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Research Paper Volume 12, Issue 4 pp 3574-3593
SERPINH1 regulates EMT and gastric cancer metastasis via the Wnt/β-catenin signaling pathway
Relevance score: 15.153123Shan Tian, Pailan Peng, Jiao Li, Huan Deng, Na Zhan, Zhi Zeng, Weiguo Dong
Keywords: epithelial-mesenchymal transition, SERPINH1, gastric cancer, Wnt/β-catenin pathway, therapeutic target
Published in Aging on February 24, 2020
Analysis of SERPINH1 mRNA expression in normal and gastric cancer (GC) tissues from 3 public databases. SERPINH1 mRNA levels are significantly lower (P<0.0001) in normal gastric mucosal than that in gastric cancer tissue samples in the (A) Cho (Normal=19; Tumor=65), (B) Cui (Normal=80; Tumor=80), and (C) Chen (Normal=29; Tumor=83) Gastric datasets from the Oncomine database; (D) STAD dataset (Normal=35; Tumor=415) from the TCGA database; and (E) GSE29272 (Normal=134; Tumor=134) and (F) GSE54129 (Normal=21; Tumor=111) datasets from the GEO databases.
Receiver operating characteristic (ROC) curve analysis to determine diagnostic relevance of SERPINH1 mRNA levels in GC patients. ROC curve analysis of SERPINH1 mRNA levels in the (A) Cho (AUC=0.945), (B) Cui (AUC=0.807), and (C) Chen (AUC=0.997) Gastric datasets from the Oncomine database; (D) STAD dataset (AUC=0.919) from the TCGA database; and (E) GSE29272 (AUC=0.931) and (F) GSE54129 (AUC=0.993) datasets from the GEO databases.
Correlation analyses between SERPINH1 mRNA levels and different clinicopathological characteristics of GC patients. The association between SERPINH1 levels and clinicopathological characteristics of GC patients, including (A) Age (P=0.48); (B) Gender (P=0.66); (C) Infection of Helicobacter pylori (HP; P=0.51); (D) Tumor grade (G) stage (P=0.85); (E) Tumor size (P=0.68); (F) Tumor Node Metastasis (TNM) stage (P=0.54); (G) Tumor (T) stage (P=0.12); (H) Node (N) stage (P=0.77); (I) Metastasis (M) stage (P=0.97); (J) Tumor status (P=0.63); (K) Overall Survival (OS; P=0.04); (L) Relapse-free survival (RFS; P=0.16).
Analysis of the prognostic significance of SERPINH1 mRNA levels in GC patients. (A) Patients with high SERPINH1 mRNA levels show significantly poorer OS than patients with low SERPINH1 mRNA levels in the TCGA-STAD dataset (N=388, HR=1.49, P=0.0198). (B) Patients with high SERPINH1 mRNA levels show poorer RFS than patients with low SERPINH1 mRNA levels in the TCGA-STAD dataset (N=324, HR=1.89, P=0.015). (C) GC patients with high SERPINH1 mRNA levels show poorer OS than the GC patients with low SERPINH1 levels in the Kaplan-Meier Plotter database (N=876, HR=1,56, P<0.0001). (D) GC patients with high SERPINH1 mRNA levels show poorer PFS than GC patients with low SERPINH1 levels in the Kaplan-Meier Plotter database (N=641, HR=1.73, P<0.0001).
Immunohistochemical analysis of SERPINH1 protein expression in human GC tissues. (A) Immunohistochemical (IHC) analysis shows that SERPINH1 protein levels are significantly higher in five pairs of matched GC tissues compared with the adjacent non-tumor gastric mucosal tissues. (B–E) Representative images show IHC staining of SERPINH1 protein in (B, C) normal gastric mucosal tissues and (D, E) gastric cancer tissues at 100X and 200X magnification, respectively. (F) Comparison of IHC scores show that SERPINH1 protein expression is significantly higher (P=0.02) in gastric cancer tissues (N=102) compared with adjacent non-tumor gastric tissues (N=48). (G) Survival curve analysis shows that GC patients with high SERPINH1 protein levels exhibit poorer OS than patients with low SERPINH1 protein levels (HR=3.35, P=0.0004).
