Low expression of <i>HLA‐DRA, HLA‐DPA1</i>, and <i>HLA‐DPB1</i> is associated with poor prognosis in pediatric adrenocortical tumors (ACT)

Leite, Fabíola A; Lira, Régia Caroline Peixoto; Fedatto, Paola Fernanda; Antonini, Sonir Roberto Rauber; Martinelli, Carlos Eduardo; Castro, Margaret de; Neder, Luciano; Ramalho, Leandra Náira Zambelli; Tucci, Sílvio; Mastelaro, Maria J; Seidinger, Ana Luíza; Cardinalli, Izilda Aparecida; Yunes, José Andrés; Brandalise, Sílvia Regina; Tone, Luíz Gonzaga; Scrideli, Carlos Alberto

doi:10.1002/pbc.25118

Cited by 32 publications

(34 citation statements)

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“…[58][59][60][61] The clinical relevance of the epigenetic control of HLA class II antigen expression was shown for esophageal squamous cell carcinoma and adrenocortical tumors promoting their recurrence and progression. 62,63 Impaired HLA class II-restricted TAA presentation due to abnormalities in the processing pathway could limit CD4 C Tcell help for the induction of CD8 C T-cell responses. 64 Intracellular li expression and occupancy of HLA class II antigen with CLIP as well as low to basal levels of GILT negatively interfere with the activation of CD4 C T cells reactive against acute myeloid leukemia (AML) and lymphoma cells.…”

Section: Deregulation Of Hla Class II Apm Components In Malignant Cellsmentioning

confidence: 99%

HLA class II antigen-processing pathway in tumors: Molecular defects and clinical relevance

2017

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The human leukocyte antigen (HLA) class II antigen-processing machinery (APM) presents to cognate CD4 C T-cells antigenic peptides mainly generated from exogeneous proteins in the endocytic compartment. These CD4 C T cells exert helper function, but may also act as effector cells, thereby recognizing HLA class II antigen-expressing tumor cells. Thus, HLA class II antigen expression by tumor cells influences the tumor antigen (TA)-specific immune responses and, depending on the cancer type, the clinical course of the disease. Many types of human cancers express HLA class II antigens, although with marked differences in their frequency. Some types of cancer lack HLA class II antigen expression, which could be due to structural defects or deregulation affecting different components of the complex HLA class II APM and/or from lack of cytokine(s) in the tumor microenvironment. In this review, we have summarized the information about HLA class II antigen distribution in normal tissues, the structural organization of the HLA class II APM, their expression and regulation in malignant cells, the defects, which have been identified in malignant cells, and their functional and clinical relevance.

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Section: Deregulation Of Hla Class II Apm Components In Malignant Cellsmentioning

confidence: 99%

HLA class II antigen-processing pathway in tumors: Molecular defects and clinical relevance

2017

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“…The human genes IGF2 (Hs01005963_m1), IGF1R (Hs00609566_m1), MAPK1 (Hs01046830_m1), MAPK3 (Hs00385075_m1), and PIK3R5 (Hs01046353_m1) were amplified by qRT-PCR using TaqMan gene assays and the ABI 7500 Real Time PCR System (Applied Biosystems). All samples were analyzed in triplicate and normalized to the endogenous reference human genes ACTB and GUSB (Applied Biosystems) as described previously (Leal et al 2011, Leite et al 2014. The relative expression was determined by the 2 −∆∆CT method (Livak & Schmittgen 2001), and the median gene expression values of all non-neoplastic adrenal tissues was used as reference and defined as 1 for analysis of tumor samples.…”

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confidence: 99%

IGF2 and IGF1R in pediatric adrenocortical tumors: roles in metastasis and steroidogenesis

