ITIH5 and ECRG4 DNA Methylation Biomarker Test (EI-BLA) for Urine-Based Non-Invasive Detection of Bladder Cancer

Rose, Michael; Bringezu, Sarah; Godfrey, Laura; Fiedler, David; Gaisa, Nadine T.; Koch, Maximilian; Bach, Christian; Füssel, S.; Herr, Alexander; Hübner, Doreen; Ellinger, Jörg; Pfister, David; Knüchel, Ruth; Wirth, Manfred P.; Böhme, Manja U.; Dahl, Edgar

doi:10.3390/ijms21031117

Cited by 19 publications

(18 citation statements)

References 42 publications

(59 reference statements)

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“…Several studies have shown that the ECRG4 promoter is frequently hypermethylated in patients with breast cancer, gastric cancer, and nasopharyngeal carcinoma, resulting in the downregulation of ECRG4 ( You et al, 2015 ; Deng et al, 2018 ; Tang et al, 2019 ). Consistent with a previous study that reported that ECRG4 is hypermethylated in BCa cells ( Rose et al, 2020 ), our results further demonstrated that ECRG4 is significantly downregulated in BCa tissues and cell lines. Furthermore, we observed that ECRG4 expression was positively correlated with OGN, which is a tumor suppressor in colorectal cancer and breast cancer ( Hu et al, 2018 ; Xu et al, 2019 ).…”

Section: Discussionsupporting

confidence: 93%

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ECRG4 Represses Cell Proliferation and Invasiveness via NFIC/OGN/NF-κB Signaling Pathway in Bladder Cancer

et al. 2020

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Bladder cancer (BCa) is a malignant tumor in the urinary system with high cancer-related mortality worldwide. However, the molecular mechanisms of many genes dysregulated in BCa are still unclear. Herein, we showed that esophageal cancer-related gene-4 (ECRG4), which is downregulated in BCa tissues and cell lines, has a positive correlation with osteoglycin (OGN). Further functional experimental studies suggested that both ECRG4 and OGN inhibit cell proliferation, migration, and invasion in BCa cells. Moreover, ECRG4 acts as a tumor repressor and promotes the expression of OGN via the upregulation of nuclear factor 1 C-type (NFIC), which can bind to the promoter region of OGN and regulate its transcription. Bioinformatics analysis revealed that NFIC is downregulated in BCa tissues and has a positive correlation with ECRG4 or OGN. Esophageal cancer-related gene-4 could positively regulate the protein levels of NFIC in BCa cells. In addition, we demonstrated for the first time that ECRG4 inhibits the nuclear factor (NF)-κB signaling pathway via the upregulation of OGN in BCa cells. Overall, these findings provide evidence that both ECRG4 and OGN function as tumor repressors and that overexpression of ECRG4 inhibits the NF-κB signaling pathway by promoting NFIC/OGN signaling in BCa cells. Our results reveal the molecular regulatory mechanisms of the ECRG4-mediated repression of the NFIC/OGN/NF-κB signaling pathway in BCa and provide potential biomarkers or therapeutic targets for BCa.

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Section: Discussionsupporting

confidence: 93%

“…To date, many studies have focused on the upstream epigenetic regulation of ECRG4 and the promoter region of ECRG4, which is frequently hypermethylated in cancers, including BCa (Rose et al, 2020). However, few studies have been reported regarding the downstream regulation mechanism of ECRG4.…”

Section: Introductionmentioning

confidence: 99%

ECRG4 Represses Cell Proliferation and Invasiveness via NFIC/OGN/NF-κB Signaling Pathway in Bladder Cancer

et al. 2020

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“…Thus, ITIH5 might be of interest to develop novel panels of predictive biomarkers helping to stratify bladder cancer patients for (neo)adjuvant treatment. ITIH5 DNA methylation, which was shown to be useful as biomarker to detect bladder cancer via urine [ 24 ], may further hold information for predicting chemo-response of bladder cancer patients.…”

Section: Discussionmentioning

confidence: 99%

“…In bladder carcinogenesis, we previously demonstrated epigenetic inactivation of ITIH5 associated with advanced tumor stages predicting unfavorable prognosis of patients diagnosed with a papillary (pT1) urothelial high-grade tumor [ 20 ]. ITIH5 promoter methylation was also characterized as putative biomarker for non-invasive detection of breast [ 23 ] and bladder cancer [ 24 ] via plasma and urine samples, respectively.…”

Section: Introductionmentioning

confidence: 99%

The ECM Modulator ITIH5 Affects Cell Adhesion, Motility and Chemotherapeutic Response of Basal/Squamous-Like (BASQ) Bladder Cancer Cells

