ITIH5, a novel member of the inter-α-trypsin inhibitor heavy chain family is downregulated in breast cancer

Himmelfarb, Marina; Klopocki, Eva; Grube, Susanne; Staub, Eike; Klaman, Irina; Hinzmann, Bernd; Kristiansen, Glen; Rosenthal, André; Dürst, Matthias; Dahl, Edgar

doi:10.1016/j.canlet.2003.09.011

Cited by 73 publications

(96 citation statements)

References 17 publications

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“…Furthermore, several lines of evidence suggest a potential role of ITIs in tumour biology, particularly in the metastatic cascade and tumour progression (Kobayashi et al, 1995;Bourguignon et al, 1999;Paris et al, 2002;Zhang et al, 2004). We have previously described cloning and RNA expression analysis of a novel member of the ITIH gene family, ITIH5, in normal and malignant breast tissues (Himmelfarb et al, 2004). We have now generated a polyclonal anti-ITIH5 antibody to evaluate ITIH5 expression at the protein level employing a comprehensive TMA.…”

Section: Discussionmentioning

confidence: 99%

“…After cloning, mapping and determination of its genomic organization, we analysed the expression of ITIH5 at the messenger RNA level in a panel of normal human tissues and a small set of normal and malignant breast tissue samples. Initial analyses showed that ITIH5 was predominantly expressed in human female reproductive tissues and strongly downregulated in breast tumours, suggesting a potential role in breast cancer development (Himmelfarb et al, 2004). In the present study, protein expression of ITIH5 was analysed in a large set of breast tumours using tissue microarrays (TMAs).…”

Section: Introductionmentioning

confidence: 95%

“…Reduced proliferation rates of MDA-MB-231 breast cancer cells after forced expression of ITIH5 A full-length ITIH5 cDNA derived from normal breast tissue was cloned into the eukaryotic expression vector pBK-CMV (Himmelfarb et al, 2004). A proliferation assay was performed for two independent ITIH5-transfected clones in MDA-MB-231 cells and two independent mock-transfected clones using XTT (2,3-Bis(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide) assays (Figure 6).…”

Section: Itih5 Downregulation In Breast Cancer Is Caused By Promoter mentioning

confidence: 99%

“…This formation of ITIH-HA complexes is thought to play an important role in the stabilization of HA-rich extracellular matrices, with TNFAIP6 acting as an essential cofactor and catalyst (Rugg et al, 2005). To date, five distinct ITIHs have been identified, encoded by five genes located on two different chromosomes (DiarraMehrpour et al, 1989;Himmelfarb et al, 2004). ITIH1, -3 and -4 have been mapped to chromosome 3p2.11-12, and ITIH2 and -5 are located on chromosome 10p14-15 (Bost et al, 1998;Himmelfarb et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

“…To date, five distinct ITIHs have been identified, encoded by five genes located on two different chromosomes (DiarraMehrpour et al, 1989;Himmelfarb et al, 2004). ITIH1, -3 and -4 have been mapped to chromosome 3p2.11-12, and ITIH2 and -5 are located on chromosome 10p14-15 (Bost et al, 1998;Himmelfarb et al, 2004). ITIH1, -2 and -3 are synthesized primarily in liver as polypeptide precursors, which undergo extensive post-translational processing; they all contain a conserved cleavage site, which enables them to form covalent bonds to bikunin via glycosaminoglycan (Enghild et al, 1991).…”

Section: Introductionmentioning

confidence: 99%

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The extracellular matrix protein ITIH5 is a novel prognostic marker in invasive node-negative breast cancer and its aberrant expression is caused by promoter hypermethylation

et al. 2007

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Inter-a-trypsin inhibitors (ITIs) are protease inhibitors stabilizing the extracellular matrix. ITIs consist of one light (bikunin) and two heavy chains (ITIHs). We have recently characterized ITIH5, a novel member of the ITIH gene family, and showed that its messenger RNA is lost in a high proportion of breast tumours. In the present study, an ITIH5-specific polyclonal antibody was generated, validated with western blot and used for immunohistochemical analysis on a tissue microarray; ITIH5 was strongly expressed in epithelial cells of normal breast (n ¼ 11/15), while it was lost or strongly reduced in 42% (92/217) of invasive breast cancers. ITIH5 expression in invasive carcinomas was associated with positive expression of oestrogen receptor (P ¼ 0.008) and histological grade (P ¼ 0.024). Correlation of ITIH5 expression with clinical outcome revealed that patients with primary tumours retaining abundant ITIH5 expression had longer recurrence-free survival (RFS; P ¼ 0.037) and overall survival (OS; P ¼ 0.044), compared to those with reduced expression (mean RFS: 102 vs 78 months; mean OS: 120 vs 105 months). Methylation-specific PCR analysis frequently showed strong methylation of the ITIH5 promoter in primary breast tumours (41%, n ¼ 109) and breast cancer cell lines (n ¼ 6). Methylation was significantly associated with mRNA loss (Po0.001; n ¼ 39), and ITIH5 expression was induced after treatment of tumour cell lines with the demethylating agent 5-aza-2 0 -deoxycytidine. Moreover, ITIH5 promoter methylation was significantly associated with reduced OS (P ¼ 0.008). The cellular function of ITIH5 was evaluated by forced expression of a full-length ITIH5 complementary DNA in the breast cancer cell line MDA-MB-231, which does not endogenously express ITIH5. ITIH5-expressing clones showed a 40% reduced proliferation rate compared to mock-transfected cells. Overall, these data show that promoter methylation-mediated loss of ITIH5 expression is associated with unfavourable outcome in breast cancer patients, and thus ITIH5 could be used as a prognostic marker, although this marker is not multivariate independent due to its close association with ER expression. Our data indicate that ITIH5 is a candidate class II tumour suppressor gene and could be involved in tumour progression, invasion and metastasis, as its absence is associated with increased proliferation rates and a prognostic value indicating poor clinical outcome.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 95%

