Association between SFRP promoter hypermethylation and different types of cancer: A systematic review and meta‑analysis

Yu, Jun; Xie, Yang; Li, Mengying; Zhou, Fenfang; Zhong, Zhenyang; Liu, Yuting; Wang, Feng; Qi, Jian

doi:10.3892/ol.2019.10709

Cited by 33 publications

(40 citation statements)

References 92 publications

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“…SFRP proteins have been demonstrated to directly and indirectly inhibit Wnt signalling (23). Accumulating evidence has suggested that SFRP expression is tightly regulated by promoter methylation (24). In the present study, SFRP1 mRNA expression was significantly downregulated in CRC cell lines compared with CCC-HIE-2 cells, a non-cancerous intestinal mucosal cell line, with concomitant hypermethylation in the SFRP1 promoter region.…”

Section: Discussionsupporting

confidence: 45%

MBD2 and EZH2 regulate the expression of SFRP1 without affecting its methylation status in a colorectal cancer cell line

Xie

Liu

et al. 2020

Exp Ther Med

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Secreted frizzled-related protein 1 (SFRP1), which is an extracellular inhibitor involved in Wnt signalling, is downregulated by promoter hypermethylation in the early stages of colorectal tumorigenesis. Polycomb (PCG) and methyl-CpG-binding domain (MBD) proteins that serve a role in epigenetic gene regulation. The aim of the present study was to determine the role of PCG and MBD proteins in the regulation of SFRP1 gene expression in colorectal cancer (CRC), specifically in CRC cell lines and the human embryo intestinal mucosa cell line CCC-HIE-2. The methylation status of the SFRP1 gene promoter were analysed using methylation-specific PCR (MSP), whereas SFRP1 mRNA expression was analysed using reverse transcription-quantitative PCR. The association between PCG and MBD proteins and the SFRP1 gene was assessed, where associated proteins were screened by chromatin immunoprecipitation and their expression were subsequently knocked down using RNA interference to determine their role in the regulation of SFRP1 gene expression. The SFRP1 promoter was demonstrated to be hypermethylated in CRC cell lines and partially methylated in the non-cancerous cell line CCC-HIE-2. SFRP1 mRNA expression was significantly lower in CRC cell lines compared with that of CCC-HIE-2 cells. The expression of PCGs enhancer of zeste homolog 2 (EZH2) and BMI1, along with MBD2, was indicated to be upregulated with SFRP1 methylation in HCT116 and SW480 cells. The SFRP1 promoter region was enriched with EZH2 in CCC-HIE-2 cells and enriched with EZH2 and MBD2 in SW480 cells, whereas none of the proteins examined were indicated on the SFRP1 promoter in HCT116 cells. The expression of SFRP1 was reactivated by MBD2 small interfering (si)RNA but not by EZH2 siRNA in SW480 cells, but combined MBD2 and EZH2 knockdown effectively restored SFRP1 gene expression without affecting the methylation status of the SFRP1 promoter. In conclusion, data from the present study revealed that MBD2 and EZH2 regulated SFRP1 expression without affecting the hypermethylation of SFRP1 in CRC cell lines. Instead, the regulation of SFRP1 expression may be through a distinct mechanism, which warrants further investigation.

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Section: Discussionsupporting

confidence: 45%

MBD2 and EZH2 regulate the expression of SFRP1 without affecting its methylation status in a colorectal cancer cell line

Xie

Liu

et al. 2020

Exp Ther Med

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“…A pan-cancer analysis suggested that SFRPs are strongly correlated with patient survival, but there is an inconsistency between family members and cancer types [17]. A systematic review and meta-analysis of the SFRP family also revealed that SFRP1 hypermethylation was significantly associated with cancer risk [18]. Therefore, in this review, epigenetic regulation of SFRP1 expression will be highlighted with additional emphasis on the potentials of SFRP1 in modulating responses toward chemotherapeutic and epigenetic-modifying drugs.…”

