Showing papers by "Jochen Hess published in 2012"
TL;DR: It is demonstrated that the nucleoporin Nup98 is required for full expression of p21, a key effector of the p53 pathway, but not several other p53 target genes.
65 citations
TL;DR: The findings show that increased PDPN expression in human GB is caused by loss of PTEN function and activation of the PI3K-AKT-AP-1 signaling pathway, accompanied by epigenetic regulation of P DPN promoter activity.
Abstract: Recently, we found strong overexpression of the mucin-type glycoprotein podoplanin (PDPN) in human astrocytic brain tumors, specifically in primary glioblastoma multiforme (GB). In the current study, we show an inverse correlation between PDPN expression and PTEN levels in primary human GB and glioma cell lines, and we report elevated PDPN protein levels in the subventricular zone of brain tissue sections of PTEN-deficient mice. In human glioma cells lacking functional PTEN, reintroduction of wild-type PTEN, inhibition of the PTEN downstream target protein kinase B/AKT, or interference with transcription factor AP-1 function resulted in efficient downregulation of PDPN expression. In addition, we observed hypoxia-dependent PDPN transcriptional control and demonstrated that PDPN expression is subject to negative transcriptional regulation by promoter methylation in human GB and in glioma cell lines. Treatment of PTEN-negative glioma cells with demethylating agents induced expression of PDPN. Together, our findings show that increased PDPN expression in human GB is caused by loss of PTEN function and activation of the PI3K-AKT-AP-1 signaling pathway, accompanied by epigenetic regulation of PDPN promoter activity. Silencing of PDPN expression leads to reduced proliferation and migration of glioma cells, suggesting a functional role of PDPN in glioma progression and malignancy. Thus, specific targeting of PDPN expression and/or function could be a promising strategy for the treatment of patients with primary GB.
54 citations
TL;DR: This review summarizes the most recent advances in the understanding of the molecular principles of HPV-related OPSCC, mainly based on functional genomic approaches, but also emphasizes the significant role played by the tumor microenvironment, especially the immune system, for improved clinical outcome and differential sensitivity ofHPV-related tumors to current treatment options.
Abstract: Human papillomavirus (HPV) infection is well established as etiological agent responsible for a number of pathologies affecting the stratified epithelia of skin and anogenital sites. More recently, the infection by (mucosal) high-risk HPV types has also been found to be causally associated with squamous cell carcinoma in the head and neck region (HNSCC), especially in the oropharynx. Intriguingly, HPV-related oropharyngeal squamous cell carcinomas (OPSCC) represent a distinct clinical entity compared to HPV-negative tumors with regard to treatment response and survival outcome, and the association between HPV infection and OPSCC has potential important implications for prevention and treatment decision making. The improved survival of patients with HPV-related tumors also raises the question, whether a better understanding of the underlying differences may guide us to identify new therapeutic concepts that could be used in targeted therapy for HPV-negative and improved therapy for HPV-positive cancers, and finally to initiate individualization of treatment based on the biology of OPSCC. This review summarizes the most recent advances in our understanding of the molecular principles of HPV-related OPSCC mainly based on functional genomic approaches, but also emphasizes the significant role played by the tumor microenvironment, especially the immune system, for improved clinical outcome and differential sensitivity of HPV-related tumors to current treatment options.
43 citations
TL;DR: Experimental evidence is provided that MYBBP1A is an important molecular switch in the regulation of tumor cell proliferation versus migration in HNSCC and it will be a major challenge for the future to proof the concept whether regulation Myb-binding protein 1a expression and/or function could serve as a novel option for anti-cancer therapy.
Abstract: Head and neck squamous cell carcinoma (HNSCC) is one of the most prevalent and lethal cancers worldwide and mortality mostly results from loco-regional recurrence and metastasis. Despite its significance, our knowledge on molecular, cellular and environmental mechanisms that drive disease pathogenesis remains largely elusive, and there are limited therapeutic options, with only negligible clinical benefit. We applied global gene expression profiling with samples derived from a recently established mouse model for oral cancer recurrence and identified a list of genes with differential expression between primary and recurrent tumors. One differentially expressed gene codes for Myb-binding protein 1a (MYBBP1A), which is known as a transcriptional co-regulator that physically interacts with nuclear transcription factors, such as NFκB and p53. We confirmed significantly reduced MYBBP1A protein levels on tissue sections of recurrent mouse tumors compared to primary tumors by immunohistochemistry, and found aberrant MYBBP1A protein levels also in tumor samples of HNSCC patients. Interestingly, silencing of MYBBP1A expression in murine SCC7 and in human HNSCC cell lines elicited increased migration but decreased cell growth. We provide experimental evidence that MYBBP1A is an important molecular switch in the regulation of tumor cell proliferation versus migration in HNSCC and it will be a major challenge for the future to proof the concept whether regulation MYBBP1A expression and/or function could serve as a novel option for anti-cancer therapy.
18 citations
TL;DR: It is demonstrated for the first time that hepatocyte-specific S 100a8 and S100a9 expression induces a systemic mobilization of neutrophils by a specific activation of Cxcl1 transcription in the liver.
Abstract: Background
Calprotectin consists of the Ca2+-binding proteins S100a8 and S100a9 that are induced in epithelial cells in response to tissue damage and infection. Both proteins are also secreted by activated innate immune cells and numerous studies demonstrate their crucial role in pathological conditions of acute and chronic inflammation.
17 citations