Abstract:BackgroundWAP four-disulfide core domain protein 2 (WFDC2) shows a tumor-restricted upregulated pattern of expression in ovarian cancer.MethodsIn this study, we evaluated the role of WFCD2 in tumor mobility, invasion and metastasis of ovarian cancer in clinical tissue and in ovarian cancer cells, both in vitro and in vivo.ResultsOur results revealed WFCD2 was overexpressed in ovarian tissues, and the expression level of WFCD2 was associated with metastasis and lymph node metastasis. Higher expression of WFCD2 … Show more
“…MMP-2 and MMP-9 are two important members of MMP family 25. A high expression level of MMP-2 and MMP-9 is found in many types of cancer, such as ovarian, cervical, hepatocellular, head and neck and thyroid, and squamous cell carcinomas 26,27. In our study, the overexpression of KCNK15-AS1 decreased the levels of MMP-2 and MMP-9.…”
BackgroundLong noncoding RNAs (lncRNAs) play an important role in gastric cancer. In this study, we aimed to uncover the epigenetic regulatory mechanism of lncRNA KCNK15-AS1 in gastric cancer progression.Patients and methodsForty patients were included in the study. The expression of KCNK15-AS1 was detected by real-time PCR (RT-PCR), the promoter of KCNK15-AS1 was detected by methylation-specific PCR, and the luciferase assay was performed to detect the relationship between KCNK15-AS1 and miR-21. The relationship of the proteins was explored by an RNA pull-down assay and RNA immunoprecipitation. Chromatin immunoprecipitation was performed to detect the relationship between the promoter and the protein.ResultsThe expression of KCNK15-AS1 was lower in the tumor tissue compared to the normal tissue. KCNK15-AS1 interacted with miR-21. Both the overexpression of KCNK15-AS1 and the knockdown of the expression of miR-21 inhibited proliferation and promoted apoptosis and decreased the level of MMP-9, bcl-2, and MMP-2 but increased the level of Bax. In addition, the methylation of KCNK15-AS1 was detected in the tumor tissue but was not detected in the normal tissue. Treatment with 5-azacytidine and chidamide decreased the level of DNMT1 and HDAC1 and increased the level of KCNK15-AS1. The RNA pull-down and RNA immunoprecipitation results showed that KCNK15-AS1 interacted with DNMT1 and HDAC1. The ChIP-seq result showed that the promoter of MAPK interacted with DNMT1, and the promoter of AKT and STAT5 interacted with HDAC1.ConclusionIn this study, we identified two regulatory axes, namely KCNK15-AS1-DNMT1-MAPK and KCNK15-AS1-HDAC1-AKT, which were associated with gastric cancer progression. Chidamide and 5-azacytidine might provide new modes for treating gastric cancer.
“…MMP-2 and MMP-9 are two important members of MMP family 25. A high expression level of MMP-2 and MMP-9 is found in many types of cancer, such as ovarian, cervical, hepatocellular, head and neck and thyroid, and squamous cell carcinomas 26,27. In our study, the overexpression of KCNK15-AS1 decreased the levels of MMP-2 and MMP-9.…”
BackgroundLong noncoding RNAs (lncRNAs) play an important role in gastric cancer. In this study, we aimed to uncover the epigenetic regulatory mechanism of lncRNA KCNK15-AS1 in gastric cancer progression.Patients and methodsForty patients were included in the study. The expression of KCNK15-AS1 was detected by real-time PCR (RT-PCR), the promoter of KCNK15-AS1 was detected by methylation-specific PCR, and the luciferase assay was performed to detect the relationship between KCNK15-AS1 and miR-21. The relationship of the proteins was explored by an RNA pull-down assay and RNA immunoprecipitation. Chromatin immunoprecipitation was performed to detect the relationship between the promoter and the protein.ResultsThe expression of KCNK15-AS1 was lower in the tumor tissue compared to the normal tissue. KCNK15-AS1 interacted with miR-21. Both the overexpression of KCNK15-AS1 and the knockdown of the expression of miR-21 inhibited proliferation and promoted apoptosis and decreased the level of MMP-9, bcl-2, and MMP-2 but increased the level of Bax. In addition, the methylation of KCNK15-AS1 was detected in the tumor tissue but was not detected in the normal tissue. Treatment with 5-azacytidine and chidamide decreased the level of DNMT1 and HDAC1 and increased the level of KCNK15-AS1. The RNA pull-down and RNA immunoprecipitation results showed that KCNK15-AS1 interacted with DNMT1 and HDAC1. The ChIP-seq result showed that the promoter of MAPK interacted with DNMT1, and the promoter of AKT and STAT5 interacted with HDAC1.ConclusionIn this study, we identified two regulatory axes, namely KCNK15-AS1-DNMT1-MAPK and KCNK15-AS1-HDAC1-AKT, which were associated with gastric cancer progression. Chidamide and 5-azacytidine might provide new modes for treating gastric cancer.
