TJP1

Gene Summary

Gene:TJP1; tight junction protein 1
Aliases: ZO-1
Location:15q13.1
Summary:This gene encodes a member of the membrane-associated guanylate kinase (MAGUK) family of proteins, and acts as a tight junction adaptor protein that also regulates adherens junctions. Tight junctions regulate the movement of ions and macromolecules between endothelial and epithelial cells. The multidomain structure of this scaffold protein, including a postsynaptic density 95/disc-large/zona occludens (PDZ) domain, a Src homology (SH3) domain, a guanylate kinase (GuK) domain and unique (U) motifs all help to co-ordinate binding of transmembrane proteins, cytosolic proteins, and F-actin, which are required for tight junction function. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Aug 2017]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:tight junction protein ZO-1
Source:NCBIAccessed: 31 August, 2019

Ontology:

What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: TJP1 (cancer-related)

Kishore C, Sundaram S, Karunagaran D
Vitamin K3 (menadione) suppresses epithelial-mesenchymal-transition and Wnt signaling pathway in human colorectal cancer cells.
Chem Biol Interact. 2019; 309:108725 [PubMed] Related Publications
Tumor recurrence and metastasis decrease the survival rate of colorectal cancer (CRC) patients. Menadione reduces the numbers and incidences of 1,2-dimethylhydrazine induced colon tumors in mouse but the mechanism of anticancer activity of menadione in colorectal cancer is not very clear. Since Wnt signaling is constitutively active in CRC and it aggravates the epithelial mesenchymal transition (EMT), the regulation of EMT and Wnt signaling by menadione (vitamin K3) was investigated in CRC cells. Menadione showed cytotoxicity against human CRC cells (SW480 and SW620) and human primary colon cancer cells but was relatively ineffective against the cells from human normal colon (CRL-1790) and human primary colon epithelial cells. Menadione suppressed invasion, migration and epithelial-mesenchymal transition in human CRC cells by upregulating the expression of E-cadherin (CDH1), ZO-1 and downregulating that of N-cadherin (CDH2), Vimentin (VIM), ZEB1, MMP2 and MMP9. Menadione decreased TOPFlash/FOPFlash luciferase activity and expression of several downstream targets of Wnt signaling and coactivators such as β-catenin (CTNNB1), TCF7L2, Bcl9l, p300 (EP300) and cyclin D1 (CCND1) was suppressed. Menadione induced differentiation and increased apoptotic cell population in SubG0 phase of cell cycle in SW480 and SW620 cells. The ability of menadione to suppress EMT, migration, invasion, Wnt signaling, cell proliferation and induce Sub G0 arrest, highlights its potential to be considered for intensive preclinical and clinical investigation in CRC.

Lu X, Yu Y, Tan S
Long non-coding XIAP-AS1 regulates cell proliferation, invasion and cell cycle in colon cancer.
Artif Cells Nanomed Biotechnol. 2019; 47(1):767-775 [PubMed] Related Publications
Colon cancer is one of the most commonly diagnosed and deadly cancers worldwide. Further understanding of the biological mechanisms is important for exploring the molecular biomarkers and therapeutic targets of this disease. Dysregulation of long non-coding RNAs (lncRNAs) has been reported to be associated with the development and progression of various cancers. XIAP-AS1 is a novel lncRNA, which can regulate apoptosis in gastric cancer cells. However, the role of XIAP-AS1 in colorectal cancer (CRC) remains unclear. In this study, we found that XIAP-AS1 expression was significantly increased in CRC tissues and its expression showed a positive correlation with TNM stage and cumulative survival rate of CRC. To investigate whether XIAP-AS1 regulates the progression of CRC, we knocked down its expression in several CRC cell lines. CCK-8 assays showed that XIAP-AS1 knockdown remarkably suppressed CRC cell growth and arrested the cell cycle at the G0/G1 phase (flow cytometric analysis). Furthermore, XIAP-AS1 knockdown also remarkably blocked cell invasion of colon cancer cells by regulating the expression of EMT markers, such as E-cadherin, ZO-1, vimentin, and N-cadherin. Importantly, we found that XIAP-AS1 knockdown significantly reduced STAT3 phosphorylation. Overall, this study suggests that lncRNA XIAP-AS1 might serve as a potential oncogene for colon cancer.

