Aberrant Methylation of Promoter Region of <i>SPINT2/HAI-2</i> Gene: An Epigenetic Mechanism in Hepatitis C Virus-Induced Hepatocarcinogenesis

Ramadan, Ragaa Abdelkader; Zaki, Moyassar Ahmad; Awad, Ahmed M.; El-Ghalid, Lamiaa A

doi:10.1089/gtmb.2015.0025

Cited by 9 publications

(15 citation statements)

References 33 publications

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“…We observed a significant increase in SPINT2/HAI‐2 levels after AZA treatment in BMMSC from MDS and de novo AML patients, though not in HD‐BMMSC. These results indicate that SPINT2/HAI‐2 is probably epigenetically silenced by methylation in these haematological neoplasms, maybe acting as a tumour suppressor gene in MDS and de novo AML, as occurs in some solid tumours, such as prostate cancer, melanoma, hepatocellular carcinoma, esophageal squamous cell carcinoma, endometrial/uterine cancer, gastric cancer, and medulloblastoma …”

Section: Discussionmentioning

confidence: 75%

“…In diverse tumours, the down‐regulation of SPINT2 expression has been associated with gene promoter hypermethylation . AZA is a DNA methyltransferase inhibitor that has been successfully used in epigenetic neoplastic therapy to reactivate epigenetically silenced tumour suppressor genes .…”

Section: Discussionmentioning

confidence: 99%

“…19 In diverse tumours, the down-regulation of SPINT2 expression has been associated with gene promoter hypermethylation. [7][8][9][10][11][12][13] AZA is a DNA methyltransferase inhibitor 20 that has been successfully used in epigenetic neoplastic therapy to reactivate epigenetically silenced tumour suppressor genes. 21 Furthermore, AZA is the first-line treatment for patients with high-risk myelodysplastic syndrome and has been successful in prolonging survival and delayed AML evolution.…”

Section: Discussionmentioning

confidence: 99%

“…Low levels of SPINT2/HAI‐2 , probably due to hypermethylation, have been highlighted in various solid cancer types and have been associated with disease progression . Pereira and colleagues hypothesized that SPINT2/HAI‐2 is involved in prostate cancer tumourigenesis probably by regulation of SPINT2/HAI‐2 .…”

Section: Introductionmentioning

confidence: 99%

“…5,6 Low levels of SPINT2/HAI-2, probably due to hypermethylation, have been highlighted in various solid cancer types and have been associated with disease progression. [7][8][9][10][11][12][13] Pereira and colleagues hypothesized that SPINT2/HAI-2 is involved in prostate cancer tumourigenesis probably by regulation of SPINT2/HAI-2. 7 We previously reported that the expression of SPINT2 mRNA is significantly lower in bone marrow mesenchymal stromal cell (BMMSC) from MDS patients compared to healthy donors (HD), which could be related with increased HGF and CXCL-12 secretion.…”

Section: Introductionmentioning

confidence: 99%

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Up‐regulation of SPINT2/HAI‐2 by Azacytidine in bone marrow mesenchymal stromal cells affects leukemic stem cell survival and adhesion

