuclear cells of HLA-A2⁺ glioma patients. The cytotoxicity was mediated by peptide-specific CD8⁺ T cells in an HLA-A2-restricted manner. The expression of EphB6v was also observed in different types of cancer (e.g. lung, colon, stomach, liver and pancreatic) cells. Taken together, the two peptides derived from EphB6v might be appropriate targets for peptide-based specific immunotherapy for HLA-A2⁺ patients with various cancers. ( Cancer Sci 2008; 99: 1656–1662)     

The role of Eph receptors and ephrin ligands in colorectal cancer

Eph receptors and their ephrin ligands constitute the largest subfamily of receptor tyrosine kinases and are components of the cell signaling pathways involved during development. Eph and ephrin overexpression have been documented in a variety of human cancers including gastrointestinal malignancies and in particular colorectal malignancies. EphB and ephrin B proteins have been implicated in the homeostasis of the gastrointestinal tract where EphB2‐ and EphB3‐ephrin B signaling regulates cell sorting in the mature epithelium. These proteins are also reported to be upregulated in colon carcinomas. The EphA/ephrin A system has also been implicated in epithelial tissue structure and function. More recently, EphA receptors and their corresponding ligands have been implicated in numerous malignancies. Of these, EphA2 in particular has been intensively investigated and has been proposed as a therapeutic target. An interesting observation emerging from these studies is the role for Ephs and ephrins in critical aspects of cell adhesion, migration and positioning, and a crucial role in tumor progression and metastasis. However, the underlying role of Ephs and ephrins in these processes has generally been studied on individual Eph or ephrin genes. Given the multiplicity of Eph expression on gut epithelial cells, a more global approach is needed to define the precise role of Eph–ephrin interaction in malignant transformation. Here, we will review the recent advances on the role of Eph–ephrin signaling in colorectal malignancies.     

Cellular distribution of a B-cell specific surface antigen (gp54) detected by a monoclonal antibody (anti-BL4)

A monoclonal antibody (anti-BL4) recognizing a previously characterized Mr 54,000 glycoprotein (gp54) was developed by immunizing BALB/c mice with cells from a precursor B-cell line (Josh-7). In normal individuals, this antigenic molecule was present on tonsillar B-cells (60-80%) and on a fraction of peripheral blood B-cells (5-25%). BL4 (gp54) expression was investigated in 186 patients with a variety of hematological malignancies using indirect immunofluorescence and flow cytometric analysis. Twenty-six of 37 cases of B-cell chronic lymphocytic leukemia (CLL) and 18 of 33 cases of B-cell non-Hodgkin's lymphoma were BL4 positive. Surface expression of BL4 on reactive cases of CLL and non-Hodgkin's lymphoma was brighter than those of B1, B2, and B4, BL4 positive CLL cases expressed a higher proportion of mouse rosette forming cells and Leu-1 positive cells than the BL4 negative subgroup and were not associated with elevated serum immunoglobulin levels. Four of 7 BL4 negative CLL cases were associated with increased serum levels of immunoglobulin M. Lymphoblasts from 14 of 14 cases of non-T acute lymphoblastic leukemia and 3 of 3 pre-B lymphoid blast crisis of chronic myeloid leukemia were BL4 negative. Neoplastic cells from 2 of 3 cases of Waldenstrom's macroglobulinemia and 4 of 7 cases of hairy cell leukemia were BL4 reactive. None of 7 cases of multiple myeloma and plasma cell leukemia were BL4 positive. All 11 T acute lymphoblastic leukemia cases, 6 other T-cell malignancies, 5 cases of Hodgkin's disease, 51 cases of acute nonlymphocytic leukemia, and 9 cases of chronic myeloid leukemia in chronic phase thus far studied were BL4 negative. An in vitro induction experiment using phorbol ester on a case of B-CLL demonstrated disappearance of BL4 accompanied with further B-cell differentiation. Our study further substantiates the previous finding that gp54 is a differentiation antigen restricted to the B-cell lineage and expressed during the intermediate stage of B-cell ontogeny.     