SERPINH1 expression regulates the proliferation and survival of GC cell lines. (A) Western blot analysis shows that SERPINH1 protein levels are higher in the four GC cell lines, HGC-27, AGS, MGC-803, SGC-7901, compared to the normal gastric mucosal cell line, GES-1. (B) Western blot analysis shows that SERPINH1 protein levels are significantly reduced in shSERPINH1 #1-transfected SGC-7901 cells compared with SGC-7901 cells transfected with shSERPINH1 #2, shSERPINH1 #2, and shNC. (C) Representative images of colonies in shSERPINH1#1-transfected SGC-7901 cells, SERPINH1-overexpression vector transfected MGC-803 cells, and their corresponding controls. (D) Histogram plots show the number of colonies in shSERPINH1#1-transfected SGC-7901 cells, SERPINH1-overexpression vector-transfected MGC-803 cells, and their corresponding controls. (E) Flow cytometry analysis shows that apoptotic rate is significantly higher in the shSERPINH1#1-transfected SGC-7901 cells and significantly lower in the SERPINH1-overexpression vector-transfected MGC-803 cells compared to their corresponding controls. (F) Histogram plot shows the percentage of apoptotic cells in shNC-, and shSERPINH1#1-transfected SGC-7901 cell cultures, as well as, empty vector and SERPINH1-overexpression vector-transfected MGC-803 cells.
SERPINH1 expression regulates in vitro migration and invasion of GC cells. (A) Wound healing assay shows that the distance between wound edges was higher in SERPINH1-silenced SGC-7901 cells than in the control SGC-7901 cells at 24 h. Conversely, the distance between wound edges was significantly lower in the SERPINH1-overexpressing MGC-803 cells than in the control MGC-803 cells at 24 h. (B) Quantitative analysis of wound healing assay in the control and SERPINH1-silenced SGC-7901 cells, as well as control and SERPINH1-overexpressing MGC-803 cells. (C) Representative images show results of the Transwell migration assay, and (D) histogram plots show the number of migrating cells in the control and SERPINH1-silenced SGC-7901 cells, as well as control and SERPINH1-overexpressing MGC-803 cells. As shown, migration is reduced in SERPINH1-silenced SGC-7901 cells and increased in SERPINH1 overexpressed MGC-803 cells compared with the corresponding controls. (E) Western blot analysis shows that MMP2 and MMP9 protein levels are significantly reduced in the shSERPINH1-silenced SGC-7901 cells and increased in the SERPINH1-overexpressing MGC-803 cells compared with the corresponding controls. (F, G) Gene expression analysis shows that (F) MMP2 (r=0.55, P<0.0001) and (G) MMP9 (r=0.24, P<0.0001) mRNA levels positively correlate with SERPINH1 mRNA levels in GC patients from the TCGA-STAD dataset.
SERPINH1 regulates EMT markers and Wnt/β-catenin signaling pathway in GC. (A) Western blot analysis shows reduced N-cadherin and increased E-cadherin expression in SERPINH1-silenced SGC-7901 cells compared with controls. Conversely, SERPINH1-overexpressing MGC-803 cells show increased N-cadherin and reduced E-cadherin expression compared with the controls. (B) Western blot analysis shows increased levels of β-catenin, Wnt2, GSK-3β, p-GSK-3β, NF-κB p65, Snail1, Slug, and TWIST in the SERPINH1-overexpressing MGC-803 cells compared with the controls, whereas SERPINH1-silenced SGC-7901 cells show reduced levels of β-catenin, Wnt2, GSK-3β, p-GSK-3β, NF-κB p65, Snail1, Slug, and TWIST compared with the controls. (C) Immunofluorescence staining of E-cadherin, N-cadherin and SERPINH1 proteins in the control and SERPINH1-silenced SGC-7901 cells, as well as, control and SERPINH1-overexpressing MGC-803 cells. (D, E) Gene expression analysis of the TCGA-STAD dataset shows (D) negative correlation of CDH1 (r=-0.12, P=0.019) or E-cadherin mRNA levels and (E) positive association of CDH2 (r=0.40, P<0.0001) or N-cadherin mRNA levels with the SERPINH1 mRNA levels.
Anti-tumor effects of CO1003 in GC cells. (A) CCK-8 assay analysis shows concentration-dependent inhibition of proliferation of SGC-7901 GC cells by CO1003 (0, 0.01, 0.1, 1, 10, 100, 1000 μM). This curve was used to determine the IC50 concentration of CO1003, which is the concentration of CO1003 required to reduce proliferation of SGC-7901 cells by 50%. IC50 for CO1003 is 47.56 μM. (B) Transwell migration and invasion assay shows reduced migration and invasion of CO1003-treated SGC-7901 cells compared to the DMSO-treated GC cells. (C, D) Histogram plots show total number of (C) migrating and (D) invading DMSO- and CO1003-treated SGC-7901 cells. (E) Representative images of wound healing assay show that the distance between wound edges was significantly higher in Co1003-treated SGC-7901 cells compared with the DMS-treated SGC-7901 cells. (F) Wound healing assay shows lower wound healing rate because of reduced migration in CO1003-treated SGC-7901 cells compared with the DMSO-treated SGC-7901 cells.