Roversi

Cury

Lopes

et al. 2018

J Cellular Molecular Medi

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The role of tumour microenvironment in neoplasm initiation and malignant evolution has been increasingly recognized. However, the bone marrow mesenchymal stromal cell (BMMSC) contribution to disease progression remains poorly explored. We previously reported that the expression of serine protease inhibitor kunitz‐type2 (SPINT2/HAI‐2), an inhibitor of hepatocyte growth factor (HGF) activation, is significantly lower in BMMSC from myelodysplastic syndromes (MDS) patients compared to healthy donors (HD). Thus, to investigate whether this loss of expression was due to SPINT2/HAI‐2 methylation, BMMSC from MDS and de novo acute myeloid leukaemia (de novo AML) patients were treated with 5‐Azacitidine (Aza), a DNA methyltransferase inhibitor. In MDS‐ and de novo AML‐BMMSC, Aza treatment resulted in a pronounced SPINT2/HAI‐2 levels up‐regulation. Moreover, Aza treatment of HD‐BMMSC did not improve SPINT2/HAI‐2 levels. To understand the role of SPINT2/HAI‐2 down‐regulation in BMMSC physiology, SPINT2/HAI‐2 expression was inhibited by lentivirus. SPINT2 underexpression resulted in an increased production of HGF by HS‐5 stromal cells and improved survival of CD34+ de novo AML cells. We also observed an increased adhesion of de novo AML hematopoietic cells to SPINT2/HAI‐2 silenced cells. Interestingly, BMMSC isolated from MDS and de novo AML patients had increased expression of the integrins CD49b, CD49d, and CD49e. Thus, SPINT2/HAI‐2 may contribute to functional and morphological abnormalities of the microenvironment niche and to stem/progenitor cancer cell progression. Hence, down‐regulation in SPINT2/HAI‐2 gene expression, due to methylation in MDS‐BMMSC and de novo AML‐BMMSC, provides novel insights into the pathogenic role of the leukemic bone marrow microenvironment.

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Section: Discussionmentioning

confidence: 75%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Up‐regulation of SPINT2/HAI‐2 by Azacytidine in bone marrow mesenchymal stromal cells affects leukemic stem cell survival and adhesion

Roversi

Cury

Lopes

et al. 2018

J Cellular Molecular Medi

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HGFAC expression decreased in liver cancer and its low expression correlated with DNA hypermethylation and poor prognosis

Lin

et al. 2019

J of Cellular Biochemistry

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As the activator of hepatocyte growth factor (HGF), hepatocyte growth factor activator (HGFAC) has been previously reported to involve in liver, kidney, and stomach regeneration in response to injury and several types of cancers. This study aimed to explore the expression of HGFAC and the correlation between decreased HGFAC and DNA methylation in liver cancer and its clinical significance. The molecular profiling of HGFAC in liver cancer was analyzed using genomic, transcriptomic, immunohistochemistry, and patient survival information from databases, including oncomine, HPA, COSMIC, UCSC Xena, MPRESS, and Kaplan-Meier plotter. It was found that HGFAC expression at transcriptional and translational level decreased in liver cancer compared with normal tissues. There is a negative correlation between the HGFAC expression and methylation around the promoter region which indicated that HGFAC expression might be controlled by DNA methylation. Moreover, the decreased HGFAC is associated with significantly short over survival time in liver cancer patients. In conclusion, decreased HGFAC expression in liver cancer associated with poor survival outcome. Hypermethylation around the promoter region contributed to the decreased expression of HGFAC. HGFAC may be a useful and predictive biomarker for the prognosis of liver cancer patients. To the best of our knowledge, this is the first report describing the relationship between HGFAC DNA methylation and its expression.

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Epigenetic Regulations in the Pathogenesis of HCC and the Clinical Application

Puszyk

Robertson

Liu

2017

Molecular Pathology Library

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Aberrant Methylation of Promoter Region of SPINT2/HAI-2 Gene: An Epigenetic Mechanism in Hepatitis C Virus-Induced Hepatocarcinogenesis

Abstract: Our study highlights the role of promoter hypermethylation in the multistep process of hepatocarcinogenesis, providing potential clinical applications in diagnosis and prognosis.

Cited by 9 publications

References 33 publications

Up‐regulation of SPINT2/HAI‐2 by Azacytidine in bone marrow mesenchymal stromal cells affects leukemic stem cell survival and adhesion

Up‐regulation of SPINT2/HAI‐2 by Azacytidine in bone marrow mesenchymal stromal cells affects leukemic stem cell survival and adhesion

HGFAC expression decreased in liver cancer and its low expression correlated with DNA hypermethylation and poor prognosis

Epigenetic Regulations in the Pathogenesis of HCC and the Clinical Application

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