Methylation-associated silencing of SFRP1 gene in high-grade serous ovarian carcinomas

Kardum, Vedran; Karin, Valentina; Glibo, Mislav; Škrtić, Anita; Martić, Tamara Nikuševa; Ibišević, Nermina; Skenderi, Faruk; Vranić, Semir; Šerman, Ljiljana

doi:10.1016/j.anndiagpath.2017.07.002

Cited by 18 publications

(10 citation statements)

References 29 publications

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“…The expression of SFRP1 mRNA is detectable in all tested human tissues and broad expression was observed in the endometrium [19], ovary [20], colon [21], prostate [22], and breast [17]. The Cancer Genome Atlas (TCGA) revealed reduced expression of SFRP1 various cancers including breast, colorectal, lung, bladder urothelial carcinoma, cervical squamous cell carcinoma, head and neck squamous cell carcinoma, glioblastoma multiforme, kidney renal clear cell carcinoma, stomach adenocarcinoma, and endometrium cancer compared to the normal tissues [23].…”

Section: Epigenetic Inactivation and Genomic Alterations In Sfrp1 Genementioning

confidence: 97%

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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Section: Epigenetic Inactivation and Genomic Alterations In Sfrp1 Genementioning

confidence: 97%

Epigenetics of SFRP1: The Dual Roles in Human Cancers

Baharudin

Tieng

Lee

et al. 2020

Cancers

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“…We observed aberrant expression level and methylation status of SFRP1 in both epithelial ovarian cancer tissues cell models, which were consistent with previous studies. The aberrant expression and methylation of SFRP1 in cancer were reported extensively: Vedran Kardum et al reported the loss of SFRP1 protein expression observed in low-grade serous ovarian carcinomas (Kardum et al, 2017). The CpG island hypermethylation of SFRP1 is a common event observed in many kinds of cancers (Atschekzei et al, 2012), which might be one of the key reasons for the lower expression in epithelial ovarian cancer.…”

Section: Discussionmentioning

confidence: 97%

SFRP1 inhibited the epithelial ovarian cancer through inhibiting Wnt/β-catenin signaling

et al. 2019

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Background: Epithelial ovarian cancer is the most malignant gynecologic neoplasm accounting for 90% of the ovarian cancer patients. Objective: Researchers proved that epigenetic alterations could disrupt gene expression as often as genetic alterations. Secreted frizzed related protein (SFRP1), a Wnt antagonist, exerts a significant effect on ovarian cancer. The aim of this research was to investigate the effects and the mechanism of action of SFRP1 on epithelial ovarian cancer. Methods: Clinical specimens (including fallopian tubes epithelium from 60 epithelial ovarian cancer patients’ and 20 healthy subjects who were undergoing surgical treatments), transgenic mice (overexpressing SFRP1 gene), and 4 epithelial ovarian cancer cell lines (including OVCAR4, SKOV3, COV644, TOV21G) were used in this study. Overexpression of SFRP1 in cells was carried out on OVCAR4 cells by transfection using Lipofectamine 2000. Gene transcription was analyzed by qRT-PCR. The methylation of SFRP1 gene was quantified by methylation-specific PCR. The level of protein expression was measured by Western blot or immunohistochemistry analysis. Cell proliferation was analyzed by CCK8 methods. The ability of cell migration and invasion were measured by wound healing assay and transwell assay. Results: Abnormal expression level and hypermethylation status of SFRP1 were found in clinical epithelial ovarian cancer samples and cell lines. We observed that SFRP1 knockdown could promote proliferation, migration and invasion abilities of epithelial ovarian cancer cells. Additionally, we discovered a potential inhibitory effect of SFRP1 on Wnt/β-catenin signaling pathway in epithelial ovarian cancer cells. Furthermore, the anti-tumor effect of SFRP1 was tested in SFRP1 transgenic mice. Conclusion: SFRP1 inhibited epithelial ovarian cancer through inhibiting Wnt/β-catenin pathway, suggesting that SFRP1 could be considered as a potential therapeutic target in epithelial ovarian cancer.

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“…Although most of the mutations promote stabilization of β-catenin and Chi-square correlation analysis of normalized low (< 1) and high (> 1) SFRP1 expression categories to different clinicopathological and experimental parameters m male, f female, DOD died of disease, NED no evidence of disease, HB hepatoblastoma, HCC hepatocellular carcinoma, TLCT transitional liver cell tumor, NSET nested stromal-epithelial liver tumor, E embryonal, F fetal, pure OS pure osteoid, C1 and C2 16-gene signature cluster C1 and C2 (Cairo et al 2008), M methylated, U unmethylated, nd no data, na not applicable (Anastas and Moon 2013;Suzuki et al 2008). In different tumor entities, an epigenetic silencing of various WNT antagonist, such as WIFs, DKKs and SFRPs, correlates with a poor prognosis or high-grade cancer (Kardum et al 2017;Lin et al 2017;Davaadorj et al 2016). Interestingly, a restoration of the WNT antagonist expression attenuated tumor growth (Shih et al 2007;Gumz et al 2007).…”

Section: Discussionmentioning

confidence: 99%

Downregulation of SFRP1 is a protumorigenic event in hepatoblastoma and correlates with beta-catenin mutations

Regel

Eichenmüller

Mahajan

et al. 2020

J Cancer Res Clin Oncol

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Background Hepatoblastoma (HB) and pediatric hepatocellular carcinoma (HCC) are the most common malignant liver tumors in childhood. Both tumor types exhibit genetic and epigenetic alterations in the WNT/β-catenin signaling pathway, which is a key regulator of liver progenitor cells in embryonic development. The tumors demonstrate a high rate of β-catenin mutations and gene expression changes of several WNT antagonists. However, the role of the WNT inhibitory factor secreted frizzled-related protein 1 (SFRP1) has not been addressed in pediatric liver cancer so far. Results In our study, we investigated the gene expression level, DNA methylation status and functional relevance of SFRP1 in HB cell lines and in pediatric liver tumor patient samples. SFRP1 was downregulated due to DNA promoter methylation in all tested HB cell lines. Overexpression of SFRP1 in HB cell lines diminished tumor cell proliferation, colony formation and migration potential. In addition, the SFRP1-expressing HB cell lines showed reduced WNT/β-catenin signaling pathway activity and decreased expression of WNT target genes. To evaluate the utility of SFRP1 as a biomarker in pediatric liver cancer, we determined the gene expression level and DNA methylation status of SFRP1 in 45 pediatric liver tumor patient samples. The correlation analysis of different clinical parameters and tumor characteristics revealed a significant correlation of reduced SFRP1 expression with the presence of mutant β-catenin. The methylation status of SFRP1 was furthermore associated to a pediatric liver tumor type with HCC-like characteristics, TERT mutations and an older age at diagnosis. Conclusion Altogether, our data demonstrate that the epigenetic suppression of the WNT/β-catenin antagonist SFRP1 has an important impact on the malignant behavior of HB cells. Although SFRP1 methylation is a common event in HCC-like pediatric liver tumors, its potential as a prognostic or diagnostic biomarker needs to be further investigated.

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Methylation-associated silencing of SFRP1 gene in high-grade serous ovarian carcinomas

Cited by 18 publications

References 29 publications

Epigenetics of SFRP1: The Dual Roles in Human Cancers

Epigenetics of SFRP1: The Dual Roles in Human Cancers

SFRP1 inhibited the epithelial ovarian cancer through inhibiting Wnt/β-catenin signaling

Downregulation of SFRP1 is a protumorigenic event in hepatoblastoma and correlates with beta-catenin mutations

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