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Research Paper Volume 12, Issue 2 pp 1527-1544
Aquaporin 9 inhibits growth and metastasis of hepatocellular carcinoma cells via Wnt/β-catenin pathway
Relevance score: 17.526304Shengtao Liao, Hongyu Chen, Min Liu, Li Gan, Chuanfei Li, Wenguang Zhang, Lin Lv, Zhechuan Mei
Keywords: aquaporin 9, hepatocellular carcinoma, prognosis, Wnt/β-catenin pathway
Published in Aging on January 22, 2020
The expression of AQP9 was reduced in HCC samples. (A–D) The levels of AQP9 were examined in HCC and paired non-tumor tissues by immunohistochemistry analysis (magnificationx200 and x400). (E and F) The levels of AQP9 were also examined using western blotting. The results were represented as mean ± SD. P<0.05 vs. para-carcinoma control. Each experiment was repeated 3 times. AQP, aquaporin 9; HCC, hepatocellular carcinoma.
The levels of AQP9 in HCC tissues were associated with the prognosis of patients. (A) The expression of AQP9 was evaluated in HCC and matched para-carcinoma samples by RT-qPCR. The levels of AQP9 were examined in HCC tissues with various tumor diameter (B) lymph node metastasis (C) and different TNM stages (D). Survival rate of 50 HCC patients with different AQP9 expression levels (E) and those in the GEPIA database (F); 182 cases with high-/low-expression were analyzed. The results were represented as mean ± SD. P<0.05 vs. control group. Each experiment was repeated 3 times. AQP, aquaporin 9; HCC, hepatocellular carcinoma; RT-qPCR, reverse transcriptase-quantitative polymerase chain reaction.
Down-regulation of AQP9 in HCC cells. (A) The mRNA levels of AQP9 in HCC cell lines were determined compared with the control. (B–D) The protein levels of AQP9 in Huh-7 and SMMC-7721 cells transfected with LV-NC or LV-AQP9 were also examined using western blotting. The results were represented as mean ± SD. P<0.05 vs. LO2 or LV-NC. Each experiment was repeated 3 times. AQP, aquaporin 9; HCC, hepatocellular carcinoma; NC, negative control.
Overexpression of AQP9 inhibited proliferation of HCC cells. (A and B) The proliferative activity of Huh-7 and SMMC-7721 cells transfected with LV-AQP9 was determined by CCK-8 assay compared with the control. (C) The expression levels of PCNA in HCC cells were examined following the transfection with LV-NC or LV-AQP9. (D–F) The expression of PCNA in Huh-7 and SMMC-7721 cells transfected with LV-NC or LV-AQP9 were evaluated using immunocytochemistry analysis. The results were represented as mean ± SD. P<0.05 vs. LV-NC. Each experiment was repeated 3 times. AQP, aquaporin 9; HCC, hepatocellular carcinoma; NC, negative control.
Overexpressed AQP9 inhibited invasion, migration and EMT in HCC cells, but promoted cell apoptosis. (A and C) The invasive abilities in Huh-7 and SMMC-7721 cells transfected with LV-NC or LV-AQP9 were determined by Transwell assay (magnificationx100). (B and D) Cell migration were examined following the transfection of LV-AQP9 (magnificationx100). (E and F) The mRNA levels of E-cad, N-cad and α-SMA in transfected Huh-7 and SMMC-7721 cells were evaluated using RT-qPCR. (G–I) The cell apoptosis rate in HCC cells transfected with LV-NC or LV-AQP9 was analyzed by flow cytometry. Data are shown as mean ± SD based on at least three independent experiments. The results were represented as mean ± SD. P<0.05 vs. LV-NC. Each experiment was repeated 3 times. AQP, aquaporin 9; HCC, hepatocellular carcinoma; NC, negative control; RT-qPCR, reverse transcriptase-quantitative polymerase chain reaction.
Overexpression of AQP9 was able to suppress Wnt/β-catenin signaling. (A–D) The mRNA and protein levels of DVL2, GSK-3β, CyclinD1 and β-catenin in Huh-7 and SMMC-7721 cells transfected with LV-NC or LV-AQP9 were examined by RT-qPCR and western blotting. (E) The expression of β-catenin in HCC cells treated with XAV939 were evaluated using RT-qPCR. (F) The mRNA levels of β-catenin in SMMC-7721 cells were determined following the treatment with SKL2001. (G) The protein levels of β-catenin in HCC cells were assessed by western blot analysis. The results were represented as mean ± SD. P<0.05 vs. NC or LV-NC. Each experiment was repeated 3 times. AQP, aquaporin 9; HCC, hepatocellular carcinoma; NC, negative control; RT-qPCR, reverse transcriptase-quantitative polymerase chain reaction.