Section: Introductionmentioning

confidence: 98%

Epigenetics of SFRP1: The Dual Roles in Human Cancers

Baharudin

Tieng

Lee

et al. 2020

Cancers

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Secreted frizzled-related protein 1 (SFRP1) is a gene that belongs to the secreted glycoprotein SFRP family. SFRP1 has been classified as a tumor suppressor gene due to the loss of expression in various human cancers, which is mainly attributed by epigenetic inactivation via DNA methylation or transcriptional silencing by microRNAs. Epigenetic silencing of SFRP1 may cause dysregulation of cell proliferation, migration, and invasion, which lead to cancer cells formation, disease progression, poor prognosis, and treatment resistance. Hence, restoration of SFRP1 expression via demethylating drugs or over-expression experiments opens the possibility for new cancer therapy approach. While the role of SFRP1 as a tumor suppressor gene is well-established, some studies also reported the possible oncogenic properties of SFRP1 in cancers. In this review, we discussed in great detail the dual roles of SFRP1 in cancers—as tumor suppressor and tumor promoter. The epigenetic regulation of SFRP1 expression will also be underscored with additional emphasis on the potentials of SFRP1 in modulating responses toward chemotherapeutic and epigenetic-modifying drugs, which may encourage the development of novel drugs for cancer treatment. We also present findings from clinical trials and patents involving SFRP1 to illustrate its clinical utility, extensiveness of each research area, and progression toward commercialization. Lastly, this review provides directions for future research to advance SFRP1 as a promising cancer biomarker.

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“…SFRP family proteins are extracellular ligands of frizzled receptors, and the functions of SFRP family proteins differ. Promoter hypermethylation of SFRP1, SFRP2, SFRP4, and SFRP5 is associated with gene suppression and higher cancer risk 28 . However, there are several databases that have shown equivocal correlation between gene expression of SFRP1 and survival of cancer patients.…”

Section: Discussionmentioning

confidence: 99%

Increased expression of secreted frizzled related protein 1 (SFRP1) predicts ampullary adenocarcinoma recurrence

Chao

Overman

et al. 2020

Sci Rep

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Ampullary adenocarcinoma is a rare gastrointestinal cancer in which WNT signalling dysregulation has been previously reported. Secreted frizzled related protein 1 (SFRP1) is one of the extracellular ligands of WNT signalling. We performed bioinformatics analyses of SFRP1 expression in human cancer. Microarray analysis of SFRP1 in periampullary adenocarcinoma was obtained from the Gene Expression Omnibus GSE39409 dataset. SFRP1 expression in ampullary adenocarcinoma was detected by immunohistochemistry staining and correlated with patients' clinical outcomes. Our results showed that SFRP1 expression had different clinical applications in all types of human cancer. no detected alteration of SFPR1 gene and SFRP1 expression in ampullary adenocarcinoma was lower than that in other periampullary adenocarcinomas. However, high expression levels of SFRP1 protein were correlated with cancer recurrence, peritoneal carcinomatosis and poor patient prognosis. Gene set enrichment analysis showed downregulation of multiple WNT-related genes in primary culture cells from ampullary adenocarcinoma, but SFRP1 expression was increased. We found an interaction between WNT, bone morphogenetic protein and hedgehog signalling with SFRP1. Furthermore, a high expression of SFRP1 predicted poor prognosis for ampullary adenocarcinoma patients. Because it is a multifunctional protein, SFRP1 targeting serves as a potential therapy for ampullary adenocarcinoma patients.

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Association between SFRP promoter hypermethylation and different types of cancer: A systematic review and meta‑analysis

Cited by 33 publications

References 92 publications

MBD2 and EZH2 regulate the expression of SFRP1 without affecting its methylation status in a colorectal cancer cell line

MBD2 and EZH2 regulate the expression of SFRP1 without affecting its methylation status in a colorectal cancer cell line

Epigenetics of SFRP1: The Dual Roles in Human Cancers

Increased expression of secreted frizzled related protein 1 (SFRP1) predicts ampullary adenocarcinoma recurrence

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