Ma X, Li B, Liu J, et al.
Phosphoglycerate dehydrogenase promotes pancreatic cancer development by interacting with eIF4A1 and eIF4E.
J Exp Clin Cancer Res. 2019; 38(1):66 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Pancreatic cancer is one of the most malignant cancers. The overall 5-year survival rate of its patients is 8%, the lowest among major cancer types. It is very urgent to study the development mechanisms of this cancer and provide potential targets for therapeutics design. Glucose, one of the most essential nutrients, is highly exploited for aerobic glycolysis in tumor cells to provide building blocks. However, the glucose consumption manner in pancreatic cancer cells is unclear. And the mechanism of the substantial metabolic pathway promoting pancreatic cancer development is also unrevealed.

Tabariès S, McNulty A, Ouellet V, et al.
Afadin cooperates with Claudin-2 to promote breast cancer metastasis.
Genes Dev. 2019; 33(3-4):180-193 [PubMed] Free Access to Full Article Related Publications
Claudin-2 promotes breast cancer liver metastasis by enabling seeding and early cancer cell survival. We now demonstrate that the PDZ-binding motif of Claudin-2 is necessary for anchorage-independent growth of cancer cells and is required for liver metastasis. Several PDZ domain-containing proteins were identified that interact with the PDZ-binding motif of Claudin-2 in liver metastatic breast cancer cells, including Afadin, Arhgap21, Pdlim2, Pdlim7, Rims2, Scrib, and ZO-1. We specifically examined the role of Afadin as a potential Claudin-2-interacting partner that promotes breast cancer liver metastasis. Afadin associates with Claudin-2, an interaction that requires the PDZ-binding motif of Claudin-2. Loss of Afadin also impairs the ability of breast cancer cells to form colonies in soft agar and metastasize to the lungs or liver. Immunohistochemical analysis of Claudin-2 and/or Afadin expression in 206 metastatic breast cancer tumors revealed that high levels of both Claudin-2 and Afadin in primary tumors were associated with poor disease-specific survival, relapse-free survival, lung-specific relapse, and liver-specific relapse. Our findings indicate that signaling downstream from a Claudin-2/Afadin complex enables the efficient formation of breast cancer metastases. Moreover, combining Claudin-2 and Afadin as prognostic markers better predicts the potential of breast cancer to metastasize to soft tissues.

Zeng Z, Li Y, Pan Y, et al.
Cancer-derived exosomal miR-25-3p promotes pre-metastatic niche formation by inducing vascular permeability and angiogenesis.
Nat Commun. 2018; 9(1):5395 [PubMed] Free Access to Full Article Related Publications
Cancer-derived exosomes are considered a major driver of cancer-induced pre-metastatic niche formation at foreign sites, but the mechanisms remain unclear. Here, we show that miR-25-3p, a metastasis-promoting miRNA of colorectal cancer (CRC), can be transferred from CRC cells to endothelial cells via exosomes. Exosomal miR-25-3p regulates the expression of VEGFR2, ZO-1, occludin and Claudin5 in endothelial cells by targeting KLF2 and KLF4, consequently promotes vascular permeability and angiogenesis. In addition, exosomal miR-25-3p from CRC cells dramatically induces vascular leakiness and enhances CRC metastasis in liver and lung of mice. Moreover, the expression level of miR-25-3p from circulating exosomes is significantly higher in CRC patients with metastasis than those without metastasis. Our work suggests that exosomal miR-25-3p is involved in pre-metastatic niche formation and may be used as a blood-based biomarker for CRC metastasis.