Blockage of Wnt/β-catenin signaling inhibited growth and metastasis of HCC cells. (A) The proliferation of Huh-7 cells treated with XAV939 was determined by CCK-8 assay. (B) The mRNA levels of E-cad, N-cad and α-SMA in transfected HCC cells were examined using RT-qPCR. (C and D) The expression of PCNA in Huh-7 cells were evaluated following the treatment with XAV939. (E to H) The invasive and migrative abilities of HCC cells treated with XAV939 were assessed by Transwell assay (magnificationx100). (I and J) Cell apoptosis following the treatment with XAV939 was determined using flow cytometry. The results were represented as mean ± SD. P<0.05 vs. NC. Each experiment was repeated 3 times. HCC, hepatocellular carcinoma; RT-qPCR, reverse transcriptase-quantitative polymerase chain reaction.
Activation of Wnt/β-catenin pathway reversed the effects of AQP9 on HCC progression. (A) The proliferation of SMMC-7721 cells transfected with LV-NC, LV-AQP9 or LV-AQP9+SKL2001 was determined. (B–D) The expression levels of PCNA, E-cad, N-cad and α-SMA in transfected HCC cells were examined using RT-qPCR. (E and F) The invasive and migration activities of SMMC-7721 cells were evaluated following the treatment with LV-NC, LV-AQP9 or LV-AQP9+SKL2001 (magnificationx100). (G) The apoptosis rate of transfected HCC cells was assessed by flow cytometry. The results were represented as mean ± SD. P<0.05 vs. LV-NC. Each experiment was repeated 3 times. AQP, aquaporin 9; HCC, hepatocellular carcinoma; NC, negative control; RT-qPCR, reverse transcriptase-quantitative polymerase chain reaction.
Overexpression of AQP9 suppressed tumor growth of HCC in vivo. (A) The growth curves of tumors from nude mice in LV-NC and LV-AQP9 group. (B and C). Orthotopic tumor volumes and weights at day 42 post-injection were calculated. (D) The protein levels of AQP9, DVL2, GSK-3β, CyclinD1 and β-catenin in isolated tumors were examined using western blotting. (E) The mRNA levels of E-cad, N-cad and α-SMA were determined by RT-qPCR. The results were represented as mean ± SD. P<0.05 vs. LV-NC. AQP, aquaporin 9; HCC, hepatocellular carcinoma; NC, negative control; RT-qPCR, reverse transcriptase-quantitative polymerase chain reaction.
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Research Paper Volume 11, Issue 12 pp 4216-4237
β-catenin-mediated hair growth induction effect of 3,4,5-tri-
Relevance score: 12.545102O -caffeoylquinic acidMeriem Bejaoui, Myra O. Villareal, Hiroko Isoda
Keywords: 3,4,5-tri-O-caffeoylquinic acid (TCQA), β-catenin, dermal papilla, anagen, Wnt/ β-catenin pathway
Published in Aging on June 29, 2019
TCQA promoted hair regrowth in C3H mice skin. (A) The back skin of eight-weeks-old male C3H mice was shaved and treated daily with topical application of 1 wt% TCQA (1 g TCQA in 100 ml milli-Q water) and with milli-Q water (control) for 30 days. (B) The area of the new generated coat was measured by ImageJ. (C) Skin from treated area from TCQA-treated group and control group were cut at thickness of 10 µM and visualized under the microscope. *Statistically significant (P ≤0.05) difference between control and TCQA-treated group. **Statistically significant (P ≤0.01) difference between control and TCQA-treated mice.
. Transcriptome changes induced by TCQA, 1235 genes were significantly selected: 435 were upregulated and 800 downregulated. (A) Summary of the functional categories of upregulated genes in response to TCQA treatment. (B) Summary of the functional categories of downregulated genes in response to TCQA treatment. Analyses for the down and upregulated genes were performed individually using Database for Annotation, Visualization and Integrated Discovery v6.8 (DAVID). Bars represent the number of genes implicated in each category. *Statistically significant (P ≤0.01). **Statistically significant (P ≤0.001). ***Statistically significant (P ≤0.0001).
