Epigenetic silencing of SFRP5 is related to malignant phenotype and chemoresistance of ovarian cancer through Wnt signaling pathway

Su, Her-Young; Lai, Hung Cheng; Lin, Yu-Shen; Liu, Chin Yun; Chen, Chi Kuan; Chou, Yu Ching; Lin, Shin Ping; Lin, Wen Ting; Lee, Hsin Yi; Mu, Yu

doi:10.1002/ijc.25083

Cited by 155 publications

(116 citation statements)

References 46 publications

(70 reference statements)

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“…This supports previous studies showing upregulation of the Wnt/β-catenin pathway in platinum-resistant ovarian cancer. 9,14 In addition, PORCN gene expression correlates with ascites cell sensitivity to WNT974 (Figure 8b). Higher PORCN expression was measured in the untreated ascites samples that produced a ≥ 30% reduction in ATP when treated with WNT974 Figure 6 Immunohistochemical analysis of survivin and p-LRP6.…”

Section: Resultsmentioning

confidence: 97%

“…We did demonstrate increased RSPO3 gene expression in samples resistant to carboplatin in support of previous studies demonstrating upregulation of the Wnt/β-catenin pathway in platinumresistant cancer cells. 9,14 PORCN expression may be a potential indicator for patients who would respond to WNT974 because higher PORCN expression was seen in the patient ascites samples with ≥ 30% reduction in ATP on ATPlite analysis.…”

Section: Discussionmentioning

confidence: 99%

“…9 The Wnt/β-catenin pathway has also been shown to contribute to chemoresistance in ovarian cancer as it promotes epithelial-to-mesenchymal transition. 14 Porcupine (PORCN) is an enzyme that is crucial to Wnt ligand transport, secretion, and activity. 15 WNT974 (Novartis, Cambridge, MA, USA) is a selective, orally bioavailable PORCN inhibitor that decreases the secretion of Wnt ligands outside the cell leading to a decrease in Wnt ligand cell surface receptor phosphorylation and a decrease in the expression of Wnt target genes.…”

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confidence: 99%

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Targeting the Wnt/β-catenin pathway in primary ovarian cancer with the porcupine inhibitor WNT974

Boone

Arend

Johnston

et al. 2016

Laboratory Investigation

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Preclinical studies in ovarian cancer have demonstrated upregulation of the Wnt/β-catenin pathway promoting tumor proliferation and chemoresistance. Our objective was to evaluate the effect of the Wnt/β-catenin pathway inhibitor, WNT974, in primary ovarian cancer ascites cells. Ascites cells from patients with papillary serous ovarian cancer were isolated and treated with 1 μM WNT974 ± 100 μM carboplatin. Viability was evaluated with the ATPlite assay. The IC 50 was calculated using a dose-response analysis. Immunohistochemistry (IHC) was performed on ascites cells and tumor. Expression of R-spondin 2 (RSPO2), RSPO3, PORCN, WLS, AXIN2, and three previously characterized RSPO fusion transcripts were assessed using Taqman assays. Sixty ascites samples were analyzed for response to WNT974. The ascites samples that showed a decrease in ATP concentration after treatment demonstrated no difference from the untreated cells in percent viability with trypan blue staining. Flow cytometry demonstrated fewer cells in the G2 phase and more in the G1 and S phases after treatment with WNT974. Combination therapy with WNT974 and carboplatin resulted in a higher percentage of samples that showed ≥ 30% reduction in ATP concentration than either single drug treatment. IHC analysis of Wnt pathway proteins suggests cell cycle arrest rather than cytotoxicity after WNT974 treatment. QPCR indicated that RSPO fusions are not prevalent in ovarian cancer tissues or ascites. However, higher PORCN expression correlated to sensitivity to WNT974 (P = 0.0073). In conclusion, WNT974 produces cytostatic effects in patient ascites cells with primary ovarian cancer through inhibition of the Wnt/β-catenin pathway. The combination of WNT974 and carboplatin induces cytotoxicity plus cell cycle arrest in a higher percentage of ascites samples than with single drug treatment. RSPO fusions do not contribute to WNT974 sensitivity; however, higher PORCN expression indicates increased WNT974 sensitivity.

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Section: Resultsmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Targeting the Wnt/β-catenin pathway in primary ovarian cancer with the porcupine inhibitor WNT974

Boone

Arend

Johnston

et al. 2016

Laboratory Investigation

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“…Our previous study demonstrated that epigenetic silencing of SFRP5 is related to ovarian cancer progression and chemoresistance 44. In this study, we focused on the roles of PSMB8 expression in tissue samples and EOC cell lines.…”

Section: Discussionmentioning

confidence: 99%

Distinct methylation profile of mucinous ovarian carcinoma reveals susceptibility to proteasome inhibitors

