Epigenetic and genetic alterations of PTEN in hepatocellular carcinoma

Wang, Li; Wang, Wenliang; Zhang, Yong; Guo, Shuangping; Zhang, Jing; Li, Qin-Long

doi:10.1111/j.1872-034x.2007.00042.x

Cited by 117 publications

(85 citation statements)

References 32 publications

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“…Indeed, cytosine-guanine dinucleotide islands in PTEN 5Ј-UTR were reported to be hypermethylated in HCC displaying low PTEN expression. 20 Consistent with these observations, HepG2 cells have a hypermethylated PTEN promoter and low PTEN expression as compared to HPHs, a feature reversed by DNA methyltransferase inhibitors. We and others also showed that histone deacetylase inhibitors stimulate PTEN mRNA expression in hepatocytes.…”

Section: Discussionsupporting

confidence: 69%

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Unsaturated fatty acids inhibit the expression of tumor suppressor phosphatase and tensin homolog (PTEN) via microRNA-21 up-regulation in hepatocytes

Vinciguerra¹,

et al. 2008

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P hosphatase and tensin homolog (PTEN) is a protein and phosphoinositide phosphatase originally identified as a tumor suppressor gene frequently mutated/deleted in human cancers. 1 Numerous studies have also strongly supported its role as a regulator of insulin/insulin-like growth factor 1 signaling. 2 In mice, liver-specific PTEN deletion leads to steatosis, insulin hypersensitivity early in life, and hepatomegaly and hepatocellular carcinoma (HCC) at later stages. 3,4 Consistent with these studies, PTEN is deleted, or weakly expressed, in HCC having a poor prognosis. 5 Interestingly, accumulating evidence indicates that deregulated PTEN expression in hepatocytes, rather than PTEN mutations/ deletions, represents a critical factor in the development of nonalcoholic fatty liver diseases (NAFLD) and HCC. 6,7 PTEN expression is regulated at the posttranscriptional level by various signaling cascades affecting its activity, stability, or intracellular localization. 8 At the transcriptional level, genetic and epigenetic mechanisms

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Section: Discussionsupporting

confidence: 69%

“…Gene methylation and histone hyperacetylation are epigenetic mechanisms regulating PTEN expression and involved in hepatic carcinogenesis. 20 However, whether UFAs inhibit PTEN expression through such mechanisms in hepatocytes is unknown.…”

Section: Resultsmentioning

confidence: 99%

Unsaturated fatty acids inhibit the expression of tumor suppressor phosphatase and tensin homolog (PTEN) via microRNA-21 up-regulation in hepatocytes

Vinciguerra¹,

et al. 2008

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“…Receptor tyrosine kinase activation rather than somatic mutations of PTEN or PI3KCA, which are rare in HCC, is likely to be responsible for activation of mTOR in HCC. Consistent with this notion, activation of AKT has been found in 40%-60% of human HCC samples (12) and is a risk factor for early recurrence and poor prognosis (13). More importantly, recent studies using knockout mice showed that mTOR activation was sufficient to cause HCC in rodent models (14), indicating the pivotal role of mTOR signaling in HCC.…”

Section: Introductionsupporting

confidence: 49%

Loss of Tuberous Sclerosis Complex 2 (TSC2) Is Frequent in Hepatocellular Carcinoma and Predicts Response to mTORC1 Inhibitor Everolimus

Huynh

Hao²,

Chan

et al. 2015

Molecular Cancer Therapeutics

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Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide and hyperactivation of mTOR signaling plays a pivotal role in HCC tumorigenesis. Tuberous sclerosis complex (TSC), a heterodimer of TSC1 and TSC2, functions as a negative regulator of mTOR signaling. In the current study, we discovered that TSC2 loss-of-function is common in HCC. TSC2 loss was found in 4 of 8 HCC cell lines and 8 of 28 (28.6%) patient-derived HCC xenografts. TSC2 mutations and deletions are likely to be the underlying cause of TSC2 loss in HCC cell lines, xenografts, and primary tumors for most cases. We further demonstrated that TSC2-null HCC cell lines and xenografts had elevated mTOR signaling and, more importantly, were significantly more sensitive to RAD001/everolimus, an mTORC1 inhibitor. These preclinical findings led to the analysis of TSC2 status in HCC samples collected in the EVOLVE-1 clinical trial of everolimus using an optimized immunohistochemistry assay and identified 15 of 139 (10.8%) samples with low to undetectable levels of TSC2. Although the sample size is too small for formal statistical analysis, TSC2-null/low tumor patients who received everolimus tended to have longer overall survival than those who received placebo. Finally, we performed an epidemiology survey of more than 239 Asian HCC tumors and found the frequency of TSC2 loss to be approximately 20% in Asian HBV þ HCC. Taken together, our data strongly argue that TSC2 loss is a predictive biomarker for the response to everolimus in HCC patients. Mol Cancer Ther; 14(5); 1224-35. Ó2015 AACR.

