Epigenetic loss of putative tumor suppressorSFRP3correlates with poor prognosis of lung adenocarcinoma patients

Abstract

Secreted frizzled related protein 3 (SFRP3) contains a cysteine-rich domain (CRD) that shares homology with Frizzled CRD and regulates WNT signaling. Independent studies showed epigenetic silencing of SFRP3 in melanoma and hepatocellular carcinoma. Moreover, a tumor suppressive function of SFRP3 was shown in androgen-independent prostate and gastric cancer cells. The current study is the first to investigate SFRP3 expression and its potential clinical impact on non-small cell lung carcinoma (NSCLC). WNT signaling components present on NSCLC subtypes were preliminary elucidated by expression data of The Cancer Genome Atlas (TCGA). We identified a distinct expression signature of relevant WNT signaling components that differ between adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC). Of interest, canonical WNT signaling is predominant in LUAD samples and non-canonical WNT signaling is predominant in LUSC. In line, high SFRP3 expression resulted in beneficial clinical outcome for LUAD but not for LUSC patients. Furthermore, SFRP3 mRNA expression was significantly decreased in NSCLC tissue compared to normal lung samples. TCGA data verified the reduction of SFRP3 in LUAD and LUSC patients. Moreover, DNA hypermethylation of SFRP3 was evaluated in the TCGA methylation dataset resulting in epigenetic inactivation of SFRP3 expression in LUAD, but not in LUSC, and was validated by pyrosequencing of our NSCLC tissue cohort and in vitro demethylation experiments. Immunohistochemistry confirmed SFRP3 protein downregulation in primary NSCLC and indicated abundant expression in normal lung tissue. Two adenocarcinoma gain-of-function models were used to analyze the functional impact of SFRP3 on cell proliferation and regulation of CyclinD1 expression in vitro.Our results indicate that SFRP3 acts as a novel putative tumor suppressor gene in adenocarcinoma of the lung possibly regulating canonical WNT signaling.

Diagnosis value of aberrantly expressed microRNA profiles in lung squamous cell carcinoma: a study based on the Cancer Genome Atlas

“…After related analysis, 577 mRNAs were obtained as the target genes and bioinformatic analyzed, revealing that some tumor-related genes were significant in cancers and protein–protein interaction. Similarly, many genes of them have reported on LUSC ( Li et al, 2016 ; Schlensog et al, 2016 ; Sun et al, 2017 ).…”

Aberrant S100A16 expression might be an independent prognostic indicator of unfavorable survival in non-small cell lung adenocarcinoma

“…Another recent study assessed the prognostic value of epithelial cell transforming 2 ( ECT2 ) in NSCLC and observed that increased ECT2 expression might independently predict poor OS and RFS in LUAD, but not in lung squamous cell carcinoma [ 17 ]. Using the same data cohort, another study found that Secreted frizzled-related protein 3 ( SFRP3 ), a putative tumor suppressor in LUAD, is epigenetically silenced and is associated with poor prognosis [ 19 ].…”

Hypermethylation of MDFI promoter with NSCLC is specific for females, non‑smokers and people younger than 65

“…Furthermore, Pan et al ( 46 ) determined an increasing Wnt reporter gene activity in the canonical Wnt signaling pathway by knocking down endogenous MDFI expression, which indicated the MDFI gene as a tumor suppressor gene ( 21 ). As poor prognosis of NSCLC has been reported to be associated with aberrant methylation through Wnt signaling, including WNT inhibitory factor 1 ( 47 ) and secreted frizzled related protein 3 ( 48 ), a similar role of MDFI promoter methylation may participate in Wnt signaling pathway regulation for different types of cancer with aggressive phenotypes. The evidence for MDFI promoter methylation as a regulatory mechanism of gene expression in NSCLC is notable and should be further explored.…”