The tumor suppressor gene DLEC1 is frequently silenced by DNA methylation in hepatocellular carcinoma and induces G1 arrest in cell cycle

e15097 Background: After deletion of 17p that removes the tumor suppressor gene (TSG) TP53, deletion of 8p is the next most common chromosome abnormality in hepatocellular carcinoma (HCC). However, 8p TSG are insufficiently defined. Methods: Integrated genomic analysis of HCC and non-malignant liver obtained at therapeutic segmentectomy from the same patients. Results: A minimally deleted region on 8p was identified by SNP array. This incorporated GATA4. Therefore, GATA4 was Sanger sequenced in paired HCC/non-malignant liver: recurrent somatic non-synonymous missense mutations were identified in exon 4 (V267M n=5) or exon 6 (S357T n=6, R362N n=2, T366R n=2). Biallelic abnormalities were deletion and mutation (n=6) or mutation and uniparental disomy (n=4), with mutation or deletion of at least one GATA4 allele in 29/47 (62%) of HCC cases. The other GATA4 exons were mutation free. Although missense mutation is not intrinsically expected to decrease GATA4 expression, GATA4 mRNA was significantly decreased in cases with mutation as well as deletion (p<0.01) compared to non-malignant liver or wild-type GATA4 HCC. GATA4 drives liver differentiation, and the biological significance of GATA4 deficiency was demonstrated by significant enrichment (49%) for liver differentiation genes (p<1.2exp-124, Benjamini corrected) amongst genes with decreased expression in HCC compared to non-malignant liver. From an oncogenesis perspective, the most important of these hepatocyte genes (e.g., HNF4A, CEBPD) antagonize MYC to terminate proliferation: GATA4 introduction (expression vector) into HCC cells containing mutated or deleted GATA4 (HepG2 and PLC respectively) restored HNF4A and CEBPD expression, suppressed MYC protein, upregulated p27/CDKN1B that mediates cell cycle exit by maturation and significantly decreased HCC proliferation without apoptosis. In objectively quantified immunohistochemical analyses (ImageIQ), HCC cases with GATA4 mutation/deletion had significantly increased MYC protein (p<0.05). Conclusions: 8p deletion/GATA4 mutation in HCC suppresses cell cycle exit by maturation, thus complementing 17p deletion that suppresses cell cycle exit by apoptosis.

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DNA Hypermethylation Modification Promotes the Development of Hepatocellular Carcinoma by Depressing the Tumor Suppressor Gene ZNF334

10.21203/rs.3.rs-1000528/v1 ◽

2021 ◽

Author(s):

Da-peng Sun ◽

Xiao-jie Gan ◽

Lei Liu ◽

Yuan Yang ◽

Dong-yang Ding ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Dna Methylation ◽

Tumor Suppressor ◽

Liver Cancer ◽

Tumor Suppressor Gene ◽

Clinical Evidence ◽

Early Stage ◽

Suppressor Gene ◽

Dna Hypermethylation ◽

Dysplastic Nodules

Abstract Background: DNA methylation plays a pivotal role in the development and progression of tumors, but studies focused on the dynamic changes of DNA methylation in the development of hepatocellular carcinoma (HCC) are rare. This manuscript is aimed to construct pre- and early DNA methylation maps of liver cancer of the same genetic background, as well as to reveal the mechanism of epigenetics regulating gene expression during the development of liver cancer, thus providing new targets and clinical evidence for early diagnosis and shedding lights on the precise treatment for liver cancer. Methods: The study includes 5 patients who were chronic hepatitis B virus infected, clinically diagnosed as primary liver cancer and pathologically diagnosed as early liver cancer with liver dysplastic nodules. Liver fibrosis tissues, dysplastic nodules and early HCC tissues from these patients have been used to measure DNA methylation. Results: We report significant differences in the DNA methylation spectrum of three types of tissues. In the early stage of HCC, DNA hypermethylation of tumor suppressor genes is predominant. Additionally, DNA hypermethylation in the early stage of HCC changes the binding of transcription factor P53 to the promoter of tumor suppressor gene ZNF334, and inhibits the expression of ZNF334 at the transcription level. Furthermore, through a series of in vivo and in vitro experiments, we have clarified the exacerbation effect of tumor suppressor gene ZNF334 deletion in the occurrence of HCC. Combined with clinical data, we found that the overall survival and disease-free survival of patients with high ZNF334 expression are longer than the lower one. Conclusions: We constructed a sequential map of DNA methylation modification during the occurrence of HCC, and clarified the biological function and regulatory mechanism of the tumor suppressor gene ZNF334, which is regulated by related DNA methylation sites, and also provide new targets and clinical evidence for the early diagnosis and precise treatment of liver cancer.