Rose

Noetzel

Kistermann

et al. 2021

Cells

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This study aims at characterizing the role of the putative tumor suppressor ITIH5 in basal-type bladder cancers (BLCA). By sub-classifying TCGA BLCA data, we revealed predominant loss of ITIH5 expression in the basal/squamous-like (BASQ) subtype. ITIH5 expression inversely correlated with basal-type makers such as KRT6A and CD44. Interestingly, Kaplan–Meier analyses showed longer recurrence-free survival in combination with strong CD44 expression, which is thought to mediate ITIH-hyaluronan (HA) binding functions. In vitro, stable ITIH5 overexpression in two basal-type BLCA cell lines showing differential CD44 expression levels, i.e., with (SCaBER) and without squamous features (HT1376), demonstrated clear inhibition of cell and colony growth of BASQ-type SCaBER cells. ITIH5 further enhanced HA-associated cell-matrix attachment, indicated by altered size and number of focal adhesion sites resulting in reduced cell migration capacities. Transcriptomic analyses revealed enrichment of pathways and processes involved in ECM organization, differentiation and cell signaling. Finally, we provide evidence that ITIH5 increase sensitivity of SCaBER cells to chemotherapeutical agents (cisplatin and gemcitabine), whereas responsiveness of HT1376 cells was not affected by ITIH5 expression. Thus, we gain further insights into the putative role of ITIH5 as tumor suppressor highlighting an impact on drug response potentially via the HA-CD44 axis in BASQ-type BLCA.

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“…15 It has been clarified that promoter methylation of the tumor suppressor gene is often negatively correlated with its expression. 16 Demethylation treatment can significantly inhibit the malignant biological behavior of tumors. 17 The methylation degree of specific gene region is directly related to lymph node metastasis, TNM stage, tumor pathological classification and prognosis.…”

Section: Discussionmentioning

confidence: 99%

<p>Identification of High-Frequency Methylation Sites in RNF180 Promoter Region Affecting Expression and Their Relationship with Prognosis of Gastric Cancer</p>

Han¹,

Liu²,

Jing³

et al. 2020

CMAR

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Background: Ring finger protein 180 (RNF180) is a tumor suppressor gene regulated by promoter methylation. We previously demonstrated that the RNF180 promoter methylation could be a risk factor for gastric cancer (GC); and eight high-frequency hypermethylated CpG sites were associated with GC. However, it is not clear whether these key sites can affect gene expression and involve in prognosis. The aim of this study was to investigate the effects of above CpG sites on the gene expression and prognosis of GC. Patients and Methods: A total of 164 GC tissues were enrolled and followed up. Tissue samples were used for DNA and RNA isolation. Methylation status of RNF180 was detected using bisulfite sequencing PCR (BSP). Expression levels of RNF180 were detected using quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR). JASPAR and PROMO databases were used to predict the transcription factors (TFs) binding to the CpG site. Results: The methylation in RNF180 promoter region increased and mRNA expression decreased in GC tissue. Correlation analysis revealed that the average methylation rate (AMR) and four CpG sites methylation rate were negatively related to RNF180 expression, including M3(−165) (Chr5:64165942), M5(−148)(Chr5:64,165,959), M7(−133)(Chr5:64,165,974) and M8(−130) (Chr5:64,165,977). Furthermore, the methylation rate of M5(−148)(Chr5:64,165,959) and M27 (−26)(Chr5:64,166,081) above 0.3 indicated poor prognosis (P M5 = 0.008, P M27 = 0.003, HR M5(−148) = 2.000 (1.201,3.332), HR M27(−26) =2.389 (1.336,4.271)), which could be independent factors of prognosis. Conclusion: By focusing on the methylation sites in the RNF180 promoter region, we identified two high-frequency methylation sites, M5(−148)(Chr5:64,165,959) and M27(−26) (Chr5:64,166,081), which could affect gene expression and predict the prognosis of GC. In the future, the possible molecular mechanism involved needs to be further studied.

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ITIH5 and ECRG4 DNA Methylation Biomarker Test (EI-BLA) for Urine-Based Non-Invasive Detection of Bladder Cancer

Cited by 19 publications

References 42 publications

ECRG4 Represses Cell Proliferation and Invasiveness via NFIC/OGN/NF-κB Signaling Pathway in Bladder Cancer

ECRG4 Represses Cell Proliferation and Invasiveness via NFIC/OGN/NF-κB Signaling Pathway in Bladder Cancer

The ECM Modulator ITIH5 Affects Cell Adhesion, Motility and Chemotherapeutic Response of Basal/Squamous-Like (BASQ) Bladder Cancer Cells

<p>Identification of High-Frequency Methylation Sites in RNF180 Promoter Region Affecting Expression and Their Relationship with Prognosis of Gastric Cancer</p>

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