Song J, Zhang P, Liu M, et al.
Novel-miR-4885 Promotes Migration and Invasion of Esophageal Cancer Cells Through Targeting CTNNA2.
DNA Cell Biol. 2019; 38(2):151-161 [PubMed] Related Publications
Esophageal cancer is one of the most common cancers worldwide. It is critical to find early diagnostic biomarkers for esophageal cancer. MicroRNAs (miRNAs) play important regulatory roles in occurrence and development of esophageal cancer, which has the diagnostic and prognostic values. The aim of the study was to evaluate the potential diagnostic value of the novel miRNA. The novel miRNA was predicted using miRDeep2 software and validated by quantitative reverse transcription PCR (qRT-PCR) and the TA-cloning sequencing of the PCR products. The expression of the novel miRNA in esophageal cancer tissues and adjacent tissues was also analyzed by qRT-PCR. The EdU staining and transwell method were used to detect the capacity of cell proliferation, migration, and invasion. Besides, the target gene CTNNA2 of novel-miR-4885 was verified via qRT-PCR, western blot, luciferase reporter assay, and RNA immunoprecipitation. We identified the novel-miR-4885, the expression level was confirmed by qRT-PCR in the esophageal cancer cells. The result of TA-cloning sequencing was consistent with the prediction and the pre-miRNA had a standard hairpin stem-loop structure. In addition, the expression of novel-miR-4885 was upregulated in esophageal cancer tissue compared with that in adjacent tissue (p < 0.05). Further, the assays showed that overexpression novel-miR-4885 could improve the cell proliferation, migration, and invasion with an average fold change of 1.19, 1.59, and 2.34, respectively. Novel-miR-4885 can bind to 3' untranslated region of CTNNA2 to reduce cell adhesion and promote epithelial-mesenchymal transition in esophageal cancer cell. The expression of N-cadherin, β-catenin, Vimentin, and α-smooth muscle actin was upregulated, while that of E-cadherin and ZO-1 proteins was downregulated through western blot. Novel miRNA present in esophageal cancer cells was validated, supplementing the miRNA database. Meantime, the possible functional mechanisms were explored, and the results showed that the novel miRNA may serve as potential biomarker for the diagnosis of esophageal cancer.

Liu Z, Chen J, Yuan W, et al.
Nuclear factor I/B promotes colorectal cancer cell proliferation, epithelial-mesenchymal transition and 5-fluorouracil resistance.
Cancer Sci. 2019; 110(1):86-98 [PubMed] Free Access to Full Article Related Publications
Nuclear factor I/B (NFIB) is a widely studied transcription factor that participates in tumor progression; nevertheless, studies on NFIB in colorectal cancer (CRC) are limited. In our study, Western blot and RT-PCR analyses showed that NFIB was overexpressed in CRC tissues and cell lines, which was consistent with our bioinformatic analysis results. Furthermore, NFIB expression was closely related to the TNM stage of CRC. NFIB promoted cell proliferation and migration and inhibited cell apoptosis in vitro. Meanwhile, we discovered that NFIB accelerated xenograft tumor growth in vivo. In addition, NFIB weakened the sensitivity of CRC cells to 5-fluorouracil (5-FU). NFIB induced epithelial-mesenchymal transition (EMT) by upregulating snail expression, which was accompanied by decreased E-cadherin and Zo-1 expression and increasedd Vimentin expression. Because the Akt pathway plays an important role in CRC progression, we examined whether there was a correlation between NFIB and the Akt pathway in cell proliferation and migration. Our results showed that NFIB promoted cell proliferation and increased 5-FU resistance by activating the Akt pathway. In summary, our findings suggested that NFIB induced EMT of CRC cells via upregulating snail expression and promoted cell proliferation and 5-FU resistance by activating the Akt pathway.

Zhong Y, Yang S, Wang W, et al.
The interaction of Lin28A/Rho associated coiled-coil containing protein kinase2 accelerates the malignancy of ovarian cancer.
Oncogene. 2019; 38(9):1381-1397 [PubMed] Free Access to Full Article Related Publications
Ovarian cancer (OC) is the leading cause of death among women with gynecologic malignant diseases, however, the molecular mechanism of ovarian cancer is not well defined. Previous studies have found that RNA binding protein Lin28A is a key factor of maintain the pluripotency of stem cells, and it is positively correlated with the degree of several cancers (breast, prostate, liver cancer, etc). Our previous study shows that Lin28A is highly expressed in OC tissues and is involved in the regulation of OC cell biological behavior. In this study, we confirmed that high expression of Lin28A promoted the survival, invasion, metastasis, and inhibited the apoptosis of OC cells. Lin28A interacts with Rho associated coiled-coil containing protein kinase2 (ROCK2) but not ROCK1 and upregulates the expression of ROCK2 in OC cells. The binding sites of each other were identified by truncated mutations and Immuno-precipitaion (IP) assay. After knock down of ROCK2 in cells with high expression of Lin28A, the survival, invasion, metastasis was significantly inhibited and early apoptosis was increased in OC cells and OC xenograft in nude mice. Our experimental data also showed that knock down of ROCK2 but not ROCK1 inhibited the invasion by decreasing the expression of N-cadherin, Slug, β-catenin and increasing ZO-1 expression. Simultaneously, knock down of ROCK2 induced cell apoptosis by increasing cleaved Caspase-9,cleaved Caspase-7, and cleaved Caspase-3. Taken together, Lin28A regulated the biological behaviors in OC cells through ROCK2 and the interaction of Lin28A/ROCK2 may be a new target for diagnosis and gene therapy of OC.

