scholarly journals Promoter methylation-mediated repression of UNC5 receptors and the associated clinical significance in human colorectal cancer

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Dong Dong ◽  
Runshi Zhang ◽  
Jie Shao ◽  
Aimin Zhang ◽  
Yichao Wang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Tumor Suppressor ◽  
Clinical Significance ◽  
Cell Lines ◽  
Tumor Suppressor Genes ◽  
Epigenetic Alterations ◽  
Suppressor Genes ◽  
Kaplan Meier

Abstract Background Deregulated methylation of tumor suppressor genes is a hallmark event in colorectal cancer (CRC) carcinogenesis. UNC5 receptors, down-regulated in various human malignancies due to epigenetic alterations, have been proposed as putative tumor suppressor genes. In this study, we focused on the methylation-mediated inhibition of UNC5 receptors and the associated clinical significance in CRC. Methods Methylation and expression analysis was performed in TCGA datasets. And the results were confirmed in vitro in CRC cell lines treated with 5-aza-deoxycytidine. Then, the expression and epigenetic alterations of UNC5 receptors were evaluated in clinical specimens. Moreover, the diagnostic and prognostic values of the methylation alterations were also analyzed. Results Methylation-mediated repression was observed in UNC5C and UNC5D, but not in UNC5A and UNC5B, which was confirmed in CRC cell lines. Except for UNC5B, significantly elevated methylation was observed in UNC5A, UNC5C, and UNC5D in CRC. The discrimination efficiency of the three receptors was comparable with that of SEPT9. Kaplan–Meier curve survival analysis showed that hypermethylation of UNC5A, UNC5C and UNC5D was associated with poor progression-free and overall survival. Moreover, methylation levels of UNC5C and UNC5D were independent predictors of CRC progression-free (P = 0.001, P = 0.003, respectively) and overall survival (P = 0.008, P = 0.004, respectively). Conclusions Hypermethylation of UNC5C and UNC5D mediates the repression and has promising diagnostic and prognostic values in CRC.

Progression of colorectal cancer is associated with multiple tumor suppressor gene defects but inhibition of tumorigenicity is accomplished by correction of any single defect via chromosome transfer

1992 ◽  
Vol 12 (3) ◽  
pp. 1387-1395
Author(s):  
M C Goyette ◽  
K Cho ◽  
C L Fasching ◽  
D B Levy ◽  
K W Kinzler ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Suppressor ◽  
Tumor Suppressor Genes ◽  
Loss Of Function ◽  
Chromosome 18 ◽  
Chromosome 5 ◽  
Suppressor Genes ◽  
Single Defect

Carcinogenesis is a multistage process that has been characterized both by the activation of cellular oncogenes and by the loss of function of tumor suppressor genes. Colorectal cancer has been associated with the activation of ras oncogenes and with the deletion of multiple chromosomal regions including chromosomes 5q, 17p, and 18q. Such chromosome loss is often suggestive of the deletion or loss of function of tumor suppressor genes. The candidate tumor suppressor genes from these regions are, respectively, MCC and/or APC, p53, and DCC. In order to further our understanding of the molecular and genetic mechanisms involved in tumor progression and, thereby, of normal cell growth, it is important to determine whether defects in one or more of these loci contribute functionally in the progression to malignancy in colorectal cancer and whether correction of any of these defects restores normal growth control in vitro and in vivo. To address this question, we have utilized the technique of microcell-mediated chromosome transfer to introduce normal human chromosomes 5, 17, and 18 individually into recipient colorectal cancer cells. Additionally, chromosome 15 was introduced into SW480 cells as an irrelevant control chromosome. While the introduction of chromosome 17 into the tumorigenic colorectal cell line SW480 yielded no viable clones, cell lines were established after the introduction of chromosomes 15, 5, and 18. Hybrids containing chromosome 18 are morphologically similar to the parental line, whereas those containing chromosome 5 are morphologically distinct from the parental cell line, being small, polygonal, and tightly packed. SW480-chromosome 5 hybrids are strongly suppressed for tumorigenicity, while SW480-chromosome 18 hybrids produce slowly growing tumors in some of the animals injected. Hybrids containing the introduced chromosome 18 but was significantly reduced in several of the tumor reconstitute cell lines. Introduction of chromosome 5 had little to no effect on responsiveness, whereas transfer ot chromosome 18 restored responsiveness to some degree. Our findings indicate that while multiple defects in tumor suppressor genes seem to be required for progression to the malignant state in colorectal cancer, correction of only a single defect can have significant effects in vivo and/or in vitro.

scholarly journals Progression of colorectal cancer is associated with multiple tumor suppressor gene defects but inhibition of tumorigenicity is accomplished by correction of any single defect via chromosome transfer.

