HIC1 Tumor Suppressor Loss Potentiates TLR2/NF-κB Signaling and Promotes Tissue Damage–Associated Tumorigenesis

Janečková, Lucie; Pospíchalová, Vendula; Fafílek, Bohumil; Vojtěchová, Martina; Turečková, Jolana; Dobeš, Jan; Dubuissez, Marion; Leprince, Dominique; Baloghová, Nikol; Horázná, Monika; Hlavatá, Adéla; Stančíková, Jitka; Šloncová, Eva; Galušková, Kateřina; Strnad, Hynek; Kor̆ínek, Vladimír

doi:10.1158/1541-7786.mcr-15-0033

Cited by 26 publications

(16 citation statements)

References 48 publications

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“…This indicated—considering the transcriptionally repressive function of HIC1—that the selected genes are not directly regulated by HIC1. Indeed, none of the previously identified HIC1-repressed genes [38] , [39] , [40] , [41] , [42] , [43] , [44] , [45] , [46] , [47] , [48] was present among the genes. Nevertheless, qRT-PCR analysis of C2CD4A and five other genes highly upregulated in HIC1-high samples using eight CRC samples from our experimental collection (four CRCs were selected as HIC1-high, additional four as HIC1-low) supported the observation made “ in silico ” ( Figure 5 B ).…”

Section: Resultsmentioning

confidence: 90%

HIC1 Expression Distinguishes Intestinal Carcinomas Sensitive to Chemotherapy

Janečková

Kolář

Švec

et al. 2016

Translational Oncology

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Neoplastic growth is frequently associated with genomic DNA methylation that causes transcriptional silencing of tumor suppressor genes. We used a collection of colorectal polyps and carcinomas in combination with bioinformatics analysis of large datasets to study the expression and methylation of Hypermethylated in cancer 1 (HIC1), a tumor suppressor gene inactivated in many neoplasms. In premalignant stages, HIC1 expression was decreased, and the decrease was linked to methylation of a specific region in the HIC1 locus. However, in carcinomas, the HIC1 expression was variable and, in some specimens, comparable to healthy tissue. Importantly, high HIC1 production distinguished a specific type of chemotherapy-responsive tumors.

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Section: Resultsmentioning

confidence: 90%

HIC1 Expression Distinguishes Intestinal Carcinomas Sensitive to Chemotherapy

Janečková

Kolář

Švec

et al. 2016

Translational Oncology

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“…1h ). Although an increase in the expression of the known Hic1 target genes Efna1 [ 24 ] and Tlr2 [ 32 ] was observed, no changes in Sirt1 were seen (Supplementary Table S1 ). Unexpectedly, gene expression microarray and gene ontology analysis revealed highly significant enrichment for pathways involved in the regulation of cell cycle, mitosis, and DNA replication consistent with the induction of cell cycle arrest (Figs.…”

Section: Resultsmentioning

confidence: 99%

The tumor suppressor Hic1 maintains chromosomal stability independent of Tp53

et al. 2018

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Hypermethylated-in-Cancer 1 (Hic1) is a tumor suppressor gene frequently inactivated by epigenetic silencing and loss-of-heterozygosity in a broad range of cancers. Loss of HIC1, a sequence-specific zinc finger transcriptional repressor, results in deregulation of genes that promote a malignant phenotype in a lineage-specific manner. In particular, upregulation of the HIC1 target gene SIRT1, a histone deacetylase, can promote tumor growth by inactivating TP53. An alternate line of evidence suggests that HIC1 can promote the repair of DNA double strand breaks through an interaction with MTA1, a component of the nucleosome remodeling and deacetylase (NuRD) complex. Using a conditional knockout mouse model of tumor initiation, we now show that inactivation of Hic1 results in cell cycle arrest, premature senescence, chromosomal instability and spontaneous transformation in vitro. This phenocopies the effects of deleting Brca1, a component of the homologous recombination DNA repair pathway, in mouse embryonic fibroblasts. These effects did not appear to be mediated by deregulation of Hic1 target gene expression or loss of Tp53 function, and rather support a role for Hic1 in maintaining genome integrity during sustained replicative stress. Loss of Hic1 function also cooperated with activation of oncogenic KRas in the adult airway epithelium of mice, resulting in the formation of highly pleomorphic adenocarcinomas with a micropapillary phenotype in vivo. These results suggest that loss of Hic1 expression in the early stages of tumor formation may contribute to malignant transformation through the acquisition of chromosomal instability.