Tsai KW, Kuo WT, Jeng SY
Tight Junction Protein 1 Dysfunction Contributes to Cell Motility in Bladder Cancer.
Anticancer Res. 2018; 38(8):4607-4615 [PubMed] Related Publications
BACKGROUND/AIM: Bladder cancer is the most common malignancy involving the urinary system. The mortality rate in late stages remains high, thus the development of effective biomarkers for diagnosis or prognosis is required in order to improve patient survival rates. Tight junction protein 1 (TJP1) is a membrane-associated protein that helps modulate cell-cell contact. However, the role of TJP1 in bladder cancer progression remains unclear.
MATERIALS AND METHODS: The expression levels of TJP1 and miR-455-5p were examined by analyzing The Cancer Genome Atlas database. The biological role of TJP1 and miR-455-5p were assessed in T24 cells with siTJP1 or miR-455-5p mimics transfection, respectively.
RESULTS: High levels of expression of TJP1 were significantly correlated with poor lymph node metastasis (pN stage; p=0.004). Knockdown of the TJP1 gene expression led to significant decrease of the growth and invasion of T24 cells. Using a bioinformatics approach, miR-455-5p was shown to suppress TJP1 expression by directly targeting its 3' prime untranslated region in bladder cancer cells. The ectopic expression of miR-455-5p revealed that bladder cancer cell migration, invasion, and proliferation were significantly suppressed.
CONCLUSION: In summary, our results indicate that dysfunction of the miR-455-TJP1 axis is involved in bladder cancer cell growth and metastasis. These findings highlight potential therapeutic targets or putative biomarkers for bladder cancer.

Gong C, Shen J, Fang Z, et al.
Abnormally expressed JunB transactivated by IL-6/STAT3 signaling promotes uveal melanoma aggressiveness via epithelial-mesenchymal transition.
Biosci Rep. 2018; 38(4) [PubMed] Free Access to Full Article Related Publications
Uveal melanoma (UM) is the most common primary intraocular tumor in adults, and it carries a high risk of metastasis and mortality. Various proinflammatory cytokines have been found to be significantly increased in the aqueous humor or vitreous fluid of UM patients; however, the role of these cytokines in UM metastasis remains elusive. In the present study, we found that long-term interleukin (IL)-6 exposure promoted the migration and invasion of UM cells, diminished cell-cell adhesion, and enhanced focal adhesion. Moreover, IL-6 treatment decreased the membranous epithelial marker TJP1 and increased the cytoplasmic mesenchymal marker Vimentin. Further investigation demonstrated that JunB played a critical role in IL-6-induced UM epithelial-mesenchymal transition (EMT). In UM cells, the expression of JunB was significantly up-regulated during the IL-6-driven EMT process. Additionally, JunB induction occurred at the transcriptional level in a manner dependent on phosphorylated STAT3, during which activated STAT3 directly bound to the JunB promoter. Importantly, the knockdown of STAT3 prevented the IL-6-induced EMT phenotype as well as cell migration and invasion, whereas JunB overexpression recovered the attenuated aggressiveness of UM cells. Similarly, with IL-6 stimulation, the stable overexpression of JunB strengthened the migratory and invasive capabilities of UM cells and induced the EMT-promoting factors (Snail, Twist1, matrix metalloproteinase (MMP)-2, MMP-14, and MMP-19). Analysis of The Cancer Genome Atlas (TCGA) database indicated that JunB was positively correlated with IL-6 and STAT3 in UM tissues. The present study proposes an IL-6/STAT3/JunB axis leading to UM aggressiveness by EMT, which illustrates the negative side of inflammatory response in UM metastasis.

