Identification of cytokeratin24 as a tumor suppressor for the management of head and neck cancer

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Désirée Gül ◽  
Negusse Habtemichael ◽  
Dimo Dietrich ◽  
Jörn Dietrich ◽  
Dorothee Gößwein ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Head And Neck ◽  
Cell Lines ◽  
Drug Targets ◽  
Structural Integrity ◽  
Data Sets ◽  
Poor Overall Survival ◽  
Primary Tumors ◽  
Novel Target ◽  
Cell Signaling Networks

Abstract To improve management of head and neck squamous cell carcinoma patients, we need to increase our understanding of carcinogenesis, to identify biomarkers, and drug targets. This study aimed to identify novel biomarkers by providing transcriptomics profiles of matched primary tumors, lymph node metastasis, and non-malignant tissue of 20 HNSCC patients as well as by bioinformatic analyses of a TCGA HNSCC cohort, comprising 554 patients. We provide cancer cell signaling networks differentially expressed in tumors versus metastases, such as mesenchymal–epithelial transition, and structural integrity networks. As a proof of principle study, we exploited the data sets and performed functional analyses of a novel cytokeratin, cytokeratin24 (cKRT24), which had not been described as biomarker for tumors before. Survival analysis revealed that low cKRT24 expression correlated with poor overall survival in HNSCC. Experimentally, downregulation of cKRT24 in primary tumors, metastases, and HNSCC cell lines was verified on mRNA and protein level. Cloning and ectopic overexpression of cKRT24 not only affected viability and growth of HNSSC cell lines, but also inhibited tumor growth in murine xenograft studies. We conclude that cKRT24 functions as a tumor suppressor in HNSCC, and may serve as an additional prognostic biomarker and novel target to support current HNSCC treatments.

scholarly journals Promoter Methylation of RASSF1A Associates to Adult Secondary Glioblastomas and Pediatric Glioblastomas

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Jorge Muñoz ◽  
María del Mar Inda ◽  
Paula Lázcoz ◽  
Idoya Zazpe ◽  
Xing Fan ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Cell Lines ◽  
Tumor Suppressor Genes ◽  
Promoter Hypermethylation ◽  
Suppressor Genes ◽  
Primary Tumors ◽  
Specific Pcr ◽  
Inactivation Mechanism ◽  
Altered Gene ◽  
Homozygous Deletions

While allelic losses and mutations of tumor suppressor genes implicated in the etiology of astrocytoma have been widely assessed, the role of epigenetics is still a matter of study. We analyzed the frequency of promoter hypermethylation by methylation-specific PCR (MSP) in five tumor suppressor genes (PTEN, MGMT, RASSF1A, p14ARF, and p16INK4A), in astrocytoma samples and cell lines. RASSF1A was the most frequently hypermethylated gene in all grades of astrocytoma samples, in cell lines, and in adult secondary GBM. It was followed by MGMT. PTEN showed a slight methylation signal in only one GBM and one pilocytic astrocytoma, and in two cell lines; while p14ARF and p16INK4A did not show any evidence of methylation in primary tumors or cell lines. In pediatric GBM, RASSF1A was again the most frequently altered gene, followed by MGMT; PTEN, p14 and p16 showed no alterations. Lack or reduced expression of RASSF1A in cell lines was correlated with the presence of methylation. RASSF1A promoter hypermethylation might be used as a diagnostic marker for secondary GBM and pediatric GBM. Promoter hypermethylation might not be an important inactivation mechanism in other genes like PTEN, p14ARF and p16INK4A, in which other alterations (mutations, homozygous deletions) are prevalent.