Multiple signaling interactions of Abl and Arg kinases with the EphB2 receptor

The Eph family of receptor tyrosine kinases and the Abl family of non-receptor tyrosine kinases have both been implicated in tissue morphogenesis. They regulate the organization of the actin cytoskeleton in the developing nervous system and participate in signaling pathways involved in axon growth. Both Eph receptors and Abl are localized in the neuronal growth cone, suggesting that they play a role in axon pathfinding. Two-hybrid screens identified regions of Abl and Arg that bind to the EphB2 and EphA4 receptors, suggesting a novel signaling connection involving the two kinase families. The association of full-length Abl and Arg with EphB2 was confirmed by co-immunoprecipitation and found to involve several distinct protein interactions. The SH2 domains of Abl and Arg bind to tyrosine-phosphorylated motifs in the juxtamembrane region of EphB2. A second, phosphorylation-independent interaction with EphB2 involves non-conserved sequences in the C-terminal tails of Abl and Arg. A third interaction between Abl and EphB2 is probably mediated by an intermediary protein because it requires tyrosine phosphorylation of EphB2, but not the binding sites for the Abl SH2 domain. The connection between EphB2 and Abl/Arg appears to be reciprocal. Activated EphB2 causes tyrosine phosphorylation of Abl and Arg, and vice versa. Interestingly, treatment of COS cells and B35 neuronal-like cells with ephrin-B1 to activate endogenous EphB2 decreased the kinase activity of endogenous Abl. These data are consistent with the opposite effects that Eph receptors and Abl have on neurite ougrowth and suggest that Eph receptors and Abl family kinases have shared signaling activities.     

Loss of EphB6 expression in metastatic melanoma

Overexpression of various members of the Eph receptor tyrosine kinases and their ephrin ligands has been frequently reported in cancer. In contrast, a loss of EphB6 gene expression has been correlated with a poor prognosis in human neuroblastoma, suggesting a distinct role for this receptor compared to other family members. More recently, an important role of EphB6 signalling in T-cells has been described, suggesting possibly deleterious immunologic effects of a loss of EphB6 in cancer progression. We investigated the expression of EphB6 in melanocytic tumors. EphB6 mRNA of 22 microdissected tissues (7 benign nevi, 7 melanomas, 8 metastases) and 10 different cell lines (normal melanocytes, non-metastatic/metastatic melanoma cell lines) were measured by quantitative real-time RT-PCR. For visualization of EphB6 protein expression, immunohistochemistry of 32 melanocytic lesions were performed. On the mRNA level, the benign nevi revealed the highest EphB6 expression (mean = 1.43), while melanomas (mean = 0.63) and metastases (mean = 0.08; p=0.001) displayed a progressive and significant reduction of EphB6 expression. Accordingly, established melanoma cell lines with metastatic potential showed low EphB6 expression in comparison to normal melanocytes and to most of the melanoma cell lines. Immunohistochemistry revealed homogeneous staining in common nevi, whereas in malignant melanomas and metastases a heterogeneously positive to completely negative EphB6 staining was observed. Remarkably, Spitz nevi stained similarly to ordinary melanocytic nevi. Taken together, we show that melanoma progression to metastatic disease is associated with a significant reduction of EphB6 gene expression which may have considerable consequences for the prognosis of malignant melanoma patients and possible gene-therapeutic approaches.     

Identification of EphB6 variant-derived epitope peptides recognized by cytotoxic T-lymphocytes from HLA-A24+ malignant glioma patients

We found previously that EphB6, a member of the erythropoietin-producing hepatocyte (Eph) receptor tyrosine kinase family, was preferentially expressed in malignant gliomas. In the present study, RT-PCR revealed a putative secretory variant form of human EphB6 that was expressed in the majority of glioma cell lines, though not in normal tissues. The variant has a unique 54 amino acid sequence that is not found in the normal EphB6. Therefore, we attempted to determine the antigenic peptides unique to the variant for immunotherapy. The two variant-derived peptides had the ability to bind to HLA-A2402 molecules and each of them could induce cytotoxic T-lymphocytes (CTLs) in vitro in peripheral blood mononuclear cells of HLA-A24(+) glioma patients. Furthermore, the cytotoxicity was mediated by peptide-specific CD8(+) T cells in an HLA-A24 restricted manner. Taken together, the two peptides derived from the variant of EphB6 might be appropriate targets for peptide-based specific immunotherapy to HLA-A24(+) patients with malignant glioma.     