Jiang X, Jiang X, Yang Z
NRAGE confers poor prognosis and promotes proliferation, invasion, and chemoresistance in gastric cancer.
Gene. 2018; 668:114-120 [PubMed] Related Publications
Neurotrophin receptor-interacting melanoma antigen-encoding protein (NRAGE) is a type II melanoma-associated antigen that plays an essential role in various processes, including cell differentiation and apoptosis. NRAGE has been shown to act as a cancer-related protein, with complex and apparently contradictory functions in a variety of cancers. In the current study, we examined the expression of NRAGE protein in 169 gastric cancer samples. NRAGE upregulation was correlated with advanced TNM stage, local invasion, and poor survival. Importantly, NRAGE could serve as an independent prognostic factor in patients with gastric cancer. We also examined the expression of NRAGE protein in GES-1 normal gastric epithelial cells and in six gastric cancer cell lines. Inhibition of NRAGE expression by transfection with small interfering RNA reduced the proliferation and invasion of MGC-803 and HGC-27 cells, as demonstrated by CCK-8 and Matrigel invasion assays. NRAGE depletion also sensitized HGC-27 and MGC-803 cells to cisplatin, as shown by CCK-8 and Annexin V/propidium iodide analyses. Western blot analysis also showed that NRAGE depletion negatively regulated Bcl-2 and p-ERK and upregulated ZO-1 and p27 expression levels. In conclusion, our results suggest that NRAGE acts as a tumor promoter in gastric cancer by facilitating cancer invasion and chemoresistance, possibly through regulation of p-ERK and Bcl-2.

Zacharopoulou N, Tsapara A, Kallergi G, et al.
The Epigenetic Factor KDM2B Regulates EMT and Small GTPases in Colon Tumor Cells.
Cell Physiol Biochem. 2018; 47(1):368-377 [PubMed] Related Publications
BACKGROUND/AIMS: The epigenetic factor KDM2B is a histone demethylase expressed in various tumors. Recently, we have shown that KDM2B regulates actin cytoskeleton organization, small Rho GTPases signaling, cell-cell adhesion and migration of prostate tumor cells. In the present study, we addressed its role in regulating EMT and small GTPases expression in colon tumor cells.
METHODS: We used RT-PCR for the transcriptional analysis of various genes, Western blotting for the assessment of protein expression and immunofluorescence microscopy for visualization of fluorescently labeled proteins.
RESULTS: We report here that KDM2B regulates EZH2 and BMI1 in HCT116 colon tumor cells. Knockdown of this epigenetic factor induced potent up-regulation of the protein levels of the epithelial markers E-cadherin and ZO-1, while the mesenchymal marker N-cadherin was downregulated. On the other hand, KDM2B overexpression downregulated the levels of both epithelial markers and upregulated the mesenchymal marker, suggesting control of EMT by KDM2B. In addition, RhoA, RhoB and RhoC protein levels diminished upon KDM2B-knockdown, while all three small GTPases became upregulated in KDM2B-overexpressing HCT116 cell clones. Interestingly, Rac1 GTPase level increased upon KDM2B-knockdown and diminished in KDM2B-overexpressing HCT116 colon tumor- and DU-145 prostate cancer cells.
CONCLUSIONS: These results establish a clear functional role of the epigenetic factor KDM2B in the regulation of EMT and small-GTPases expression in colon tumor cells and further support the recently postulated oncogenic role of this histone demethylase in various tumors.