1992 ◽  
Vol 12 (3) ◽  
pp. 1387-1395 ◽  
Author(s):  
M C Goyette ◽  
K Cho ◽  
C L Fasching ◽  
D B Levy ◽  
K W Kinzler ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Suppressor ◽  
Tumor Suppressor Genes ◽  
Loss Of Function ◽  
Chromosome 18 ◽  
Chromosome 5 ◽  
Suppressor Genes ◽  
Single Defect

Carcinogenesis is a multistage process that has been characterized both by the activation of cellular oncogenes and by the loss of function of tumor suppressor genes. Colorectal cancer has been associated with the activation of ras oncogenes and with the deletion of multiple chromosomal regions including chromosomes 5q, 17p, and 18q. Such chromosome loss is often suggestive of the deletion or loss of function of tumor suppressor genes. The candidate tumor suppressor genes from these regions are, respectively, MCC and/or APC, p53, and DCC. In order to further our understanding of the molecular and genetic mechanisms involved in tumor progression and, thereby, of normal cell growth, it is important to determine whether defects in one or more of these loci contribute functionally in the progression to malignancy in colorectal cancer and whether correction of any of these defects restores normal growth control in vitro and in vivo. To address this question, we have utilized the technique of microcell-mediated chromosome transfer to introduce normal human chromosomes 5, 17, and 18 individually into recipient colorectal cancer cells. Additionally, chromosome 15 was introduced into SW480 cells as an irrelevant control chromosome. While the introduction of chromosome 17 into the tumorigenic colorectal cell line SW480 yielded no viable clones, cell lines were established after the introduction of chromosomes 15, 5, and 18. Hybrids containing chromosome 18 are morphologically similar to the parental line, whereas those containing chromosome 5 are morphologically distinct from the parental cell line, being small, polygonal, and tightly packed. SW480-chromosome 5 hybrids are strongly suppressed for tumorigenicity, while SW480-chromosome 18 hybrids produce slowly growing tumors in some of the animals injected. Hybrids containing the introduced chromosome 18 but was significantly reduced in several of the tumor reconstitute cell lines. Introduction of chromosome 5 had little to no effect on responsiveness, whereas transfer ot chromosome 18 restored responsiveness to some degree. Our findings indicate that while multiple defects in tumor suppressor genes seem to be required for progression to the malignant state in colorectal cancer, correction of only a single defect can have significant effects in vivo and/or in vitro.

Efficient one-pot synthesis of trans-Pt(ii)(salicylaldimine)(4-picoline)Cl complexes: effective agents for enhanced expression of p53 tumor suppressor genes

2015 ◽  
Vol 44 (21) ◽  
pp. 9872-9880 ◽  
Author(s):  
Faiz-Ur Rahman ◽  
Amjad Ali ◽  
Rong Guo ◽  
Wei-Kun Wang ◽  
Hui Wang ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Cell Lines ◽  
Cancer Cell ◽  
Tumor Suppressor Genes ◽  
One Pot ◽  
Suppressor Genes ◽  
One Pot Synthesis ◽  
Enhanced Expression ◽  
Mcf 7

One-pot synthesizedtrans-Pt(ii)(salicylaldimine)(4-picoline)Cl complexes showed promisingin vitrocytotoxicity in MCF-7 and A549 cancer cell lines.

Lenalidomide Inhibits Multiple Myeloma Cell Proliferation in Vitro Via Its Effect On Expression of Oncogenes and Tumor Suppressor Genes.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2855-2855
Author(s):  
Ling-Hua Zhang ◽  
Mary Adams ◽  
Jolanta Kosek ◽  
Peter H Schafer ◽  
J. Blake Bartlett
Keyword(s):  
Multiple Myeloma ◽  
Tumor Suppressor ◽  
Cyclin D1 ◽  
Cell Lines ◽  
Tumor Suppressor Genes ◽  
Inhibitory Effects ◽  
Drug Induced ◽  
Suppressor Genes ◽  
Baseline Levels