Lira¹,

Fedatto²,

Antônio³

et al. 2016

Endocrine-Related Cancer

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Deregulation of the IGF system observed in human tumors indicates a role in malignant cell transformation and in tumor cell proliferation. Although overexpression of the IGF2 and IGF1R genes was described in adrenocortical tumors (ACTs), few studies reported their profiles in pediatric ACTs. In this study, the IGF2 and IGF1R expression was evaluated by RT-qPCR according to the patient's clinical/pathological features in 60 pediatric ACT samples, and IGF1R protein was investigated in 45 samples by immunohistochemistry (IHC). Whole transcriptome and functional assays were conducted after IGF1R inhibition with OSI-906 in NCI-H295A cell line. Significant IGF2 overexpression was found in tumor samples when compared with non-neoplastic samples (P < 0.001), significantly higher levels of IGF1R in patients with relapse/metastasis (P = 0.031) and moderate/strong IGF1R immunostaining in 62.2% of ACTs, but no other relationship with patient survival and clinical/pathological features was observed. OSI-906 treatment downregulated genes associated with MAPK activity, induced limited reduction of cell viability and increased the apoptosis rate. After 24 h, the treatment also decreased the expression of genes related to the steroid biosynthetic process, the protein levels of the steroidogenic acute regulatory protein (STAR), and androgen secretion in cell medium, supporting the role of IGF1R in steroidogenesis of adrenocortical carcinoma cells. Our data showed that the IGF1R overexpression could be indicative of aggressive ACTs in children. However, in vitro treatments with high concentrations of OSI-906 (>1 μM) showed limited reduction of cell viability, suggesting that OSI-906 alone could not be a suitable therapy to abolish carcinoma cell growth. 23:6Research R C P Lira et al.IGF1R in pediatric adrenocortical tumor IGF2 and IGF1R in pediatric adrenocortical tumors: roles in metastasis and steroidogenesis

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“…Its primary role in immune response is presenting peptides derived from extracellular proteins. Furthermore, a reduction in HLA-DR gene expression, which is observed in cancer and in sepsis, correlates with an impaired TNFα response (Cajander et al 2013;Leite et al 2014;Winkler et al 2017). The HLA-DRA mediates effects of insulin, insulinlike growth factor 1, and other cytokines by acting as a molecular adaptor between diverse receptor tyrosine kinases and downstream effectors through phosphorylation by the insulin receptor tyrosine kinase upon receptor stimulation as well as other kinases (Wu et al 2017).…”

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confidence: 99%

Insulin resistance in obese adolescents affects the expression of genes associated with immune response

Minchenko

2019

Endocrine Regulations

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Objective. The development of obesity and its metabolic complications is associated with dysregulation of various intrinsic mechanisms, which control basic metabolic processes through changes in the expression of numerous regulatory genes.Methods. The expression level of HLA-DRA, HLA-DRB1, HLA-G, HLA-F, and NFX1 genes as well as miR-190b was measured in the blood of obese adolescents without signs of resistance to insulin and with insulin resistance in comparison with the group of relative healthy control individuals without signs of obesity.Results. It was shown that obesity without signs of insulin resistance is associated with upregulation of the expression level of HLA-DRA and HLA-DRB1 genes, but with down-regulation of HLA-G gene expression in the blood as compared to control group of relative healthy adolescents. At the same time, no significant changes were observed in the expression level of HLA-F and NFX1 genes in the blood of this group of obese adolescents. Development of insulin resistance in obese individuals leads to significant down-regulation of HLA-DRA, HLA-DRB1, HLA-G, and HLA-F gene expressions as well as to up-regulation of NFX1 gene as well as microRNA miR-190b in the blood as compared to obese patients without signs of insulin resistance.Conclusions. Results of this study provide evidence that obesity affects the expression of the subset of genes related to immune response in the blood and that development of insulin resistance in obese adolescents is associated with strong down-regulation of the expressions of HLA-DRA, HLA-DRB1, HLA-F, and HLA-G genes, which may be contribute to the development of obesity complications. It is possible that transcription factor NFX1 and miR-190b participate in downregulation of HLA-DRA gene expression in the blood of obese adolescents with insulin resistance.

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Low expression of HLA‐DRA, HLA‐DPA1, and HLA‐DPB1 is associated with poor prognosis in pediatric adrenocortical tumors (ACT)

Abstract: Our results suggest that lower expression of HLA-DRA, HLA-DPA1, and HLA-DPB1 genes may contribute to more aggressive disease in pediatric ACT. HLA-DPA1 immunostaining may represent potential aggressiveness marker in this tumor.

Cited by 32 publications

References 37 publications

HLA class II antigen-processing pathway in tumors: Molecular defects and clinical relevance

HLA class II antigen-processing pathway in tumors: Molecular defects and clinical relevance

IGF2 and IGF1R in pediatric adrenocortical tumors: roles in metastasis and steroidogenesis

Insulin resistance in obese adolescents affects the expression of genes associated with immune response

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