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Ionizing Radiation Induces Cell Cycle G1 Arrest and Tumor Suppressor Gene P16, P21, P27 Expression in Keloid Fibroblasts

International Journal of Radiation Oncology*Biology*Physics ◽

10.1016/j.ijrobp.2013.06.1662 ◽

2013 ◽

Vol 87 (2) ◽

pp. S629 ◽

Cited By ~ 2

Author(s):

J. Ji ◽

Y. Tian ◽

S. Ji ◽

L. Zhang ◽

Y. Zhu ◽

...

Keyword(s):

Cell Cycle ◽

Tumor Suppressor ◽

Ionizing Radiation ◽

Tumor Suppressor Gene ◽

Suppressor Gene ◽

G1 Arrest ◽

Keloid Fibroblasts

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Epigenetic inactivation of the tumor suppressor gene RIZ1 in hepatocellular carcinoma involves both DNA methylation and histone modifications

Journal of Hepatology ◽

10.1016/j.jhep.2010.05.012 ◽

2010 ◽

Vol 53 (5) ◽

pp. 889-895 ◽

Cited By ~ 45

Author(s):

Cuijuan Zhang ◽

Hiuming Li ◽

Yan Wang ◽

Wenjun Liu ◽

Qinghui Zhang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Dna Methylation ◽

Tumor Suppressor ◽

Tumor Suppressor Gene ◽

Histone Modifications ◽

Suppressor Gene ◽

Epigenetic Inactivation

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Neuroradiology Manifestations of Li-Fraumeni Syndrome: Epidemiology, Genetics, Imaging Findings, and Management

Neurographics ◽

10.3174/ng.2000003 ◽

2020 ◽

Vol 10 (4) ◽

pp. 228-235

Author(s):

S. Naganawa ◽

T. Donohue ◽

A. Capizzano ◽

Y. Ota ◽

J. Kim ◽

...

Keyword(s):

Cell Cycle ◽

Tumor Suppressor ◽

Tumor Suppressor Gene ◽

Soft Tissue Sarcomas ◽

Suppressor Gene ◽

Imaging Findings ◽

Li Fraumeni Syndrome ◽

Increased Risk ◽

Li Fraumeni ◽

Risk Of Cancer

Li-Fraumeni syndrome is a familial cancer predisposition syndrome associated with germline mutation of the tumor suppressor gene 53, which encodes the tumor suppressor p53 protein. Affected patients are predisposed to an increased risk of cancer development, including soft-tissue sarcomas, breast cancer, brain tumors, and adrenocortical carcinoma, among other malignancies. The tumor suppressor gene TP53 plays an important, complex role in regulating the cell cycle, collaborating with transcription factors and other proteins. The disruption of appropriate cell cycle regulation by mutated TP53 is considered to be the cause of tumorigenesis in Li-Fraumeni syndrome. Appropriate surveillance, predominantly by using MR imaging, is used for early malignancy screening in an effort to improve the survival rate among individuals who are affected. Patients with Li-Fraumeni syndrome are also at increased risk for neoplasm development after radiation exposure, and, therefore, avoiding unnecessary radiation in both the diagnostic and therapeutic settings is paramount. Here, we review the epidemiology, genetics, imaging findings, and the current standard surveillance protocol for Li-Fraumeni syndrome from the National Comprehensive Cancer Network as well as potential treatment options.Learning Objective: Describe the cause of second primary malignancy among patients with Li-Fraumeni syndrome.

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