Inactivation of p16INK4a in Primary Tumors and Cell Lines of Head and Neck Squamous Cell Carcinoma

2000 ◽  
Vol 10 (5) ◽  
pp. 557-565 ◽  
Author(s):  
Ho-Seok Kim ◽  
Woon-Bok Chung ◽  
Su-Hyung Hong ◽  
Jin-A Kim ◽  
Sun-Young Na ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Head And Neck ◽  
Cell Lines ◽  
Squamous Cell ◽  
Neck Squamous Cell Carcinoma ◽  
Primary Tumors

Cooperative Anti-Leukemic Effects of Imatinib and Mcl-1 Antisense: Identification of Mcl-1 as a Novel Target in CML.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2972-2972
Author(s):  
Karl J. Aichberger ◽  
Matthias Mayerhofer ◽  
Maria-Theresa Krauth ◽  
Hans Skvara ◽  
Stefan Florian ◽  
...  
Keyword(s):  
Cell Lines ◽  
Drug Targets ◽  
Kinase Inhibitor ◽  
Constitutive Expression ◽  
K562 Cells ◽  
Mek Inhibitor ◽  
Long Term Results ◽  
High Expectations ◽  
Novel Target ◽  
Transformed Cell Lines

Abstract The BCR-ABL tyrosine kinase inhibitor STI571 (Imatinib) has successfully been introduced in the treatment of patients with CML. However, despite encouraging initial data and high expectations long term results are not available yet, and recent data suggest that resistance against STI571 can occur. Therefore, current studies focus on novel potential drug targets in CML cells. Recently, several anti-apoptotic members of the Bcl-2-family including Mcl-1 have been implicated in the regulation of survival of BCR/ABL+ cell lines and therefore proposed as potential targets. We have examined expression of Mcl-1 in primary CML cells and various BCR/ABL-transformed cell lines. Independent of the phase of disease, isolated primary CML cells expressed Mcl-1 mRNA and the Mcl-1 protein in a constitutive manner. The BCR/ABL-inhibitor STI571 decreased the expression of Mcl-1 in these cells. Correspondingly, BCR/ABL enhanced Mcl-1 promoter activity, Mcl-1 mRNA, and Mcl-1 protein in Ba/F3 cells. BCR/ABL-dependent expression of Mcl-1 in Ba/F3 cells was counteracted by the MEK-inhibitor PD98059, but not by the PI3-kinase inhibitor LY294002. Identical results were obtained for constitutive expression of Mcl-1 in primary CML cells and the CML-derived cell lines K562 and KU812. To investigate the role of Mcl-1 as a survival-related target gene in CML cells, Mcl-1 siRNA or an Mcl-1 antisense oligonucleotide (ASO) were applied. Both the ASO and the siRNA-induced downregulation of Mcl-1 were found to be associated with a substantial decrease in viability of K562 cells. Moreover, the Mcl-1 ASO was found to cooperate with STI571 in producing growth-inhibition in both STI571-sensitive and STI571-resistant K562 cells. Together, our data identify Mcl-1 as a survival factor and novel target in CML. Whether this concept is of clinical significance remains to be determined in forthcoming clinical trials.

Lack of BRCA2 alterations in primary head and neck squamous cell carcinoma

1998 ◽  
Vol 119 (1) ◽  
pp. 21-25 ◽  
Author(s):  
H. Myra Nawroz-Danish ◽  
Wayne M. Koch ◽  
William H. Westra ◽  
George Yoo ◽  
David Sidransky
Keyword(s):  
Head And Neck Cancer ◽  
Head And Neck ◽  
Cell Lines ◽  
Neck Cancer ◽  
Squamous Cell ◽  
Brca2 Gene ◽  
Suppressor Gene ◽  
Primary Tumors ◽  
Exon 11 ◽  
Minimal Region

