Low VHL mRNA Expression is Associated with More Aggressive Tumor Features of Papillary Thyroid Carcinoma

Stanojević, Boban; Saenko, Vladimir; Todorović, Ljubomir; Petrović, Nina; Nikolić, D.; Živaljević, Vladan; Paunović, Ivan; Nakashima, Masahiro; Yamashita, Shunichi; Džodić, Radan

doi:10.1371/journal.pone.0114511

Cited by 9 publications

(11 citation statements)

References 65 publications

(56 reference statements)

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“…The hypermethylation of tumor-suppressor genes (TSG) is significantly associated with tumor cell proliferation, cell migration, and cell invasion [34]. The condition of VHL promoter methylation has been reported in various cancers, including papillary thyroid carcinoma [35], RCC [36], and colorectal cancer [37]. However, we found that the reported frequency of VHL promoter methylation in RCC is still controversial, with a range from 0% [38] to 35.3% [20].…”

Section: Discussionmentioning

confidence: 85%

The Clinicopathological Significance of Epigenetic Silencing of VHL Promoter and Renal Cell Carcinoma: A Meta-Analysis

Yang

Zhao²,

Zhao³

et al. 2016

Cell Physiol Biochem

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Background/Aims: Von Hippel-Lindau gene (VHL) has been reported as a tumor-suppressor gene in some cancers. However, the association between VHL promoter hypermethylation and renal cell carcinoma (RCC) remains to be clarified. We are the first to systematically integrate published papers to assess the role of hypermethylated VHL in RCC. Methods: The potential relevant papers were searched via PubMed, Embase, EBSCO, CNKI, and Wanfang databases. The overall odds ratio (OR) and corresponding 95% confidence interval (95% CI) were calculated to evaluate the relationship between VHL promoter hypermethylation and RCC. Results: Finally, a total of 1,998 RCC patients and 294 controls from 13 eligible articles were included in this meta-analysis. Under the fixed-effects model, the pooled OR from seven studies including 596 RCC and 294 nonmalignant samples showed that VHL promoter hypermethylation was significantly higher in cancer than in controls (OR = 7.93, 95% CI = 2.84- 22.15, P < 0.001). Subgroup analysis based on ethnic population and testing method revealed that hypermethylated VHL had a significantly similar OR value in different races and detection methodologies. No significant association was found between hypermethylated VHL and tumor grade, tumor stage, tumor size, histological types, and lymph node status in cancer (all P > 0.05). In the current study, there was no evidence of publication bias as determined by Egger's test (all P > 0.05). Conclusions: In the investigated patients, VHL promoter hypermethylation, which may play an important role in carcinogenesis of RCC, is significantly associated with an increased risk of RCC. However, VHL promoter hypermethylation is not correlated with specific clinicopathological characteristics. Additional future studies are needed to confirm our results.

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Section: Discussionmentioning

confidence: 85%

The Clinicopathological Significance of Epigenetic Silencing of VHL Promoter and Renal Cell Carcinoma: A Meta-Analysis

Yang

Zhao²,

Zhao³

et al. 2016

Cell Physiol Biochem

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“…No somatic mutations or evidence of VHL downregulation via promoter hypermethylation were found. However, low VHL mRNA levels strongly associated with older patient's age, advanced clinical stage, classical PTC variant, and multifocality (Stanojevic et al 2015). The authors noticed also a marginal influence of low VHL expression on disease-free interval (DFI) (p = 0.0502).…”

Section: Discussionmentioning

confidence: 94%

“…To date, relative few studies have attempted to investigate the effects of a deregulated VHL expression in DTC evolution (The Cancer Genome Atlas Research Network, 2014;Stanojevic et al 2015;Hinze et al 2000;Hunt et al 2003). Earlier immunohistochemical analyses demonstrated the presence of pVHL in normal thyroid follicular epithelium as well as in non-neoplastic lesions, and in DTC (Hinze et al 2000).…”