Abstract Abstract 2855 Poster Board II-831 Lenalidomide is an oral anti-proliferative and immunomodulatory drug. In combination with dexamethasone, it is indicated for the treatment of patients with multiple myeloma (MM) who have received at least one prior therapy. In this study we investigated direct antimyeloma effects of lenalidomide in vitro using a panel of human MM cell lines with various cytogenetic features and bone marrow cells from patients with active MM. We also assessed the effect of lenalidomide on expression of tumor suppressor and enhancer genes such as p21cip1, SPARC, ING1/4, p57kip2, p53, cyclin D1/2, IRF4/MUM1 and IRF8/ICSBP. At attainable plasma levels in treated patients, lenalidomide directly inhibited human MM cell proliferation. Lenalidomide strongly increased expression of tumor suppressor genes such as p21waf1/cip1, SPARC, IRF8, ING4 and p57kip2. In the MM cell lines tested, lenalidomide had partial but consistent inhibitory effects on expression of IRF4, an important MM survival factor. However, lenalidomide had no marked effect on expression of tumor enhancer genes such as VEGF, cyclin D1/2 and MAF or tumor suppressor genes such as ING1 and p53 in most lines of cells. This suggests that the antiproliferative effects of lenalidomide on MM cells may be related to the upregulation of some tumor suppressor gene expression. Statistical analyses show that the antiproliferative effect of lenalidomide is significantly correlated with the drug induced upregulation of SPARC and IRF8 expression (p=0.0016; p=0.012, respectively), but not with the drug induced changes of p21 (p> 0.05) and IRF4 expression (p> 0.05). Furthermore, the antiproliferative effect of lenalidomide was significantly correlated with the constitutive expression levels of cyclin D1 (p=0.021) and IRF4 (p=0.027), and inversely correlated with the constitutive level of cyclin D2 (p=0.041) in these MM cell lines. Using bone marrow myeloma cells from patients, we confirmed that the sensitivity of cells to lenalidomide was associated with SPARC and IRF8 upregulation and baseline levels of cyclin D1/2 and IRF4 expression. Using MM cell lines adapted to prolonged exposure (5 months) to lenalidomide, we found that cells became resistant to the drug in association with decreased baseline levels of cyclin D1 and IRF4. In conclusion, lenalidomide demonstrates direct inhibitory effects on proliferation various MM cells. These antimyeloma activities may help explain the clinical efficacy seen in patients treated with lenalidomide. Lenalidomide treatment of MM cells increased SPARC and IRF8 mRNA expression, whereas pre-treatment cyclin D1/2 and IRF4 mRNA levels were associated with increased sensitivity and may have prognostic potential for MM therapy with lenalidomide. Disclosures: Zhang: Celgene Corporation: Employment. Adams:Celgene Corporation: Employment. Kosek:Celgene Corporation: Employment. Schafer:Celgene Corporation: Employment. Bartlett:Celgene Corporation: Employment.

scholarly journals Patterns of somatic uniparental disomy identify novel tumor suppressor genes in colorectal cancer

2015 ◽  
Vol 36 (10) ◽  
pp. 1103-1110 ◽  
Author(s):  
Keyvan Torabi ◽  
Rosa Miró ◽  
Nora Fernández-Jiménez ◽  
Isabel Quintanilla ◽  
Laia Ramos ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Suppressor ◽  
Tumor Suppressor Genes ◽  
Uniparental Disomy ◽  
Suppressor Genes

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 tumor suppressor genes and deregulation of the c-myc gene in urothelial cancer cell lines

1995 ◽  
Vol 23 (5) ◽  
pp. 293-300 ◽  
Author(s):  
M.-O. Grimm ◽  
B. J�rgens ◽  
W. A. Schulz ◽  
K. Decken ◽  
D. Makri ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Cell Lines ◽  
Cancer Cell ◽  
Tumor Suppressor Genes ◽  
Urothelial Cancer ◽  
Cancer Cell Lines ◽  
Suppressor Genes ◽  
Myc Gene ◽  
Urothelial Cancer Cell

scholarly journals Screening of tumor suppressor genes on 1q31.1-32.1 in Chinese patients with sporadic colorectal cancer

2008 ◽  
Vol 121 (24) ◽  
pp. 2479-2486 ◽  
Author(s):  
Chong-zhi ZHOU ◽  
Guo-qiang QIU ◽  
Xiao-liang WANG ◽  
Jun-wei FAN ◽  
Hua-mei TANG ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Suppressor ◽  
Tumor Suppressor Genes ◽  
Chinese Patients ◽  
Sporadic Colorectal Cancer ◽  
Suppressor Genes
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