We previously demonstrated that loss of 13q occurred in greater than 50% of primary head and neck squamous cell carcinomas. Although the minimal region of loss at 13q14.1–14.3 included the Rb1 gene, Rb1 inactivation was found to be rare. To further investigate possible targets of 13q loss in head and neck cancer, 32 primary tumors were fine mapped by microsatellite analysis with the use of 10 new markers spanning the minimal region. Twenty-one (66%) of 32 tumors displayed loss of heterozygosity and once again the minimal region of loss was confirmed to be 13q14.1–14.3. In addition to 6 monosomies, 11 tumors had regions of loss that either selectively deleted (one tumor) or stretched into the BRCA2 region 13q12–13 (10 tumors). Therefore we pursued investigation of the BRCA2 gene by a coupled transcription and translation assay of its largest exon (exon 11; 4932 base pairs) to detect functional truncations indicative of mutation in 37 primary head and neck tumors with 13q loss. These tumors included 17 of the 32 tumors recently analyzed and 20 other tumors with 13q loss from a previous study. Additionally, we performed the transcription and translation assay on five head and neck cancer cell lines. We found no alterations in exon 11 of the BRCA2 gene in any of the tumors or cell lines suggesting that perhaps another tumor suppressor gene on 13q is involved in head and neck cancer. (Otolaryngol Head Neck Surg 1998; 119:21–5.)

Analysis of Transcriptomic Similarity between Osteosarcoma Cell Lines and Primary Tumors

Oncology ◽  
2020 ◽  
Vol 98 (11) ◽  
pp. 814-816
Author(s):  
Sai Batchu ◽  
Justin Lee Gold
Keyword(s):  
Gene Expression ◽  
Gene Ontology ◽  
Cell Lines ◽  
Disease Process ◽  
Published Data ◽  
Data Sets ◽  
Osteosarcoma Cell ◽  
Gene Ontology Analysis ◽  
Primary Tumors

<b><i>Background:</i></b> Osteosarcoma (OS) cell lines are commonly used to mimic tumors for in vitro experiments. The present study explores the resemblance of OS cell lines to OS primary tumors in regard to gene expression. <b><i>Methods:</i></b> Transcriptomic data were retrieved from published data sets for 18 primary tumor samples and 13 commonly used OS cell lines. Tumor purity was accounted for when correlating tumor and cell line gene expression. Differentially expressed genes between tumors and cell lines were discovered and gene ontology analysis was performed. <b><i>Results:</i></b> Certain commonly used cell lines, including NY, NOS1, and U2OS, display less resemblance to OS tumors than do other cell lines. For genes overexpressed in tumors, and consequently underexpressed in cell lines, gene ontology analysis enriched pathways related to cell-cell adhesion and stimulus detection. <b><i>Conclusion:</i></b> The pathways dysregulated between cell lines and tumors have been implicated in OS pathogenesis. Therefore, the findings suggest that the transcriptome of OS cell lines may not be completely representative of OS primary tumors’ gene expression and the disease process.

scholarly journals TCEB3C a putative tumor suppressor gene of small intestinal neuroendocrine tumors

2013 ◽  
Vol 21 (2) ◽  
pp. 275-284 ◽  
Author(s):  
Katarina Edfeldt ◽  
Tanveer Ahmad ◽  
Göran Åkerström ◽  
Eva Tiensuu Janson ◽  
Per Hellman ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Cell Lines ◽  
Suppressor Gene ◽  
Gene Copy ◽  
Cell Type ◽  
Primary Tumors ◽  
Cell Type Specific ◽  
Small Intestinal