Wang JH, Lee EJ, Ji M, Park SM
HDAC inhibitors, trichostatin A and valproic acid, increase E‑cadherin and vimentin expression but inhibit migration and invasion of cholangiocarcinoma cells.
Oncol Rep. 2018; 40(1):346-354 [PubMed] Related Publications
The effects of histone deacetylase (HDAC) inhibitors on epithelial-mesenchymal transition (EMT) differ in various cancers. E‑cadherin is a cell‑to‑cell adhesion protein, whereas accumulation of vimentin is related to the development of the spindle shape of the mesenchymal cell phenotype. We investigated the EMT phenotypes of human cholangiocellular carcinoma HuCC‑T1, JCK and SNU‑1079 cell lines. To this end, we measured the expression of E‑cadherin or zonula occludens (ZO)‑1 and vimentin, epithelial and mesenchymal cell markers, respectively, using real‑time reverse transcription‑polymerase chain reaction, western blotting, and immunofluorescence microscopy following treatment with trichostatin A (TSA, 200 nM) or valproic acid (VPA, 0.5 mM) with or without gemcitabine (GEM, 50 nM) for 24 h. In addition, we performed cell morphology, migration, and invasion assays. HuCC‑T1 cells changed from spindle‑ to rectangular‑shaped after co‑treatment with GEM and TSA or VPA. Furthermore, cells co‑treated with GEM and TSA or VPA exhibited protein levels of E‑cadherin or ZO‑1 that were higher than those in cells treated with GEM alone, indicating stronger inhibition of EMT. However, vimentin expression was also increased. Confocal microscopy revealed enhanced expression of E‑cadherin or ZO‑1 and vimentin in all three cell lines. Migration and invasion were inhibited in HuCC‑T1 cells co‑treated with GEM and TSA or VPA, compared to those treated with GEM alone. In conclusion, co‑treatment of cholangiocarcinoma cells with TSA or VPA and GEM suppressed EMT with tolerable cytotoxicity. However, the HDAC inhibitors augmented both E‑cadherin and vimentin expression and their effects varied in different cholangiocarcinoma cell lines. Therefore, the clinical use of HDAC inhibitors in biliary cancer should be considered cautiously.

Gao F, Alwhaibi A, Artham S, et al.
Endothelial Akt1 loss promotes prostate cancer metastasis via β-catenin-regulated tight-junction protein turnover.
Br J Cancer. 2018; 118(11):1464-1475 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Cancer research, in general, is focused on targeting tumour cells to limit tumour growth. These studies, however, do not account for the specific effects of chemotherapy on tumour endothelium, in turn, affecting metastasis.
METHODS: We determined how endothelial deletion of Akt1 promotes prostate cancer cell invasion in vitro and metastasis to the lungs in vivo in endothelial-specific Akt1 knockdown mice.
RESULTS: Here we show that metastatic human PC3 and DU145 prostate cancer cells invade through Akt1-deficient human lung endothelial cell (HLEC) monolayer with higher efficiency compared to control HLEC. Although the endothelial Akt1 loss in mice had no significant effect on RM1 tumour xenograft growth in vivo, it promoted metastasis to the lungs compared to the wild-type mice. Mechanistically, Akt1-deficient endothelial cells exhibited increased phosphorylation and nuclear translocation of phosphorylated β-catenin, and reduced expression of tight-junction proteins claudin-5, ZO-1 and ZO-2. Pharmacological inhibition of β-catenin nuclear translocation using compounds ICG001 and IWR-1 restored HLEC tight-junction integrity and inhibited prostate cancer cell transendothelial migration in vitro and lung metastasis in vivo.
CONCLUSIONS: Here we show for the first time that endothelial-specific loss of Akt1 promotes cancer metastasis in vivo involving β-catenin pathway.

Leng Z, Xia Q, Chen J, et al.
Lgr5+CD44+EpCAM+ Strictly Defines Cancer Stem Cells in Human Colorectal Cancer.
Cell Physiol Biochem. 2018; 46(2):860-872 [PubMed] Related Publications
BACKGROUND/AIMS: Although EpCAM+CD44+ cells exhibit more stem-like properties than did EpCAM-CD44- cells, the specificity of EpCAM combined with CD44 in defining CSCs needs further improvement. Lgr5 is used as a biomarker to isolate cancer stem cells (CSCs) in colorectal cancer. However, it remains unclear whether Lgr5, along with EpCAM and CD44, can further identify and define CSCs in colorectal cancer.
METHODS: Lgr5+CD44+EpCAM+, Lgr5+CD44+EpCAM-, Lgr5+CD44-EpCAM+, Lgr5-CD44+EpCAM+, and Lgr5-CD44-EpCAM-cells were separately isolated using fluorescence-activated cell sorting (FACS). Colony formation, self-renewal, differentiation, and tumorigenic properties of these cells were investigated through in vitro experiments and in vivo tumor xenograft models. The expression of stemness genes and CSC- and epithelial-mesenchymal transition (EMT)-related genes, such as KLF4, Oct4, Sox2, Nanog, CD133, CD44, CD166, ALDH1, Lgr5, E-cadherin, ZO-1, Vimentin, Snail, Slug, and Twist, was examined using real-time PCR.
RESULTS: Lgr5-positive subpopulations exhibited higher capacities for colony formation, self-renewal, differentiation, and tumorigenicity as well as higher expression of stemness genes and mesenchymal genes and lower expression of epithelial genes than did Lgr5-negative subpopulations.
CONCLUSION: Our data revealed that tumorigenic cells were highly restricted to Lgr5-positive subpopulations. Most importantly, Lgr5+CD44+EpCAM+ cells exhibited more pronounced CSC-like traits than did any other subpopulation, indicating that Lgr5 combined with CD44 and EpCAM can further improve the stem-like traits of CSCs in colorectal cancer.

