Abstract:ObjectiveSecreted frizzled-related proteins (SFRPs) as Wnt signaling antagonists have been found to be dysregulated by promoter hypermethylation in several cancers including acute myeloid leukemia (AML). This study aimed to investigate the methylated status of SFRPs promoter region and its clinical relevance in Chinese non-M3 AML patients.MethodsSFRPs methylation in 139 primary non-M3 AML patients was determined using methylation-specific real-time quantitative polymerase chain reaction.ResultsThe frequency of… Show more
“…Hypermethylation of SFRP1 occurs in 37.5% of acute myeloid leukemia (AML), whereby patients that exhibit intermediate-risk karyotyping with concurrent methylated SFRP1 showed poor prognosis, especially in the subgroup 60 years old and younger patients [103]. Association between SFRP1 hypermethylation and poor prognosis was further supported by another study conducted among non-M3 AML patients [51].…”
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.
“…Hypermethylation of SFRP1 occurs in 37.5% of acute myeloid leukemia (AML), whereby patients that exhibit intermediate-risk karyotyping with concurrent methylated SFRP1 showed poor prognosis, especially in the subgroup 60 years old and younger patients [103]. Association between SFRP1 hypermethylation and poor prognosis was further supported by another study conducted among non-M3 AML patients [51].…”
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.
“…1b). Among them, PCDH17 has been reported as a negative regulator of the Wnt/β-catenin pathway [30], and since our group has already established the prognostic significance of several Wnt antagonists in AML [31–33], subsequent studies focused on the clinical impact of PCDH17 gene.Fig. 1Identification of potential tumor suppressor genes that are repressed early in LSC.…”
Section: Resultsmentioning
confidence: 99%
“…Thus, it is possible that repressed PCDH17 contributes Wnt pathway activation and enhanced proliferation of leukemic cells, which is consistent with our observation of higher WBC counts and percentages of BM and PB blasts in patients with low PCDH17 expression. In addition to PCDH17 , our earlier studies have established the prognostic significances of some other Wnt antagonists in AML, such as SOX17 , NKD2 , and SFRP genes [31–33], highlighting the importance of deregulated Wnt signaling in leukemogenesis.…”
Background
Leukemia stem cell (LSC)-enriched genes have been shown to be highly prognostic in acute myeloid leukemia (AML). However, the prognostic value of tumor suppressor genes (TSGs) that are repressed early in LSC remains largely unknown.
Methods
We compared the public available expression/methylation profiling data of LSCs with that of hematopoietic stem cells (HSCs), in order to identify potential tumor suppressor genes in LSC. The prognostic relevance of
PCDH17
was analyzed on a cohort of 173 AML patients from The Cancer Genome Atlas (TCGA), and further validated in three independent cohorts (n = 339).
Results
We identified protocadherin17 (
PCDH17
) and demonstrated that it was significantly down-regulated and hypermethylated in LSCs compared with HSCs. Our analyses of primary AML patient samples also confirmed these deregulations. Clinically, low
PCDH17
expression was associated with female sex (
P
= 0.01), higher WBC (
P
< 0.0001), higher percentages of blasts in bone marrow (BM) and peripheral blood (PB) (
P
= 0.04 and < 0.001, respectively), presence of
FLT3
-internal tandem duplications (
P
= 0.002), mutated
NPM1
(
P
= 0.02), and wild-type
TP53
(
P
= 0.005). Moreover, low
PCDH17
expression predicted worse overall survival (OS) in four independent cohorts as well as in the molecularly defined subgroups of AML patients. In multivariable analyses, low
PCDH17
expression retained independent prognostic value for OS. Biologically,
PCDH17
expression-associated gene signatures were characterized by deregulations of EMT- and Wnt pathway-related genes.
Conclusions
PCDH17
gene was silenced by DNA methylation in AML. Low
PCDH17
expression is associated with distinct clinical and biological features and improves risk stratification in patients with AML.
Electronic supplementary material
The online version of this article (10.1186/s12967-019-1851-1) contains supplementary material, which is available to authorized users.
“…The reason for the decreased gene expression of both SFRP‐14 and DKK‐1 is CpG hypermethylation. This correlates with the poor prognosis of the disease 34,35 . A similar epigenetic mechanism may be considered to be involved in SSc.…”
Section: Discussionmentioning
confidence: 98%
“…This correlates with the poor prognosis of the disease. 34,35 A similar epigenetic mechanism may be considered to be involved in SSc.…”
is an autoimmune disease affecting skin and different internal organs. 1 It is a rare disease with a prevalence ranging from 31 to 659 per million. 1 As with many other autoimmune diseases, women are at higher risk than men. 2-4 Three main mechanisms are responsible for clinical and pathological progression. These are vascular damage (especially microcirculation), inflammation and fibrosis with immune system activation. In SSc, dermis thickening and extracellular matrix (ECM) increase are observed. 5-7 Clinically SSc is a heterogeneous disease in which different autoantibodies are observed in different clinical subgroups and can be easily detected with skin involvement. 2,8 There is no biomarker or laboratory test for SSc diagnosis, and various classification criteria have been proposed. American College of Rheumatology (ACR)/ European League Against
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