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.

Role of the p16 tumor suppressor gene in cancer.

1998 ◽  
Vol 16 (3) ◽  
pp. 1197-1206 ◽  
Author(s):  
W H Liggett ◽  
D Sidransky
Keyword(s):  
Cell Cycle ◽  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Human Cancer ◽  
Suppressor Gene ◽  
Premalignant Lesions ◽  
Early Event ◽  
Cyclin Dependent Kinase ◽  
Primary Tumors

Since its discovery as a CDKI (cyclin-dependent kinase inhibitor) in 1993, the tumor suppressor p16 (INK4A/MTS-1/CDKN2A) has gained widespread importance in cancer. The frequent mutations and deletions of p16 in human cancer cell lines first suggested an important role for p16 in carcinogenesis. This genetic evidence for a causal role was significantly strengthened by the observation that p16 was frequently inactivated in familial melanoma kindreds. Since then, a high frequency of p16 gene alterations were observed in many primary tumors. In human neoplasms, p16 is silenced in at least three ways: homozygous deletion, methylation of the promoter, and point mutation. The first two mechanisms comprise the majority of inactivation events in most primary tumors. Additionally, the loss of p16 may be an early event in cancer progression, because deletion of at least one copy is quite high in some premalignant lesions. p16 is a major target in carcinogenesis, rivaled in frequency only by the p53 tumor-suppressor gene. Its mechanism of action as a CDKI has been elegantly elucidated and involves binding to and inactivating the cyclin D-cyclin-dependent kinase 4 (or 6) complex, and thus renders the retinoblastoma protein inactive. This effect blocks the transcription of important cell-cycle regulatory proteins and results in cell-cycle arrest. Although p16 may be involved in cell senescence, the physiologic role of p16 is still unclear. Future work will focus on studies of the upstream events that lead to p16 expression and its mechanism of regulation, and perhaps lead to better therapeutic strategies that can improve the clinical course of many lethal cancers.

scholarly journals PTPRM, a candidate tumor suppressor gene in small intestinal neuroendocrine tumors

2019 ◽  
Vol 8 (8) ◽  
pp. 1126-1135 ◽  
Author(s):  
Elham Barazeghi ◽  
Per Hellman ◽  
Gunnar Westin ◽  
Peter Stålberg
Keyword(s):  
Cell Growth ◽  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Cell Lines ◽  
Neuroendocrine Tumors ◽  
Tyrosine Phosphatase ◽  
Suppressor Gene ◽  
Cpg Methylation ◽  
Candidate Tumor Suppressor Gene ◽  
Small Intestinal

Small intestinal neuroendocrine tumors (SI-NETs) are small, slow growing neoplasms with loss of one copy of chromosome 18 as a common event. Frequently mutated genes on chromosome 18 or elsewhere have not been found so far. The aim of this study was to investigate a possible tumor suppressor role of the transmembrane receptor type tyrosine phosphatase PTPµ (PTPRM at 18p11) in SI-NETs. Immunohistochemistry, quantitative RT-PCR, colony formation assay and quantitative CpG methylation analysis by pyrosequencing were performed. Undetectable/very low levels of PTPRM or aberrant pattern of immunostaining, with both negative and positive areas, were detected in the majority of tumors (33/40), and a significantly reduced mRNA expression in metastases compared to primary tumors was observed. Both the DNA methylation inhibitor 5-aza-2′-deoxycytidine and the S-adenosylhomocysteine hydrolase inhibitor 3-deazaneplanocin A (DZNep) induced PTPRM expression in CNDT2.5 and KRJ-I SI-NET cells. CpG methylation of upstream regulatory regions, the promoter region and the exon 1/intron 1 boundary was detected by pyrosequencing analysis of the two cell lines and not in the analyzed SI-NETs. Overexpression of PTPRM in the SI-NET cell lines reduced cell growth and cell proliferation and induced apoptosis. The tyrosine phosphatase activity of PTPRM was not involved in cell growth inhibition. The results support a role for PTPRM as a dysregulated candidate tumor suppressor gene in SI-NETs and further analyses of the involved mechanisms are warranted.

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

Mutations in tumor suppressor gene, FBXW7, are associated with carboplatin resistance in endometrial cancer cell lines

2015 ◽  
Vol 139 (1) ◽  
pp. 194 ◽  
Author(s):  
Alexandre Buckley de Meritens ◽  
Ayesha Joshi ◽  
Christopher Miller ◽  
Lora Hedrick Ellenson ◽  
Divya Gupta
Keyword(s):  
Endometrial Cancer ◽  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cancer Cell Lines ◽  
Suppressor Gene ◽  
Endometrial Cancer Cell

scholarly journals Nkx2.5 Functions as a Conditional Tumor Suppressor Gene in Colorectal Cancer Cells via Acting as a Transcriptional Coactivator in p53-Mediated p21 Expression

2021 ◽  
Vol 11 ◽  
Author(s):  
Huili Li ◽  
Jiliang Wang ◽  
Kun Huang ◽  
Tao Zhang ◽  
Lu Gao ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Expression Pattern ◽  
Cell Lines ◽  
Suppressor Gene ◽  
Transcriptional Coactivator ◽  
Wild Type ◽  
Mutational Status ◽  
Sw480 Cells

