Epigenetic loss of putative tumor suppressor SFRP3 correlates with poor prognosis of lung adenocarcinoma patients.
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.
a Institute of Pathology , Medical Faculty of the RWTH Aachen University , Aachen , Germany.
Martin
M
Schlensog
a Institute of Pathology , Medical Faculty of the RWTH Aachen University , Aachen , Germany.
Lara
L
Magnus
a Institute of Pathology , Medical Faculty of the RWTH Aachen University , Aachen , Germany.
Timon
T
Heide
a Institute of Pathology , Medical Faculty of the RWTH Aachen University , Aachen , Germany.
Julian
J
Eschenbruch
a Institute of Pathology , Medical Faculty of the RWTH Aachen University , Aachen , Germany.
Florian
F
Steib
a Institute of Pathology , Medical Faculty of the RWTH Aachen University , Aachen , Germany.
Maximilian
M
Tator
a Institute of Pathology , Medical Faculty of the RWTH Aachen University , Aachen , Germany.
Vera
V
Kloten
a Institute of Pathology , Medical Faculty of the RWTH Aachen University , Aachen , Germany.
Michael
M
Rose
b Institute of Complex Systems, Research Center Jülich , Jülich , Germany.
Erik
E
Noetzel
a Institute of Pathology , Medical Faculty of the RWTH Aachen University , Aachen , Germany.
Nadine T
NT
Gaisa
a Institute of Pathology , Medical Faculty of the RWTH Aachen University , Aachen , Germany.
Ruth
R
Knüchel
a Institute of Pathology , Medical Faculty of the RWTH Aachen University , Aachen , Germany.|c RWTH centralized Biomaterial Bank (RWTH cBMB) at the Institute of Pathology , Medical Faculty of the RWTH Aachen University , Aachen , Germany.
Edgar
E
Dahl
D000072283:A549 Cells; D000077192:Adenocarcinoma of Lung / Q000235:genetics* / Q000473:pathology; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology; D049109:Cell Proliferation / Q000235:genetics; D019938:Cyclin D1 / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D011379:Prognosis; D000077982:Progression-Free Survival; D060449:Wnt Signaling Pathway / Q000235:genetics; D000099274:Frizzled-Related Proteins
D019938:Cyclin D1; D047908:Intracellular Signaling Peptides and Proteins; D000099274:Frizzled-Related Proteins
DNA methylation; Lung cancer; NSCLC; SFRP3; WNT signaling