“…To further confirm the correlation with WFDC2 and MMP-2, we also examined the expression of WFDC2 and MMP-2 in clinical samples with IHC and did the correlation assay. As shown in Figure 1D, a positive correlation between MMP-2 and WFDC2 expression was observed in 100 ovarian cancer patients (tumor characteristics for ovarian cancer patient see in Table S1 or reference21). Figure 1 WFDC2 knockdown suppressed the expression of MMP-2.…”
Section: Resultsmentioning
confidence: 76%
“…Previous data have shown that WFDC2 knockdown significantly attenuates migration and invasiveness of ovarian cancer cells 5,21. MMPs, especially MMP-2 and MMP-9, can degrade the ECM to regulate cell migration and invasion 16–21.…”
Section: Resultsmentioning
confidence: 98%
“…While WAP-type proteins had been identified to be closely related to tumor metastasis by more and more evidence, especially SLPI and P13 (encode secretory leukocyte protease inhibitor[SLPI] and Elafin, respectively) 1–4. Our former work had shown that WFDC2 is a survival factor for ovarian cancer and its increased expression is associated with malignant and metastasis advantages both in vitro and in vivo 1,5,21. Otherwise, its physiological and pathological mechanisms in tumorigenesis and metastasis have not been elucidated.…”
Objective:
To understand the role of
WFDC2
in metastasis of ovarian cancer.
Methods:
By knockdown or overexpression of
WFDC2
, we demonstrated the role of
WFDC2
in epithelial–mesenchymal transition (EMT).
Results:
We demonstrated that stable knockdown of
WFDC2
suppressed EMT along with the upregulation of E-cadherin and the downregulation of Vimentin. In addition,
WFDC2
knockdown decreases matrix metalloproteinase-2 (MMP-2) expression in in vitro cell model and in in vivo nude mice xenografts. The correlation of
WFDC2
and MMP-2 expression in the clinical sample confirmed that
WFDC2
was tightly correlated with the development of tumor. More importantly, the EMT phenotype and cell invasion induced by
WFDC2
overexpressing can be reversed by the siMMP-2 and P13K/AKT signaling inhibitor.
Conclusion:
WFDC2
contributed to ovarian cancer metastasis and EMT as a positive regulator by activating AKT signaling pathway and inducing MMP-2 expression.
“…The median (pct 25-75 ) follow-up time was 21 (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26) months. In the present analysis we used the 1,611 patients who had both HFrEF (defined by HF and a LVEF ≤40%) and circulating biomarkers measured.…”
Aims
Elderly patients with heart failure with reduced ejection fraction (HFrEF) have worse prognosis and less often receive guideline-recommended therapies. We aim to better understand the underlying pathophysiological processes associated with aging in HFrEF potentially leading to targeted therapies in this vulnerable population.
Methods and Results
From a panel of 363 cardiovascular biomarkers available in 1,611 patients with HFrEF in the BIOSTAT-CHF index cohort and cross-validated in 823 patients in the BIOSTAT-CHF validation cohort, we tested which biomarkers were dysregulated in patients aged > 75yr versus <65yr. Secondly, pathway overrepresentation analyses were performed to identify biological pathways linked to higher plasma concentrations of biomarkers in elderly versus younger patients. After adjustment, multiple test correction (FDR 1%), and cross-validation, 27/363 biomarkers were associated with older age, 22 positively, and 5 negatively. The biomarkers that were positively associated with older age were associated with tumor cell regulation, extra-cellular matrix organization, and inflammatory processes, whereas biomarkers negatively associated with older age were associated with pathways that may point to cell proliferation and tumorigenesis. Among the 27 biomarkers, WFDC2 (WAP Four-Disulfide-Core-Domain-2) – that broadly functions as a protease inhibitor - was associated with older age and had the strongest association with all outcomes. No protein-by-sex interaction was observed.
Conclusions
In elderly HFrEF patients, pathways associated with extra-cellular matrix organization, inflammatory processes, and tumor cell regulation were activated, while pathways associated with tumor proliferation functions were down-regulated. These findings may help in a better understanding of the aging processes in HFrEF and identify potential therapeutic targets.
Translational perspective
Elderly patients with heart failure with reduced ejection fraction (HFrEF) have worse prognosis and less often receive guideline-recommended therapies. Using a large set of circulating proteins, elderly patients had higher concentrations of proteins associated with tumor cell regulation, extra-cellular matrix organization, and inflammatory processes, whereas pathways that may point to cell proliferation and tumorigenesis were down-regulated. WAP Four-Disulfide-Core-Domain-2 was associated with older age and had the strongest association with an increased risk of all outcomes. Understanding the underlying pathophysiological processes associated with aging in HFrEF may potentially lead to targeted therapies in this vulnerable population.
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