Transcriptome changes induced by TCQA, 1235 genes were significantly selected: 435 were upregulated and 800 downregulated. (C) Hierarchical clustering of the genes altered after treatment with TCQA using Euclidean distance and average linkage algorithm of the TIGR Mev version 3.0.3 software (The Institute for Genomic Research, MD, USA). Horizontal stripes represent genes and columns represent control and TCQA. The significant fold change in gene expression is 2-fold change (control vs TCQA). (D) The volcano plot represents the regulated genes between the control and TCQA. The red color represents the upregulated genes, the green color the downregulated genes, and the grey color the unregulated genes. The expression of the genes above or below, left or right, the lines differed more than 2-fold change between the control and TCQA group.
TCQA enhanced β-catenin expression in the hair follicle. (A) Immunohistochemistry was performed to measure β-catenin expression in the hair follicle and the epidermis in skin collected from the treated area from mice dorsal skin at 30 days after treatment. The figure is divided into four panels, the first panel is the phase, the second is DAPI to stain the nucleus, the third is for β-catenin staining, and the last panel is a merge between β-catenin and the nucleus. (B) Ctnnb1 mRNA relative expression was measured after treatment with TCQA at 30 days after treatment. The mRNA level was quantified using TaqMan real-time PCR from RNA extracted from the treated area (TCQA or milli-Q water) from the mice dorsal back.
TCQA enhanced β-catenin expression in the hair follicle. (C) β-catenin protein expression was determined at the end of the treatment period. The protein was extracted from the treated area from the mice dorsal part, and western blot was carried away. (D) Band intensities was done assessed using LI-COR system. Results represent the mean ± SD of three independent experiments. *Statistically significant (P ≤0.05) difference between control and TCQA-treated mice. **Statistically significant (P ≤0.01) difference between control and TCQA-treated mice. (E) Summary of the up and downregulated genes modulated by TCQA compared with the control. The red color represents the upregulated genes and the green color the downregulated genes.
TCQA stimulated hair bulb cells proliferation. (A) Cell proliferation of human epidermal melanocytes (HEM) was assessed after 48 and 72 h treatment with various concentrations of TCQA. (B) Cell proliferation of human hair follicle dermal papilla cells (HFDPCs) was assessed after 48 and 72 h treatment with various concentrations of TCQA. (C) ATP content determination after treatment with 5 and 10 µM of TCQA and 0.1 µM of minoxidil (Minox) used as positive control. (D) Gene expression of ALPL (Alkaline Phosphatase) after 6 and 12 h treatment with 0, 10 µM TCQA, and 0.1 Minox. The mRNA level was quantified using TaqMan real-time PCR after treatment. Results represent the mean ± SD of three independent experiments. *Statistically significant (P ≤0.05) difference between control and treated cells. **Statistically significant (P ≤0.01) difference between control and treated cells. ##Statistically significant (P ≤0.01) difference between Minox-treated cells and TCQA-treated cells.
TCQA stimulated β-catenin expression in human hair follicle dermal papilla cells (HFDPCs). (A) β-catenin protein expression after 12 and 24 h treatment with 0 and 10 µM TCQA and 0.1 µM Minox. (B) Band intensities was done using LI-COR system after 12 h and 24 h treatment.
TCQA stimulated β-catenin expression in human hair follicle dermal papilla cells (HFDPCs). (C) Immunocytochemistry of β-catenin expression in HFDPC after 24 h treatment with 0, 10 µM TCQA and 0.1 µM Minox. Scale bar=25 µm; magnificence 40 X. (D) Gene expression of CTNNB1 (β-catenin) after treatment with 0 and 10 µM TCQA, and 0.1 µM Minox for 6 h and 12 h. The mRNA level was quantified using TaqMan real-time PCR after treatment.
TCQA stimulated β-catenin expression in human hair follicle dermal papilla cells (HFDPCs) (E) Cell proliferation of HFDPC was assessed after 48 h treatment with various concentrations of XAV939 (β-catenin inhibitor). (F) Gene expression expressions of CTNNB1 (β-catenin) after treatment with 10 µM XAV939 for 6 and 12 h, with 10 µM XAV939 for 6 and 12 h then with 10 µM TCQA for 6 h and 12 h (XAV939/TCQA), and finally with co-treatment of 10 µM XAV939 and 10 µM TCQA for 6 and 12 h (XAV939+TCQA). Results represent the mean ± SD of three independent experiments. *Statistically significant (P ≤0.05) difference between control and treated cells. **Statistically significant (P ≤0.01) difference between control and treated cells. ##Statistically significant (P ≤0.01) difference between Minox-treated cells and TCQA-treated cells.