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“…The future challenge is to further understand the roles of these possible epigenetic mechanisms of PTEN alteration and their biological relevance is a challenge for the future. PTEN inactivation via epigenetic mechanisms was first demonstrated in prostate cancer cell lines 38 and later found in prostate cancer and melanoma 39 . Ojesina et al 40 implicated somatic mutations in PIK3CA, PTEN, TP53, STK11 and KRAS as well as several copy-number alterations in the pathogenesis of cervical carcinomas and reported whole-exome sequencing analysis of 115 cervical carcinoma-normal paired samples, transcriptome sequencing of 79 cases and whole-genome sequencing of 14 tumour-normal pairs.…”

Section: Referencesmentioning

confidence: 99%

PTEN expression in patients with carcinoma of the cervix and its association with p53, Ki-67 and CD31

Loures¹,

Cândido²,

Vidigal³

et al. 2014

Rev. Bras. Ginecol. Obstet.

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PURPOSE: To investigate protein expression and mutations in phosphatase and tensin homolog (PTEN) in patients with stage IB cervical squamous cell carcinoma (CSCC) and the association with clinical-pathologic features, tumor p53 expression, cell proliferation and angiogenesis. METHODS: Women with stage IB CSCC (n=20 -Study Group) and uterine myoma (n=20 -Control Group), aged 49.1±1.7 years (mean±standard deviation, range 27-78 years), were prospectively evaluated. Patients with cervical cancer were submitted to Piver-Rutledge class III radical hysterectomy and pelvic lymphadenectomy and patients in the Control Group underwent vaginal hysterectomy. Tissue samples from the procedures were stained with hematoxylin and eosin for histological evaluation. Protein expression was detected by immunohistochemistry. Staining for PTEN, p53, Ki-67 and CD31 was evaluated. The intensity of PTEN immunostaining was estimated by computer-assisted image analysis, based on previously reported protocols. Data were analyzed using the Student's t-test to evaluate significant differences between the groups. Level of significance was set at p<0.05. RESULTS: The PTEN expression intensity was lower in the CSCC group than in the Control (benign cervix) samples (150.5±5.2 versus 204.2±2.6; p<0.001). Our study did not identify any mutations after sequencing all nine PTEN exons. PTEN expression was not associated with tumor expression of p53 (p=0.9), CD31 (p=0.8) or Ki-67 (p=0.3) or clinical-pathologic features in patients with invasive carcinoma of the cervix. CONCLUSIONS: Our findings demonstrate that the PTEN protein expression is significantly diminished in CSCC.

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Epigenetic and genetic alterations of PTEN in hepatocellular carcinoma

Abstract: The level of PTEN protein was altered in part of the HCC. The downregulation of PTEN expression may not be mainly associated with the PTEN mutations, but partly due to PTEN promoter methylation and other epigenetic regulation.

Cited by 117 publications

References 32 publications

Unsaturated fatty acids inhibit the expression of tumor suppressor phosphatase and tensin homolog (PTEN) via microRNA-21 up-regulation in hepatocytes

Unsaturated fatty acids inhibit the expression of tumor suppressor phosphatase and tensin homolog (PTEN) via microRNA-21 up-regulation in hepatocytes

Loss of Tuberous Sclerosis Complex 2 (TSC2) Is Frequent in Hepatocellular Carcinoma and Predicts Response to mTORC1 Inhibitor Everolimus

PTEN expression in patients with carcinoma of the cervix and its association with p53, Ki-67 and CD31

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