Section: Itih5 Downregulation In Breast Cancer Is Caused By Promoter mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The extracellular matrix protein ITIH5 is a novel prognostic marker in invasive node-negative breast cancer and its aberrant expression is caused by promoter hypermethylation

et al. 2007

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ITIH5 as a multifaceted player in pancreatic cancer suppression, impairing tyrosine kinase signaling, cell adhesion and migration

Kosinski,

Sechi,

Hain

et al. 2024

Molecular Oncology

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Inter‐alpha‐trypsin inhibitor heavy chain 5 (ITIH5) has been identified as a metastasis suppressor gene in pancreatic cancer. Here, we analyzed ITIH5 promoter methylation and protein expression in The Cancer Genome Atlas (TCGA) dataset and three tissue microarray cohorts (n = 618), respectively. Cellular effects, including cell migration, focal adhesion formation and protein tyrosine kinase activity, induced by forced ITIH5 expression in pancreatic cancer cell lines were studied in stable transfectants. ITIH5 promoter hypermethylation was associated with unfavorable prognosis, while immunohistochemistry demonstrated loss of ITIH5 in the metastatic setting and worsened overall survival. Gain‐of‐function models showed a significant reduction in migration capacity, but no alteration in proliferation. Focal adhesions in cells re‐expressing ITIH5 exhibited a smaller and more rounded phenotype, typical for slow‐moving cells. An impressive increase of acetylated alpha‐tubulin was observed in ITIH5‐positive cells, indicating more stable microtubules. In addition, we found significantly decreased activities of kinases related to focal adhesion. Our results indicate that loss of ITIH5 in pancreatic cancer profoundly affects its molecular profile: ITIH5 potentially interferes with a variety of oncogenic signaling pathways, including the PI3K/AKT pathway. This may lead to altered cell migration and focal adhesion formation. These cellular alterations may contribute to the metastasis‐inhibiting properties of ITIH5 in pancreatic cancer.

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Alpha‐2‐Heremans‐Schmid‐glycoprotein (AHSG) a potential biomarker associated with prognosis of chromophobe renal cell carcinoma: The PROPOLIS study

2022

Health Science Reports

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Background and Aims Chromophobe renal cell carcinoma (chRCC) is the third common pathological subtype in renal cancers. However, the underlying mechanisms of specific genetic characteristics of chRCC are currently unclear. In this study, protein expression profiles, gene ontology (GO), and survival plots were provided by integrated bioinformatics analysis to investigate key genes associated with the mechanism of tumorigenesis and prognosis of chRCC. Methods The chRCC data set of gene expression profiles and clinical data were obtained from the gdc‐client ( https://portal.gdc.cancer.gov ) deposited on The Cancer Genome Atlas (TCGA) data portal. Differentially expressed genes (DEGs) in chRCC, compared with normal samples, were analyzed by R packages “DESeq2,” “edgeR,” and “limma.” Heat maps, volcano plots, and principal component analysis (PCA) were performed for integrated analyses. GUniGO, mutant analysis, and survival plots were performed by R packages. A protein–protein interaction (PPI) network was generated and analyzed by R packages, online String software, and Cytoscape software. Survival analysis and gene expressing comparison in tumor and normal samples were used to detect the core genes of chRCC. Furthermore, the top interacting proteins were reanalyzed. Results A total of 306 upregulated genes and 678 downregulated genes were identified by a Venn diagram. Ten hub genes were extracted from PPI network. Furthermore, Alpha‐2‐Heremans‐Schmid‐glycoprotein (AHSG), one of 10 hub genes, was found to be associated with chRCC, and had a big difference in expression between survival and dead events. AHSG could predict potential prognostic and may be a diagnostic biomarker in chRCC. Conclusion This study illustrated that AHSG may be a potential therapeutic target and prognostic genetic marker for chRCC.

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ITIH5, a novel member of the inter-α-trypsin inhibitor heavy chain family is downregulated in breast cancer

Cited by 73 publications

References 17 publications

The extracellular matrix protein ITIH5 is a novel prognostic marker in invasive node-negative breast cancer and its aberrant expression is caused by promoter hypermethylation

The extracellular matrix protein ITIH5 is a novel prognostic marker in invasive node-negative breast cancer and its aberrant expression is caused by promoter hypermethylation

ITIH5 as a multifaceted player in pancreatic cancer suppression, impairing tyrosine kinase signaling, cell adhesion and migration

Alpha‐2‐Heremans‐Schmid‐glycoprotein (AHSG) a potential biomarker associated with prognosis of chromophobe renal cell carcinoma: The PROPOLIS study

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