Small intestinal neuroendocrine tumors (SI-NETs), formerly known as midgut carcinoids, are rare and slow-growing neoplasms. Frequent loss of one copy of chromosome 18 in primary tumors and metastases has been observed. The aim of the study was to investigate a possible role of TCEB3C (Elongin A3), currently the only imprinted gene on chromosome 18, as a tumor suppressor gene in SI-NETs, and whether its expression is epigenetically regulated. Primary tumors, metastases, the human SI-NET cell line CNDT2.5, and two other cell lines were included. Immunohistochemistry, gene copy number determination by PCR, colony formation assay, western blotting, real-time quantitative RT-PCR, RNA interference, and quantitative CpG methylation analysis by pyrosequencing were performed. A large majority of tumors (33/43) showed very low to undetectable Elongin A3 expression and as expected 89% (40/45) displayed one gene copy of TCEB3C. The DNA hypomethylating agent 5-aza-2′-deoxycytidine induced TCEB3C expression in CNDT2.5 cells, in primary SI-NET cells prepared directly after surgery, but not in two other cell lines. Also siRNA to DNMT1 and treatment with the general histone methyltransferase inhibitor 3-deazaneplanocin A induced TCEB3C expression in a cell type-specific way. CpG methylation at the TCEB3C promoter was observed in all analyzed tissues and thus not related to expression. Overexpression of TCEB3C resulted in a 50% decrease in clonogenic survival of CNDT2.5 cells, but not of control cells. The results support a putative role of TCEB3C as a tumor suppressor gene in SI-NETs. Epigenetic repression of TCEB3C seems to be tumor cell type-specific and involves both DNA and histone methylation.

scholarly journals Loss of expression of the candidate tumor suppressor gene ZAC in breast cancer cell lines and primary tumors

Oncogene ◽  
1999 ◽  
Vol 18 (27) ◽  
pp. 3979-3988 ◽  
Author(s):  
Benoit Bilanges ◽  
Annie Varrault ◽  
Eugenia Basyuk ◽  
Carmen Rodriguez ◽  
Abhijit Mazumdar ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Suppressor Gene ◽  
Breast Cancer Cell Lines ◽  
Primary Tumors ◽  
Candidate Tumor Suppressor Gene

EXTH-34. ION CHANNELS AS A THERAPEUTIC TARGET IN PAEDIATRIC HIGH-GRADE GLIOMAS

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi170-vi171
Author(s):  
Michaela Griffin ◽  
Stuart Smith ◽  
Raheela Khan ◽  
Surajit Basu ◽  
Joshua Branter
Keyword(s):  
Ion Channels ◽  
Cell Lines ◽  
Brain Tumours ◽  
Cell Cycle Control ◽  
Expression Patterns ◽  
Low Frequency ◽  
High Grade Glioma ◽  
Data Sets ◽  
High Grade ◽  
Poor Overall Survival

Abstract Pediatric Glioblastoma Multiforme (GBM) is a leading cause of CNS cancer-related death in children. The scarcity of treatments for GBM has opened the field to new pathways in adults, such as tumour treating fields(TTF). Studies have identified the clinical benefit of electrotherapy in combination with chemotherapeutics, however the mechanistic action is unclear. Increasing evidence suggests that ion channels not only regulate electrical signalling of excitable cells, but are also crucial in the development/progression of brain tumours. Ion channels are essential in cell-cycle control, invasion and migration of cancer cells, therefore presenting as valuable therapeutic targets. Candidate ion channel genes(ICG) associated with high-grade glioma (HGG) were identified via analysis of inhouse and publicly available data sets. Expression patterns of selected ICGs were assessed along with clinician correlations.. Protein and RNA expression of target ICGs was assessed in pGBM cell lines/ TMAs. Finally, the Human ClariomTMS array was used for whole transcriptome gene expression analysis of paediatric GBM cell lines treated with tumour treating fields or low frequency electrical fields via deep brain stimulating electrodes. Paediatric brain tumour cells were exposed to genetic and pharmacological manipulation of CLIC1 and CLIC4 ion channels individually or in combination. We have shown that HGG exhibit increased expression of CLIC4 and CLIC1 at protein and RNA levels in both publically available data sets and inhouse cell lines / TMAs. Clinical correlation determined that high CLIC4 and CLIC1 expression was associated with poor overall survival. Further to this, DNA array analysis revealed a downregulation of CLIC1 and CLIC4 ion channels genes in KNS42 cells when treated with electrotherapy compared to untreated cells. Inhibition of CLIC1 and CLIC4 reduces Cl- flux across cell membranes and reduces cell proliferation. These data provide rationale that manipulation of ICGs will reduce the capacity of childhood brain tumours to proliferate and invade.

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