NK2 homeobox 5 (Nkx2.5), a homeobox-containing transcription factor, is associated with a spectrum of congenital heart diseases. Recently, Nkx2.5 was also found to be differentially expressed in several kinds of tumors. In colorectal cancer (CRC) tissue and cells, hypermethylation of Nkx2.5 was observed. However, the roles of Nkx2.5 in CRC cells have not been fully elucidated. In the present study, we assessed the relationship between Nkx2.5 and CRC by analyzing the expression pattern of Nkx2.5 in CRC samples and the adjacent normal colonic mucosa (NCM) samples, as well as in CRC cell lines. We found higher expression of Nkx2.5 in CRC compared with NCM samples. CRC cell lines with poorer differentiation also had higher expression of Nkx2.5. Although this expression pattern makes Nkx2.5 seem like an oncogene, in vitro and in vivo tumor suppressive effects of Nkx2.5 were detected in HCT116 cells by establishing Nkx2.5-overexpressed CRC cells. However, Nkx2.5 overexpression was incapacitated in SW480 cells. To further assess the mechanism, different expression levels and mutational status of p53 were observed in HCT116 and SW480 cells. The expression of p21WAF1/CIP1, a downstream antitumor effector of p53, in CRC cells depends on both expression level and mutational status of p53. Overexpressed Nkx2.5 could elevate the expression of p21WAF1/CIP1 only in CRC cells with wild-type p53 (HCT116), rather than in CRC cells with mutated p53 (SW480). Mechanistically, Nkx2.5 could interact with p53 and increase the transcription of p21WAF1/CIP1 without affecting the expression of p53. In conclusion, our findings demonstrate that Nkx2.5 could act as a conditional tumor suppressor gene in CRC cells with respect to the mutational status of p53. The tumor suppressive effect of Nkx2.5 could be mediated by its role as a transcriptional coactivator in wild-type p53-mediated p21WAF1/CIP1 expression.

scholarly journals Functional evidence for a second tumor suppressor gene on human chromosome 17

1994 ◽  
Vol 14 (1) ◽  
pp. 534-542
Author(s):  
P Chen ◽  
N Ellmore ◽  
B E Weissman
Keyword(s):  
Tumor Suppressor ◽  
Cell Line ◽  
Tumor Suppressor Gene ◽  
Cell Lines ◽  
Suppressor Gene ◽  
Chromosome 17 ◽  
Hybrid Cells ◽  
Tumorigenic Potential ◽  
Normal Human ◽  
Second Tumor

The development and progression of human tumors often involves inactivation of tumor suppressor gene function. Observations that specific chromosome deletions correlate with distinct groups of cancer suggest that some types of tumors may share common defective tumor suppressor genes. In support of this notion, our initial studies showed that four human carcinoma cell lines belong to the same complementation group for tumorigenic potential. In this investigation, we have extended these studies to six human soft tissue sarcoma cell lines. Our data showed that hybrid cells between a peripheral neuroepithelioma (PNET) cell line and normal human fibroblasts or HeLa cells were nontumorigenic. However, hybrid cells between the PNET cell line and five other soft tissue sarcoma cell lines remained highly tumorigenic, suggesting at least one common genetic defect in the control of tumorigenic potential in these cells. To determine the location of this common tumor suppressor gene, we examined biochemical and molecular polymorphic markers in matched pairs of tumorigenic and nontumorigenic hybrid cells between the PNET cell line and a normal human fibroblast. The data showed that loss of the fibroblast-derived chromosome 17 correlated with the conversion from nontumorigenic to tumorigenic cells. Transfer of two different chromosome 17s containing a mutant form of the p53 gene into the PNET cell line caused suppression of tumorigenic potential, implying the presence of a second tumor suppressor gene on chromosome 17.

scholarly journals Alterations of the p53 tumor suppressor gene in diffuse large cell lymphomas with translocations of the c-MYC and BCL-2 proto-oncogenes

Blood ◽  
1994 ◽  
Vol 83 (1) ◽  
pp. 191-198 ◽  
Author(s):  
MM Farrugia ◽  
LJ Duan ◽  
MD Reis ◽  
BY Ngan ◽  
NL Berinstein
Keyword(s):  
Tumor Suppressor ◽  
Cell Line ◽  
Tumor Suppressor Gene ◽  
Cell Lines ◽  
Cell Lymphoma ◽  
Large Cell ◽  
Suppressor Gene ◽  
Diffuse Large Cell Lymphoma ◽  
P53 Tumor Suppressor Gene ◽  
Large Cell Lymphoma

Abstract Diffuse large cell lymphomas are aggressive tumors of B-cell origin. In some cases they arise from low-grade follicular lymphomas carrying the t(14;18) translocation, an event that leads to the overexpression of the BCL-2 gene product. More frequently, however, they lack the t(14;18) translocation. Rearrangements of the c-MYC proto-oncogene and mutations of the p53 tumor suppressor gene have also been documented in these lymphomas. This study examines the extent to which alterations in the BCL-2, c-MYC, and p53 genes co-exist within individual lymphomas. Eight diffuse large cell lymphoma cell lines and 11 diffuse large cell lymphoma tumors were assessed for genetic alterations in these three genes. Our results indicate that there is a heterogeneity in the oncogene/suppressor gene profile among diffuse large cell lymphomas. Two cell lines and one tumor carried alterations in all three genes, one cell line carried alterations of c-MYC and p53, and one primary tumor and one cell line carried p53 mutations and the t(14;18). Single alterations of BCL-2 and p53 were also observed. Another cell line had no alterations in any of these genes. The heterogeneity indicates that varied mechanisms may be involved in the generation of diffuse large cell lymphomas.

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