Downregulation of major histocompatibility complex antigens in invading glioma cells: stealth invasion of the brain

Zagzag, David; Salnikow, Konstantin; Chiriboga, Luis; Yee, Herman; Lan, Li; Ali, M. Aktar; Garcı́a, Roberto; Demaria, Sandra; Newcomb, Elizabeth W.

doi:10.1038/labinvest.3700233

Cited by 156 publications

(121 citation statements)

References 60 publications

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“…It was previously reported that renal cell carcinomas and other tumors downregulate expression of the MHC I and II HLA genes (Gastl et al, 1996;Osborne et al, 1997;Atkins et al, 2004;Satoh et al, 2004;Zagzag et al, 2005). As it is commonly believed that abnormalities in antigen presentation may help tumors evade the full-scale immune response (Seliger et al, 2000), the molecular mechanisms of such deficiencies may provide a clue to novel therapeutic approaches.…”

Section: Discussionmentioning

confidence: 99%

Hypoxic repression of STAT1 and its downstream genes by a pVHL/HIF-1 target DEC1/STRA13

et al. 2006

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DEC1/STRA13 is a bHLH type transcriptional regulator involved with immune regulation, hypoxia response and carcinogenesis. We recently demonstrated that STRA13 interacts with STAT3 in the transcriptional activation of STAT-dependent promoters. Here, we pursue STRA13 involvement in the JAK/STAT pathway by studying its role in STAT1 expression. First, we showed that VHL deficiency or HIF-1 activation resulted in the repression of endogenous STAT1 mediated by STRA13. We then characterized the STAT1 proximal promoter to assess its response to STRA13 by transient coexpression in a luciferase reporter assay. Using sequential truncation and site-directed mutagenesis of the STAT1 promoter with STRA13 deletion constructs, we showed that the STRA13 C-terminal trans-activation domain, which is known to bind HDAC1, mostly determines the repressive activity. Involvement of HDAC activity in STAT1 regulation was validated by TSA inhibition and chromatin immunoprecipitation (ChIP) assay. Thus, we demonstrate that STRA13-mediated repression of STAT1 transcription utilizes an HDAC1-dependent mechanism. Furthermore, we show that targets of unphosphorylated STAT1, such as antigen presenting genes and CASP1, are also repressed by hypoxia possibly through the same STRA13-mediated mechanism. Thus, the newly discovered link between HIF-1 and STAT1 reveals a previously unknown role of STRA13 in hypoxia and carcinogenesis. Oncogene Shuai and Liu, 2003). STAT1 and STAT3 are that two principal signal transducers in this pathway that serve disparate physiological roles through transcriptional activation of different targets (Qing and Stark, 2004). In carcinogenesis, these proteins have opposite effects on cell growth and survival; while STAT3 is an oncogene (Bromberg et al., 1999), STAT1 possesses tumor suppressor properties (Kaplan et al., 1998;Bromberg and Darnell, 2000). STAT1's major functions, executed through the IFNg-induced Y701 phosphorylation, are inhibition of proliferation, activation of antimicrobial and antiviral responses, and induction of antitumor immune defense (Shuai et al., 1996;Kaplan et al., 1998;Stark et al., 1998). Recent data suggest that unphosphorylated STAT1 may also play an important role in the regulation of constitutive expression of certain genes (Kumar et al., 1997;Chatterjee-Kishore et al., 2000;Meyer et al., 2002).In this study, we identify STAT1 as a transcriptional target of STRA13, investigate the molecular mechanisms of STRA13 activity on the STAT1 promoter, and assess the downstream effects of this activity. Results Introduction of VHL in clear cell carcinoma cells stimulates STAT1 expressionOur previous study revealed functional interaction between a VHL/HIF-1 target STRA13 and STAT3 (Ivanova et al., 2004). To find out if STRA13 can be associated with other constituents of the JAK/STAT pathway, we took advantage of cell lines with different VHL status. The original clear cell carcinoma cell lines UM-RC-6 and 786-0 contain frameshift mutations in the remaining VHL allele that make aberrant proteins...