Ligand-dependent EphB1 signaling suppresses glioma invasion and correlates with patient survival

Background

Extensive evidence implicates the Eph receptor family of tyrosine kinases and its ligand, ephrin, in glioma invasion, but it remains incompletely understood how these receptors affect chemotactic behavior of glioma. We sought to identify the Eph family members that correlate with patients'' survival and to reveal the function of Eph in glioma invasion.

Methods

Clinical relevance of EphB genes was confirmed in a clinically annotated expression data set of 195 brain biopsy specimens. The function of EphB was analyzed in vitro and in vivo.

Results

Levels of mRNA of certain EphB members were significantly different in histological grades of glioma. According to Kaplan–Meier analysis, only the EphB1 level among 5 members of EphB emerged to be a powerful predictor of favorable survival in malignant glioma (n = 97, P = .0048), although the levels of EphB1 expression did not vary across the tumor grades. Immunoprecipitation showed that tyrosine phosphorylated EphB1 was not detected in all glioma cells tested. Forced overexpression and autophosphorylation of EphB1 in low expressor cell lines (U251, U87) did not affect cell migration or invasion in vitro, whereas EphB1 phosphorylation induced by ephrin-B2/Fc significantly decreased migration and invasion. Cells expressing ephrin-B2 showed noteworthy morphological changes consistent with migration induction; this alteration was negated by EphB1 overexpression. Concomitantly, overexpression of EphB1 abrogated the increased migration and invasion induced by ephrin-B2 in vitro and in vivo.

Conclusions

These data suggest that ligand-dependent EphB1 signaling negatively regulates glioma cell invasion, identifying EphB1 as a favorable prognostic factor in malignant glioma.     

Loss of EphB4 receptor tyrosine kinase protein expression during carcinogenesis of the human breast

Members of the Eph family of receptor tyrosine kinase have been implicated in cell-cell communication and tissue integrity during embryogenesis. We have previously demonstrated cell type specific and hormone dependent EphB4 expression in the mouse mammary parenchyma suggesting involvement in the homeostasis of this organ. Since disruption of tissue organization is crucial for metastatic dissemination, we have investigated the expression of EphB4 during carcinogenesis of the human breast. Immunohistochemical analysis of 24 normal human breast samples and 124 consecutive breast carcinomas was correlated with tumor characteristics (stage, histology, grade, lymph node involvement) and the expression of ER, PR, Ki-67, p53 and HER2. In normal breast tissue, the EphB4 protein was expressed exclusively in parenchymal cells. Strikingly, a drastic reduction in the number of EphB4 protein expressing cells was observed in almost all invasive carcinomas analyzed, irrespective of the tumor type (p<0.0001). Furthermore, we found a highly significant correlation between EphB4 positivity and low histological grading of the tumor cells (p=0.002) suggesting that in breast cancer, EphB4 expression is not compatible with tumor progression. This raises the possibility that EphB4 could represent a potent tool for therapeutic intervention.     

The mechanism of action of interferon-alpha (IFN-alpha) in hairy-cell leukaemia; Hu-IFN-alpha 2 receptor expression by hairy cells and other normal and leukaemic cell types

To investigate the possible direct effects of interferon-alpha (IFN-alpha) in hairy-cell leukaemia, IFN-alpha receptor expression by hairy cells (HCs) (11 cases) was measured by a radiolabelling technique and compared with that of MOLT-4, chronic lymphocytic leukaemia (CLL; 14 cases) and various other leukaemic and normal cell types. Purified peripheral blood (PB) and splenic HCs showed higher levels of receptor expression (approx. 1000 +/- 200 binding sites/cell; 11 cases tested) than other normal and leukaemic cells types. Purified normal PB and tonsil B cells showed low levels of receptors (approx. 120 +/- 100 binding sites/cell), while a range of B-cell leukaemias displayed intermediate levels of expression (approx. 100-500 sites/cell). In the 15 cases of CLL tested, 530 +/- 330 binding sites/cell were demonstrated, the high standard deviation reflecting the fact that approximately one third of cases had receptor levels comparable with those in HCL. Normal and HCL T cells, red cells and platelets had no demonstrable IFN receptors. It is suggested that these findings may be relevant to the efficacy of IFN in hairy-cell leukaemia.     

