Epigenetic inactivation of the novel candidate tumor suppressor gene<i>ITIH5</i>in colon cancer predicts unfavorable overall survival in the CpG island methylator phenotype

Kloten, Vera; Rose, Michael; Kaspar, Sophie; Stillfried, Saskia von; Knüchel, Ruth; Dahl, Edgar

doi:10.4161/epi.32089

Cited by 29 publications

(52 citation statements)

References 44 publications

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“…These observations are consistent with the results by Rose et al in a human bladder cancer cell line [34]. However, in vitro growth of colon and breast cancer cell lines in which ITIH5 was over-expressed has been observed [30, 35]. The suppressive effects of ITIH5 may be cell/tissue-type specific.…”

Section: Discussionsupporting

confidence: 90%

“…Recent examination of the ITIH5 promoter in circulating free DNA in serum suggests that ITIH5 may be a biomarker for early breast cancer detection [31]. Down-regulation of ITIH5 due to the promoter hypermethylation is associated with progression of acute myeloid leukemia, squamous cell carcinoma of the tongue, bladder carcinoma, and colon cancers [32-35]. Decreased ITIH5 expression is also associated with development of thyroid and gastric cancers [36, 37].…”

Section: Discussionmentioning

confidence: 99%

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Genome-wide in vivo RNAi screen identifies ITIH5 as a metastasis suppressor in pancreatic cancer

Sasaki

Kurahara

Young

et al. 2017

Clin Exp Metastasis

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The overwhelming majority of pancreatic ductal adenocarcinoma (PDAC) is not diagnosed until the cancer has metastasized, leading to an abysmal average life expectancy (3-6 months post-diagnosis). Earlier detection and more effective treatments have been hampered by inadequate understanding of the underlying molecular mechanisms controlling metastasis. We hypothesized that metastasis suppressors are involved in controlling metastasis in pancreatic cancer. Using an unbiased genome-wide shRNA screen, an shRNA library was transduced into the non-metastatic PDAC line S2-028 followed by intrasplenic injection. Resulting liver metastases were individually isolated from these mice. One liver metastatic nodule contained shRNA for ITIH5 (Inter-alpha-trypsin inhibitor heavy chain 5), suggesting that ITIH5 may act as a metastasis suppressor. Consistent with this notion, metastatic PDAC cell lines had significantly lower protein expression of ITIH5 compared to immortalized pancreatic ductal epithelial cells and non-/poorly-metastatic PDAC cell lines. By manipulating expression of ITIH5 in different PDAC cell lines (over-expression in metastatic, knockdown in non-metastatic) functional and selective regulation of metastasis was observed for ITIH5. Orthotopic tumor growth of PDAC cells was not blocked following orthotopic injection. In vitro ITIH5 over-expression inhibited motility and invasion. Immunohistochemical analysis of a human PDAC tissue microarray revealed that ITIH5 expression inversely correlated with both survival and invasion/metastasis. ITIH5 is, therefore, functionally validated as a PDAC metastasis suppressor and shows promise as a prognostic biomarker.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Genome-wide in vivo RNAi screen identifies ITIH5 as a metastasis suppressor in pancreatic cancer

Sasaki

Kurahara

Young

et al. 2017

Clin Exp Metastasis

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“…In a recent study, we showed that ITIH5 promoter hypermethylation is the molecular cause for ITIH5 gene silencing in breast 13 , colon, 14 and bladder 15 cancer, which was associated with unfavorable patients' outcome. To investigate the biological relevance of ITIH5 in lung cancer we initially analyzed mRNA expression in 10 NSCLC tumor and 11 normal lung tissues by real-time PCR.…”

Section: Itih5 Expression Is Lost In Non-small-cell Lung Carcinomamentioning

confidence: 98%

“…In this context, suppressor function in breast 13 , colon,14 and bladder 15 cancer. Furthermore, the ITI heavy chains effectively stabilize the ECM16 and have been shown to suppress processes such as tumor invasion17 and metastasis18 , while the biological relevance of ITIH5 in NSCLC has not been investigated yet.The present study is the first to show that expression of ITIH5 is clearly deregulated in NSCLC, providing evidence for a potential role as tumor suppressor particularly in adenocarcinoma of the lung.…”

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confidence: 98%

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Low expression of ITIH5 in adenocarcinoma of the lung is associated with unfavorable patients' outcome

et al. 2015

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Inter-α-trypsin inhibitor heavy chain 5 (ITIH5) is supposed to be involved in extracellular matrix stability and thus may play a key role in the inhibition of tumor progression. The current study is the first to analyze in depth ITIH5 expression and DNA methylation, as well as its potential clinical impact in non-small-cell lung carcinoma (NSCLC). We examined ITIH5 mRNA expression in tumor and adjacent normal lung tissue specimens of NSCLC patients. In addition, methylation frequency of the ITIH5 promoter was investigated using methylation-specific PCR and pyrosequencing. Significance of our data was validated by independent data sets from The Cancer Genome Atlas and the Kaplan-Meier Plotter platform. Furthermore, ITIH5 protein expression was evaluated by immunohistochemistry utilizing a tissue microarray with 385 distinct lung tissue samples. Based on our tissue collections, ITIH5 mRNA expression was significantly decreased in NSCLC compared to normal lung tissue in line with an increased methylation frequency in lung cancer tissue. Independent TCGA data confirmed significant expression loss of ITIH5 in lung cancer concordant with ITIH5 promoter hypermethylation in NSCLC. Of interest, low ITIH5 mRNA expression was particularly found in the magnoid and squamoid ADC expression subtype, concordant with an unfavorable patients' outcome in squamoid as well as tobacco smoking ADC patients. In conclusion, ITIH5 may be a novel putative tumor suppressor gene in NSCLC with a potential molecular significance in the squamoid ADC subtype and further clinical impact for risk stratification of adenocarcinoma patients. In addition, ITIH5 may serve as a novel biomarker for prognosis of tobacco smoking ADC patients.

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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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Epigenetic inactivation of the novel candidate tumor suppressor geneITIH5in colon cancer predicts unfavorable overall survival in the CpG island methylator phenotype

Cited by 29 publications

References 44 publications

Genome-wide in vivo RNAi screen identifies ITIH5 as a metastasis suppressor in pancreatic cancer

Genome-wide in vivo RNAi screen identifies ITIH5 as a metastasis suppressor in pancreatic cancer

Low expression of ITIH5 in adenocarcinoma of the lung is associated with unfavorable patients' outcome

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

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