Aberrantly Expressed OTX Homeobox Genes Deregulate B-Cell Differentiation in Hodgkin Lymphoma

Abstract

In Hodgkin lymphoma (HL) we recently reported that deregulated homeobox gene MSX1 mediates repression of the B-cell specific transcription factor ZHX2. In this study we investigated regulation of MSX1 in this B-cell malignancy. Accordingly, we analyzed expression and function of OTX homeobox genes which activate MSX1 transcription during embryonal development in the neural plate border region. Our data demonstrate that OTX1 and OTX2 are aberrantly expressed in both HL patients and cell lines. Moreover, both OTX loci are targeted by genomic gains in overexpressing cell lines. Comparative expression profiling and subsequent pathway modulations in HL cell lines indicated that aberrantly enhanced FGF2-signalling activates the expression of OTX2. Downstream analyses of OTX2 demonstrated transcriptional activation of genes encoding transcription factors MSX1, FOXC1 and ZHX1. Interestingly, examination of the physiological expression profile of ZHX1 in normal hematopoietic cells revealed elevated levels in T-cells and reduced expression in B-cells, indicating a discriminatory role in lymphopoiesis. Furthermore, two OTX-negative HL cell lines overexpressed ZHX1 in correlation with genomic amplification of its locus at chromosomal band 8q24, supporting the oncogenic potential of this gene in HL. Taken together, our data demonstrate that deregulated homeobox genes MSX1 and OTX2 respectively impact transcriptional inhibition of (B-cell specific) ZHX2 and activation of (T-cell specific) ZHX1. Thus, we show how reactivation of a specific embryonal gene regulatory network promotes disturbed B-cell differentiation in HL.

lncRNA DLG1-AS1 Promotes Cell Proliferation by Competitively Binding with miR-107 and Up-Regulating ZHX1 Expression in Cervical Cancer

“…In breast cancer, ZHX1 overexpression is associated with cancer cell invasion [24,25]. In addition, ZHX1 can inhibit B cell differentiation, which is associated with the pathogenesis of Hodgkin's lymphoma [26]. In the present study, the expression level of ZHX1 in cervical cancer tissues was positively correlated with DLG1-AS1 expression, but negatively correlated with miR-107, suggesting that DLG1-AS1, miR-107, and ZHX1 may form a ceRNA network.…”

ZHX1 Promotes the Proliferation, Migration and Invasion of Cholangiocarcinoma Cells

“…For example, in CTLL-2 cells (cytotoxic T cells), IL-2 increased ZHX1 gene expression and CTLL-2 proliferation [28], and in malignant breast cancer, an elevated ZHX1 level was associated with cancer cell invasion [18, 19]. In addition, in Hodgkin’s lymphoma, ZHX1 was found to inhibit B-cell differentiation and to be associated with the pathogenesis of lymphoid malignancy [9]. Similarly, in the present study, ZHX1 knockdown reduced and its overexpression increased cell proliferation in cholangiocarcinoma cell lines (Fig 2 and S2 Fig).…”

“…Furthermore, the homeodomain in this family is specific to vertebrate lineage. All three ZHX proteins are associated with hematopoietic cell differentiation, glomerular diseases, and hepatocellular carcinoma [9–11]. ZHX1 was firstly identified in a mouse bone marrow stromal cell line, and found to be expressed at moderate levels in lungs, spleen, and testes, and at low levels in liver and kidneys [12].…”

Learning to see again: biological constraints on cortical plasticity and the implications for sight restoration technologies

“…In animal models disruption of Ox2 has proved sufficient to reopen plasticity in adult mice (Beurdeley et al 2012, Spatazza et al 2013). However, pharmacological enhancement of OTX2 raises serious safety concerns given that over-expression of OXT2 is associated with a variety of cancers (Di et al 2005, Nagel et al 2015). …”