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Section: Discussionmentioning

confidence: 99%

Hypoxic repression of STAT1 and its downstream genes by a pVHL/HIF-1 target DEC1/STRA13

et al. 2006

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“…Further study of their functions and expressions in glioma tissue or cell lines will improve our knowledge of their roles as potential circulating biomarkers for high-grade glioma. A2M has been found to be synthesized and secreted by human glioma cells and up-regulated in migrating human glioma cells compared with non-migrating glioma cells (21). The A2M receptor, LRP, is overexpressed in human malignant astrocytomas, especially in GBM (22), and A2M can cross the blood-brain barrier in an LRP-dependent manner (23).…”

Section: Discussionmentioning

confidence: 99%

Identification of blood protein biomarkers that aid in the clinical assessment of patients with malignant glioma

Gowda

et al. 2012

Int J Oncol

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Abstract. Analyzing molecular biomarkers using blood is an important approach for clinical assessment of malignant glioma. We investigated a molecular proteomic biomarkerbased approach for glioblastoma using patients' blood samples. The expression levels of a list of candidate proteins were quantified in plasma and serum samples from two different cohorts of patients with malignant glioma and normal controls. The biological function was studied for one of the identified markers. Additionally, the prognostic significance of protein marker expression was measured by survival analysis. As a result, protein biomarkers associated with malignant glioma were identified from the blood specimens and five of the protein biomarkers were common to both cohorts. Immunohistochemical analysis demonstrated that many of the protein biomarkers identified in peripheral blood specimens were expressed in malignant gliomas. Staining levels for one of the biomarkers, MIP-1α, was found to correlate with WHO grade among invasive gliomas, and we demonstrate that MIP-1α promotes human glioblastoma cell proliferation and migration. Additionally, four prognostic protein biomarkers were identified. In conclusion, we demonstrate that both peripheral blood plasma and serum specimens are highly valuable and complementary to each other in the quest for protein biomarkers of malignant glioma. Sets of novel protein biomarkers were identified that may aid in the diagnosis and prognosis of patients with malignant glioma.

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“…A Perier et al to downregulate HLA-I and II genes (Osborne et al, 1997;Atkins et al, 2004;Zagzag et al, 2005). Abnormalities in the expression of HLA molecules altering antigen presentation may contribute to tumors evading the adaptive immune response (Seliger et al, 2000), but promote NK activation.…”

Section: Mutated Vhl Rcc Cells and Nk Cell Activationmentioning

confidence: 99%

Mutations of the von Hippel–Lindau gene confer increased susceptibility to natural killer cells of clear-cell renal cell carcinoma

et al. 2011

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The tumor suppressor gene von Hippel-Lindau (VHL) is involved in the development of sporadic clear-cell renal cell carcinoma (RCC). VHL interferes with angiogenesis and also controls cell adhesion and invasion. Therapies that target VHL-controlled genes are currently being evaluated in RCC patients. RCC is a immunogenic tumor and treatment with interleukin-2 (IL2) or interferon (IFN)-a results in regression in some patients. We used two renal tumor cell lines (RCC6 and RCC4) carrying VHL loss-of-function mutations to investigate the role of mutant VHL in susceptibility to natural killer (NK) cellmediated lysis. The RCC6 and RCC4 cell lines were transfected with the wild-type gene to restore the function of VHL. The presence of the gene in RCC cells downregulated hypoxia-inducible factor (HIF)-1a and subsequently decreased vascular endothelial growth factor (VEGF) production. Relative to control transfectants and parental cells, pVHL-transfected cell lines activated resting and IL2-activated NK cells less strongly, as assessed by IFNc secretion, NK degranulation and cell lysis. NKG2A, a human leukocyte antigen (HLA)-Ispecific inhibitory NK receptor, controls the lysis of tumor targets. We show that HLA-I expression in RCC-pVHL cells is stronger than that in parental and controls cells, although the expression of activating receptor NK ligands remains unchanged. Blocking NKG2A/HLA-I interactions substantially increased lysis of RCC-pVHL, but had little effect on the lysis of VHL-mutated RCC cell lines. In addition, in response to IFNa, the exponential growth of RCC-pVHL was inhibited more than that of RCC-pE cells, indicating that VHL mutations may be involved in IFNa resistance. These results indicate that a decreased expression of HLA-I molecules in mutated VHL renal tumor cells sensitizes them to NK-mediated lysis. These results suggest that combined immunotherapy with antiangiogenic drugs may be beneficial for patients with mutated VHL.

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Downregulation of major histocompatibility complex antigens in invading glioma cells: stealth invasion of the brain

Cited by 156 publications

References 60 publications

Hypoxic repression of STAT1 and its downstream genes by a pVHL/HIF-1 target DEC1/STRA13

Hypoxic repression of STAT1 and its downstream genes by a pVHL/HIF-1 target DEC1/STRA13

Identification of blood protein biomarkers that aid in the clinical assessment of patients with malignant glioma

Mutations of the von Hippel–Lindau gene confer increased susceptibility to natural killer cells of clear-cell renal cell carcinoma

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