No expansion of the pre-B and B-cell compartments in the bone marrow of patients with multiple myeloma

We have recently demonstrated that the CD24 antigen density of bone marrow (BM) lymphoid cells discriminates between pre-B cells and mature B-cells. Using this new method, we evaluated the B-cell lineage in the BM and peripheral blood (PB) of 18 patients with multiple myeloma (MM). First, the percentage of pre-B cells was significantly reduced by 40% in the BM of patients with MM: 2.3% +/- 2.2% versus 5.7% +/- 2.8% of normal BM lymphoid cells (P less than 0.01). This finding was associated with a significant reduction (50%) of the percentage of mature B-cells in both BM and PB, especially in patients with progressive disease (P less than 0.05). In contrast to what has been reported previously, we have not found any pre-B cells in the PB of these patients with MM. Secondly, BM pre-B and B-cell patients with MM did not express any activation markers (CD23, CD25, or CD71 antigens) and no CD5+ B-cells were found in the BM unlike in PB (8% CD5+ B-cells). Taken together, these data do not support the concept of a direct involvement (i.e, expansion or activation) of pre-B cells in MM without excluding the possibility of an early oncogenic event at the pre-B cell stage. Furthermore, our data emphasize this important reduction of the B-cell compartment (including that of pre-B cell) as a major cause of the humoral immunodeficiency in MM.     

Microenvironmental interactions and survival of CLL B-cells

Chronic Lymphocytic Leukemia (CLL) B cells display characteristics consistent with a defect in programmed cell death (apoptosis) and exhibit prolonged survival in vivo. When recovered from peripheral blood or lymphoid tissues from the patient and cultured in vitro, these malignant cells rapidly undergo spontaneous apoptosis. This observation suggests that the selective survival advantage enjoyed by CLL B-cells is not entirely autonomous, raising the possibility of manipulating CLL B-cell survival by iatrogenic means. The extended survival of the neoplastic B-cells creates a permissive soil on which oncogene activation, genetic instability and accumulation of gene mutations favoring disease progression can occur. In addition, such survival-promoting microenvironments can rescue leukemia cells from cytotoxic therapy, giving way to disease relapse. Survival of CLL B-cells is influenced by interactions with non-leukemia cells in the microenvironment of lymph nodes, marrow and other tissues. CLL B-cells have developed many different ways to escape undergoing apoptosis. These include: (a) expression of survival receptor as well as their ligands, giving rise to autocrine survival pathways which are leukemia cell specific; (b) defects in plasma membrane receptor cell signaling, triggered by death receptors such as Fas- and TRAIL; and (c) constitutively active survival signaling pathways such as NFκB and PI3K/Akt. Here we discuss some of the molecular mechanisms by which interaction with other cells and factors in the microenvironment provides survival advantages to CLL B-cells in specific in vivo niches, and we suggest some strategies for overcoming these anti-apoptotic mechanisms for improving treatment of CLL.     

Is miR-29 an oncogene or tumor suppressor in CLL?

B-cell chronic lymphocytic leukemia (CLL), the most common leukemia in the Western world. CLL occurs in two forms, aggressive and indolent. Aggressive CLL is characterized by high ZAP-70 expression and unmutated IgH V(H); indolent CLL shows low ZAP-70 expression and mutated IgH V(H). We recently found that miR-29 is up-regulated in indolent human B-CLL, compared to aggressive B-CLL and normal CD19(+) B-cells. To determine the role of miR-29 in CLL, we generated transgenic mice over-expressing miR-29 in mouse B-cells. Recently we reported that miR-29 transgenic mice develop indolent CLL phenotype. Interestingly, our previous findings suggest that miR-29 targets expression of TCL1, a critical oncogene in aggressive CLL, indicating that miR-29 might function as a tumor suppressor in CLL. Here we discuss these results and provide additional insights into function of miR-29 in CLL.     

Coexpression of EphB4 and ephrinB2 in tumour advancement of ovarian cancers

EphB4 and ephrinB2 expressions in ovarian cancers were studied to analyse EphB4/ephrinB2 functions against clinical backgrounds. EphB4 and ephrinB2 were dominantly localised in ovarian cancer cells of all cases studied. Both the histoscores and mRNA levels of EphB4 and ephrinB2 significantly increased with clinical stages (I相似文献