Liew

Huang

Weng

et al. 2018

Intl Journal of Cancer

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Mucinous type of epithelial ovarian cancer (MuOC) is a unique subtype with a poor survival outcome in recurrent and advanced stages. The role of type‐specific epigenomics and its clinical significance remains uncertain. We analyzed the methylomic profiles of 6 benign mucinous adenomas, 24 MuOCs, 103 serous type of epithelial ovarian cancers (SeOCs) and 337 nonepithelial ovarian cancers. MuOC and SeOC exhibited distinct DNA methylation profiles comprising 101 genes, 81 of which exhibited low methylation in MuOC and were associated with the response to glucocorticoid, ATP hydrolysis‐coupled proton transport, proteolysis involved in the cellular protein catabolic process and ion transmembrane transport. Hierarchical clustering analysis showed that the profiles of MuOC were similar to colorectal adenocarcinoma and stomach adenocarcinoma. Genetic interaction network analysis of differentially methylated genes in MuOC showed a dominant network module is the proteasome subunit beta (PSMB) family. Combined functional module and methylation analysis identified PSMB8 as a candidate marker for MuOC. Immunohistochemical staining of PSMB8 used to validate in 94 samples of ovarian tumors (mucinous adenoma, MuOC or SeOC) and 62 samples of gastrointestinal cancer. PSMB8 was commonly expressed in MuOC and gastrointestinal cancer samples, predominantly as strong cytoplasmic and occasionally weak nuclei staining, but was not expressed in SeOC samples. Carfilzomib, a second‐generation proteasome inhibitor, suppressed MuOC cell growth in vitro. This study unveiled a mucinous‐type‐specific methylation profile and suggests the potential use of a proteasome inhibitor to treat MuOC.

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“…Wnt inhibition, either by monoclonal antibodies, small-interfering RNAs (siRNAs) targeting Wnt components or the overexpression of Wnt antagonists, retards lung cancer progression in various in vitro and in vivo tumor models (5,6). Furthermore, inactivation of Wnt/β-catenin signaling sensitizes chemotherapy by inducing apoptosis and growth arrest in cancer cells, suggesting the potential role of Wnt signaling inhibitors in the reversal of cisplatin resistance (7)(8)(9).…”

Section: Introductionmentioning

confidence: 99%

Dickkopf-3 (Dkk3) induces apoptosis in cisplatin-resistant lung adenocarcinoma cells via the Wnt/β-catenin pathway

Wang

et al. 2014

Oncology Reports

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Abstract. Previous studies have shown that is inactivated in lung cancer cells, while the inactivation of the Wnt/β-catenin signaling pathway by Dkk3 inhibits lung cancer progression. In the present study, we investigated whether Dkk3 enhances the sensitivity of lung cancer cells to cisplatin. A549, Calu1 and H460 lung adenocarcinoma cell lines were transfected with DKK3 siRNA, while the cisplatin-resistant subline A549cis was transfected with DKK3. DKK3 expression was attenuated in A549cis, Calu1cis and H460cis compared to A549, Calu1 and H460, respectively. Lung adenocarcinoma cell growth, proliferation, apoptosis, cell cycle in vitro and in vivo were then analyzed. DKK3 knockdown by siRNA transfection rendered A549, Calu1 and H460 resistant to cisplatin. As a result of DKK3 transfection, the expression of DKK3 and E-cadherin was significantly upregulated, while that of MMP7, survivin, c-myc and cyclin D1 was downregulated. DKK3 overexpression retarded cell proliferation, induced cell cycle arrest and apoptosis, and reduced cell invasive ability in the A549 and A549cis cells. In addition, the proportions of apoptotic cells and the PARP level were significantly increased in A549cis-and H460cis-DKK3 cells treated with cisplatin. Moreover, tumor growth was retarded more in cisplatin-treated nude mice seeded with A549cis-DKK3 cells than with A549cis cells. Cell viability increased with the pretreatment of SB216763 for 2 h in A549cis and A549cis-DKK3 cells incubated with cisplatin (1 µM) for 72 h. In conclusion, the re-activation of Dkk3 enhances the chemosensitivity to cisplatin in cisplatin-resistant lung adenocarcinoma cell lines, which requires additional studies to realize this potential in clinical use. IntroductionLung cancer has emerged as the third leading cause of cancer-related mortality worldwide (1). In the USA, over 200,000 new lung cancer cases are diagnosed annually, causing over 150,000 deaths in one year (1). Approximately 85% of lung cancer patients suffer from non-small cell lung cancer (NSCLC). Due to the comparative therapeutic advantage, cisplatin-based combination regimens are recommended as the optimal choice currently for the majority of NSCLC patients indicative of chemotherapy or adjuvant chemotherapy (2). However, the average survival time for patients with advanced stage of NSCLC receiving cisplatin plus gemcitabine treatment is ~16 months and may even be reduced to 12 months in those with cisplatin-resistance (3). The dilemma in managing late-stage NSCLC requires the elucidation of the mechanisms in cisplatin resistance to define novel, effective and applicable therapeutic targets for lung cancer (2,3).Several signal transduction pathways controlling chemosensitivity are aberrantly activated in various types of cancer, among which Wnt is of special significance (4). The role of Wnt1/Int-1 in the induction of mouse mammary tumor as an integration site for mouse mammary tumor virus (MMTV) was first recognized 30 years ago (4). Wnt/β-catenin signaling is initiated by the binding of secre...

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Epigenetic silencing of SFRP5 is related to malignant phenotype and chemoresistance of ovarian cancer through Wnt signaling pathway

Cited by 155 publications

References 46 publications

Targeting the Wnt/β-catenin pathway in primary ovarian cancer with the porcupine inhibitor WNT974

Targeting the Wnt/β-catenin pathway in primary ovarian cancer with the porcupine inhibitor WNT974

Distinct methylation profile of mucinous ovarian carcinoma reveals susceptibility to proteasome inhibitors

Dickkopf-3 (Dkk3) induces apoptosis in cisplatin-resistant lung adenocarcinoma cells via the Wnt/β-catenin pathway

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