Section: Discussionmentioning

confidence: 99%

“…Some reports suggested that pVHL could play a role also in the progression of epithelial thyroid cancer (TC) (The Cancer Genome Atlas Research Network, 2014;Stanojevic et al 2015;Hinze et al 2000;Hunt et al 2003). The latter represents the most common endocrine malignancy accounting for roughly 1% of all human cancers, and its incidence has been increasing over the last decades mainly due to the improved ability to diagnose malignant transformation in small nonpalpable thyroid nodules (Jemal et al 2009;Davies and Welch, 2006;Kinder, 2003;Patel and Shaha, 2006;Pasieka, 2003).…”

Section: Introductionmentioning

confidence: 99%

“…Although, to date, no loss-of-function mutations of the VHL gene in PTC tissues have been described, recent studies demonstrated that a subset of PTCs was characterized by low levels of VHL mRNA, which associated with more aggressive PTCs (The Cancer Genome Atlas Research Network, 2014; Stanojevic et al 2015).…”

Section: Introductionmentioning

confidence: 99%

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Deregulated expression of VHL mRNA variants in papillary thyroid cancer

Baldini

Tuccilli

Arlot‐Bonnemains

et al. 2017

Molecular and Cellular Endocrinology

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Recent findings demonstrated that a subset of papillary thyroid cancers (PTCs) is characterized by reduced expression of the von Hippel-Lindau (VHL) tumor suppressor gene, and that lowest levels associated with more aggressive PTCs. In the present study, the levels of the two VHL mRNA splicing variants, VHL-213 (V1) and VHL-172 (V2), were measured in a series of 96 PTC and corresponding normal matched tissues by means of quantitative RT-PCR. Variations in the mRNA levels were correlated with patients' clinicopathological parameters and disease-free interval (DFI).The analysis of VHL mRNA in tumor tissues, compared to normal matched tissues, revealed that its expression was either up-or down-regulated in the majority of PTC. In particular, V1 and V2 mRNA levels were altered, respectively, in 78 (81.3%) and 65 (67.7%) out of the 96 PTCs analyzed. A significant positive correlation between the two mRNA variants was observed (p<0.001). Univariate analysis documented the lack of association between each variant and clinicopathological parameters such as age, tumor size, histology, TNM stage, lymph node metastases, and BRAF mutational status. However, a strong correlation was found between altered V1 or V2 mRNA levels and DFI. Multivariate regression analysis indicated higher V1 mRNA values, along with lymph node metastases at diagnosis, as independent prognostic factors predicting DFI. In conclusion, the data reported demonstrate that VHL gene expression is deregulated in the majority of PTC tissues. Of particular interest is the apparent protective role exerted by VHL transcripts against PTC recurrences.

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The Elephant in the Room: The Role of Microtubules in Cancer

Cirillo

Gotta

Meraldi

2017

Advances in Experimental Medicine and Biology

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Microtubules are the backbone of all eukaryotic cells cytoskeleton. Their dynamic behaviour constitutes the basis for many biological processes such as cellular motility, cytoplasmic transport and cell division. Some the most effective chemotherapeutics, such as the taxanes, are microtubule interfering drugs. Moreover, many studies suggest that microtubule dynamics are altered in cancer cell divisions and linked to chromosomal instability, aneuploidy and development of drug resistances. The elephant in the room, however, is that despite all these evidences, the exact role of microtubules in malignancies remains elusive, partially due to the lack of clear genetic alterations linking microtubules to cancer. This review will discuss the molecular mechanisms that might alter microtubule dynamics in cancer cells, the pro and cons of the different theories linking these alterations to cancer progression, and the possible directions to address future key questions.

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Low VHL mRNA Expression is Associated with More Aggressive Tumor Features of Papillary Thyroid Carcinoma

Cited by 9 publications

References 65 publications

The Clinicopathological Significance of Epigenetic Silencing of VHL Promoter and Renal Cell Carcinoma: A Meta-Analysis

The Clinicopathological Significance of Epigenetic Silencing of VHL Promoter and Renal Cell Carcinoma: A Meta-Analysis

Deregulated expression of VHL mRNA variants in papillary thyroid cancer

The Elephant in the Room: The Role of Microtubules in Cancer

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