Akizuki R, Maruhashi R, Eguchi H, et al.
Decrease in paracellular permeability and chemosensitivity to doxorubicin by claudin-1 in spheroid culture models of human lung adenocarcinoma A549 cells.
Biochim Biophys Acta Mol Cell Res. 2018; 1865(5):769-780 [PubMed] Related Publications
Chemotherapy resistance is a major problem in the treatment of cancer, but the underlying mechanisms are not fully understood. We found that the expression levels of claudin-1 (CLDN1) and 3, tight junctional proteins, are upregulated in cisplatin (CDDP)-resistant human lung adenocarcinoma A549 (A549R) cells. A549R cells showed cross-resistance to doxorubicin (DXR). Here, the expression mechanism and function of CLDN1 and 3 were examined. CLDN1 and 3 were mainly localized at tight junctions concomitant with zonula occludens (ZO)-1, a scaffolding protein, in A549 and A549R cells. The phosphorylation levels of Src, MEK, ERK, c-Fos, and Akt in A549R cells were higher than those in A549 cells. The expression levels of CLDN1 and 3 were decreased by LY-294002, a phosphoinositide 3-kinase (PI3K) inhibitor, and BAY 11-7082, an NF-κB inhibitor. The overexpression of CLDN1 and 3 decreased the paracellular permeability of DXR in A549 cells. Hypoxia levels in A549R and CLDN1-overexpressing cells (CLDN1/A549) were greater than those in A549, mock/A549, and CLDN3/A549 cells in a spheroid culture model. In contrast, accumulation in the region inside the spheroids and the toxicity of DXR in A549R and CLDN1/A549 cells were lower than those in other cells. Furthermore, the accumulation and toxicity of DXR were rescued by CLDN1 siRNA in A549R cells. We suggest that CLDN1 is upregulated by CDDP resistance through activation of a PI3K/Akt/NF-κB pathway, resulting in the inhibition of penetration of anticancer drugs into the inner area of spheroids.

Kim KS, Kim J, Oh N, et al.
ELK3-GATA3 axis modulates MDA-MB-231 metastasis by regulating cell-cell adhesion-related genes.
Biochem Biophys Res Commun. 2018; 498(3):509-515 [PubMed] Related Publications
GATA3 is a master regulator that drives mammary epithelial cell differentiation, and the suppression of GATA3 expression is associated with the development of aggressive breast cancer. However, the mechanism through which GATA3 loss drives cancer development is poorly understood. Previously, we reported that ELK3 suppression in MDA-MB-231 (ELK3 KD) resulted in the reprogramming of these cells from a basal to luminal subtype, which was associated with the induction of GATA3 expression, and that the ELK3-GATA3 axis orchestrated the metastatic characteristics of MDA-MB-231. Here, we show that GATA3 suppression in ELK3 knockdown MDA-MB-231 cells (ELK3/GATA3 DKD) restores the metastatic ability comparably to that of control MDA-MB-231 cells, even though the epithelial cell morphology and TGF-β signaling of ELK3 KD are not recovered in ELK3/GATA3 DKD. The expression of E-cadherin and tight junctional proteins, including occludin, claudin and ZO-1, which is activated in ELK3 KD, is suppressed in ELK3/GATA3 DKD. These results reveal the possibility that the ELK3-GATA3 axis determines the metastatic characteristics of MDA-MB-231 by regulating the expression of cell-cell adhesion factors.

