591 Lack of MicroRNA-101 Causes E-cadherin Functional Deregulation Through EZH2 Upregulation in Intestinal Gastric Cancer

Carvalho, Joana; Grieken, Nicole van; Pereira, Patrícia M.; Diosdado, Begoña; Santos, Mafalda; Meijer, G.A.; Buffart, Tineke E.; Seruca, Raquel; Carvalho, Benilton; Oliveira, Carla

doi:10.1016/s0959-8049(12)71248-0

Cited by 5 publications

(9 citation statements)

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“…[44][45][46][47] Following this idea, we have recently reported that miR-101 downregulation with consequent EZH2 upregulation constitutes an additional mechanism by which E-cadherin becomes dysfunctional, mainly in intestinal-type GC retaining allele(s) untargeted by classical CDH1 inactivating mechanisms. 28 In conclusion, our data provide, for the first time to our knowledge, a detailed analysis of somatic CDH1 alterations in different clinical settings and histologic types of GC, highlighting subsets of patients with distinct clinical outcomes. In particular, this work defined a group of patients (FIGC with CDH1 structural alterations) with the worst prognosis among all GCs analyzed.…”

Section: Discussionmentioning

confidence: 67%

“…These frequencies are lower than most earlier reported frequencies, but are similar to those recently reported in several independent series. 28,30,31 Discrepancies are most likely a result of different methodologies used. Interestingly, we demonstrate that CDH1 somatic epigenetic and structural alterations are as frequent in intestinal as in diffuse GC, suggesting histotype independence.…”

Section: Discussionmentioning

confidence: 99%

“…[28][29][30][31][32] Importantly, the presence of concomitant CDH1 inactivation mechanisms was rarely described in this setting. 28,29,33 Nevertheless, most of these studies have been limited by the series size, the type of molecular mechanisms studied, different methodologic approaches, and the lack of extensive correlations with clinical parameters, thus hampering potential translation of genetic data into medical practice. 34 The goal of this study was to analyze the impact of somatic CDH1 alterations in prognosis and survival of patients with GC.…”

Section: -31mentioning

confidence: 99%

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Somatic Mutations and Deletions of the E-Cadherin Gene Predict Poor Survival of Patients With Gastric Cancer

Corso

Carvalho

Marrelli

et al. 2013

JCO

153

114

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Purpose The prognosis of gastric cancer (GC) is poor, and the molecular pathogenesis players are vastly unknown. Surgery remains the primary option in GC treatment. The aim of this study was to investigate the impact of somatic CDH1 alterations in prognosis and survival of patients with GC. Patients and Methods A series of patients with sporadic and familial GC (diffuse and intestinal; n = 246) were analyzed for somatic CDH1 mutations, promoter hypermethylation, and loss of heterozygosity (LOH) by polymerase chain reaction sequencing. E-cadherin protein expression was determined by immunohistochemistry. Associations between molecular, clinicopathologic, and survival data were analyzed. Results CDH1 somatic alterations were found in approximately 30% of all patients with GC. Both histologic types of sporadic GC displayed LOH in 7.5%, mutations in 1.7%, and hypermethylation in 18.4% of patients. Primary tumors from hereditary diffuse GC, lacking germline CDH1 alterations, showed exclusively CDH1 promoter hypermethylation in 50% of patients. Familial intestinal GC (FIGC) tumors showed LOH in 9.4% and hypermethylation in 17.0%. CDH1 alterations did not associate with a particular pattern of E-cadherin expression. Importantly, the worst patient survival rate among all GCs analyzed was seen in patients with tumors carrying CDH1 structural alterations, preferentially those belonging to FIGC families. Conclusion CDH1 somatic alterations exist in all clinical settings and histotypes of GC and associate with different survival rates. Their screening at GC diagnosis may predict patient prognosis and is likely to improve management of patients with this disease.