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“…One of the genes targeted by both bta-mir-19b and bta-mir-19b2 is HIC1 (Hypermethylated In Cancer 1), which showed an increased expression only in the PP group which is consistent with the decrease in the miRNAs levels. HIC1 controls the expression of toll-like receptor 2, which enhances the NF-kB related axis [ 77 ] and pro-inflammatory cytokine secretion. NF-kB activation, and an enhanced production of inflammatory mediators, has been observed in macrophages and other cells types after Mycobacterium tuberculosis infection, as well as in intestinal epithelial cells after mycobacteria challenge [ 78 ].…”

Section: Discussionmentioning

confidence: 99%

Responses of Bovine Innate Immunity to Mycobacterium avium subsp. paratuberculosis Infection Revealed by Changes in Gene Expression and Levels of MicroRNA

et al. 2016

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Paratuberculosis in cattle is a chronic granulomatous gastroenteritis caused by Mycobacterium avium subsp. paratubercolosis (MAP) which is endemic worldwide. In dairy herds, it is responsible for huge economic losses. However, current diagnostic methods do not detect subclinical infection making control of the disease difficult. The identification of MAP infected animals during the sub-clinical phase of infection would play a key role in preventing the dissemination of the pathogen and in reducing transmission. Gene expression and circulating microRNA (miRNA) signatures have been proposed as biomarkers of disease both in the human and veterinary medicine. In this paper, gene expression and related miRNA levels were investigated in cows positive for MAP, by ELISA and culture, in order to identify potential biomarkers to improve diagnosis of MAP infection. Three groups, each of 5 animals, were used to compare the results of gene expression from positive, exposed and negative cows. Overall 258 differentially expressed genes were identified between unexposed, exposed, but ELISA negative and positive groups which were involved in biological functions related to inflammatory response, lipid metabolism and small molecule biochemistry. Differentially expressed miRNA was also found among the three groups: 7 miRNAs were at a lower level and 2 at a higher level in positive animals vs unexposed animals, while 5 and 3 miRNAs were respectively reduced and increased in the exposed group compared to the unexposed group. Among the differentially expressed miRNAs 6 have been previously described as immune-response related and two were novel miRNAs. Analysis of the miRNA levels showed correlation with expression of their target genes, known to be involved in the immune process. This study suggests that miRNA expression is affected by MAP infection and play a key role in tuning the host response to infection. The miRNA and gene expression profiles may be biomarkers of infection and potential diagnostic of MAP infection earlier than the current ELISA based diagnostic tests.

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HIC1 Tumor Suppressor Loss Potentiates TLR2/NF-κB Signaling and Promotes Tissue Damage–Associated Tumorigenesis

Abstract: Hypermethylated in cancer 1 (HIC1) represents a prototypic tumor suppressor gene frequently inactivated by DNA methylation in many types of solid tumors.

Cited by 26 publications

References 48 publications

HIC1 Expression Distinguishes Intestinal Carcinomas Sensitive to Chemotherapy

HIC1 Expression Distinguishes Intestinal Carcinomas Sensitive to Chemotherapy

The tumor suppressor Hic1 maintains chromosomal stability independent of Tp53

Responses of Bovine Innate Immunity to Mycobacterium avium subsp. paratuberculosis Infection Revealed by Changes in Gene Expression and Levels of MicroRNA

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