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Section: Discussionmentioning

confidence: 67%

Section: Discussionmentioning

confidence: 99%

Section: -31mentioning

confidence: 99%

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Somatic Mutations and Deletions of the E-Cadherin Gene Predict Poor Survival of Patients With Gastric Cancer

Corso

Carvalho

Marrelli

et al. 2013

JCO

153

114

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“…A growing number of reports have implicated hsa‐miR‐101 ( miR‐101 ) as a possible tumour suppressor and data demonstrate that miR‐101 expression is reduced in several human cancers . Furthermore, miR‐101 has been found to inhibit the expression of tumour‐promoting genes . In 2009, we demonstrated that miR‐101 is a direct repressor of human COX‐2 mRNA translation and we also showed an inverse correlation between miR‐101 and COX‐2 expression in human CRC specimens and cell lines .…”

Section: Introductionmentioning

confidence: 63%

“…In particular, specific miRNAs (called oncomiRs) can act as oncogenes or tumour suppressors and their expression has been found dysregulated in human cancers . A growing number of reports have implicated hsa‐miR‐101 ( miR‐101 ) as a possible tumour suppressor and data demonstrate that miR‐101 expression is reduced in several human cancers . Furthermore, miR‐101 has been found to inhibit the expression of tumour‐promoting genes .…”

Section: Introductionmentioning

confidence: 99%

Loss ofmiR‐101expression promotes Wnt/β‐catenin signalling pathway activation and malignancy in colon cancer cells

Strillacci

Valerii

Sansone

et al. 2012

The Journal of Pathology

107

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Colorectal cancer (CRC) is the second leading cause of cancer-related mortality in Western countries. Although the aberrant expression of several microRNAs (oncomiRs) is associated with CRC progression, the molecular mechanisms of this phenomenon are still under investigation. Here we show that miR-101 expression is differentially impaired in CRC specimens, depending on tumour grade. miR-101 re-expression suppresses cell growth in 3D, hypoxic survival and invasive potential in CRC cells showing low levels of miR-101. Additionally, we provide molecular evidence of a bidirectional regulatory mechanism between miR-101 expression and important CRC pro-malignant features, such as inflammation, activation of the Wnt/β-catenin signalling pathway and epithelial-mesenchymal transition (EMT). We then propose that up-regulated miR-101 may function as a tumour suppressor in CRC and that its pharmacological restoration might hamper the aggressive behaviour of CRC in vivo. MiR-101 expression may also represent a cancer biomarker for CRC diagnosis and prognosis.

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Non‐coding RNAs and EZH2 interactions in cancer: Long and short tales from the transcriptome

Benetatos¹,

Voulgaris

Vartholomatos

et al. 2012

Intl Journal of Cancer

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A large amount of data indicates that non‐coding RNAs represent more than the “dark matter” of the genome. Both microRNAs and long non‐coding RNAs are involved in several fundamental biologic processes, and their deregulation may lead in oncogenesis. Interacting with the Polycomb‐repressive complex 2 subunit EZH2, they could affect the expression of protein‐coding genes and form feedback networks and autoregulatory loops. They can also form networks with upstream and downstream important factors, in which EZH2 represent the stabilizing factor of the pathway. As such non‐coding RNAs affect the epigenetic modifications leading to malignant transformation.

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591 Lack of MicroRNA-101 Causes E-cadherin Functional Deregulation Through EZH2 Upregulation in Intestinal Gastric Cancer

Cited by 5 publications

References 0 publications

Somatic Mutations and Deletions of the E-Cadherin Gene Predict Poor Survival of Patients With Gastric Cancer

Somatic Mutations and Deletions of the E-Cadherin Gene Predict Poor Survival of Patients With Gastric Cancer

Loss ofmiR‐101expression promotes Wnt/β‐catenin signalling pathway activation and malignancy in colon cancer cells

Non‐coding RNAs and EZH2 interactions in cancer: Long and short tales from the transcriptome

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