Lin X, Meng G, Liu X, et al.
The Differentially Expressed Genes of Human Sporadic Cerebral Cavernous Malformations.
World Neurosurg. 2018; 113:e247-e270 [PubMed] Related Publications
OBJECTIVES: To understand the development of sporadic cerebral cavernous malformations (SCCM) comprehensively, we analyzed gene expression profiles in SCCMs by gene microarray.
METHODS: The total number of the specimens collected in our study was 14, 7 of which were SCCMs, and the others were controls that were obtained from normal brain vessels. The total RNA was extracted and hybridized with oligonucleotide array containing 21522 genes. The analysis of Gene Ontology (GO) items and molecular pathways was performed based on the GO and Kyoto Encyclopedia of Genes and Genomes databases. The gene coexpression networks were constructed to identify the core genes regulating the progression of SCCMs.
RESULTS: A total of 785 probes, showing differentially expressed genes (DEGs) between the 2 groups, were found by the gene chips. According to the analysis based on GO and Kyoto Encyclopedia of Genes and Genomes, 286 GO terms and 53 pathways were identified to be significantly relevant with the DEGs. All differential gene interactions were analyzed and the core genes were selected in the coexpression networks.
CONCLUSIONS: The gene expression profiles obtained from SCCMs were significantly distinct from those of control brain vascular specimens. These DEGs are related to multiple molecular signal pathways, such as the mitogen-activated protein kinase pathway, cytokine-cytokine receptor interaction, focal adhesion, and inflammatory response. According to the analysis of the core genes selected in the gene coexpression networks, we postulated that CSF1R, XCL1, KCNMB1, RHOG, and TJP1 might exert enormous functions in the pathogenesis of SCCMs. However, further studies are required to aid in the clinical diagnosis and prevention of SCCMs.

Zacharopoulou N, Tsapara A, Kallergi G, et al.
The epigenetic factor KDM2B regulates cell adhesion, small rho GTPases, actin cytoskeleton and migration in prostate cancer cells.
Biochim Biophys Acta Mol Cell Res. 2018; 1865(4):587-597 [PubMed] Related Publications
The histone demethylase KDM2B is an epigenetic factor with oncogenic properties that is regulated by the basic fibroblasts growth factor (FGF-2). It has recently been shown that KDM2B co-operates with Polycomb Group proteins to promote cell migration and angiogenesis in tumors. In the present study we addressed the role of KDM2B in regulating actin cytoskeleton signaling, cell-cell adhesion and migration of prostate tumor cells. We report here that KDM2B is functionally expressed in DU-145 prostate cancer cells, activated by FGF-2 and regulates EZH2. KDM2B knockdown induced potent up-regulation of gene transcription and protein expression of the epithelial markers E-cadherin and ZO-1, while KDM2B overexpression down-regulated the levels of both markers, suggesting control of cell adhesion by KDM2B. RhoA and RhoB protein expression and activity were diminished upon KDM2B-knockdown and upregulated in KDM2B-overexpressing cell clones. In accordance, actin reorganization with formation of stress fibers became evident in KDM2B-overexpressing cells and abolished in the presence of the Rho inhibitor C3 transferase. DU-145 cell migration was significantly enhanced in KDM2B overexpressing cells and abolished in C3-pretreated cells. Conversely, the retardation of cell migration observed in KDM2B knockdown cells was enhanced in C3-pretreated cells. These results establish a clear functional link between the epigenetic factor KDM2B and the regulation of cell adhesion and Rho-GTPases signaling that controls actin reorganization and cell migration.

Kim SG, Yooun JH, Kim DE, et al.
A novel anti-cancer agent, FPDHP, induces anoikis in various human cancer cells through activation of calpain, and downregulation of anoikis-related molecules.
J Cell Biochem. 2018; 119(7):5620-5631 [PubMed] Related Publications
Resistance to anoikis and growth in anchorage-independent conditions are hallmarks of highly metastatic cancer cells. Anoikis is a type of apoptosis induced by inadequate cell/extracellular matrix (ECM) attachment and an attractive anti-cancer therapeutic strategy in cancer chemotherapeutic field. Therefore, the development of anoikis-inducing agents is useful and promising to overcome cancer. When FPDHP, a novel anoikis-inducing agent, was treated within 3 h, FPDHP induced massive cell detachment in various human cancer cells, irrespective of apoptosis. Moreover, FPDHP decreased the expression of integrins, FAK, focal adhesion signaling effectors (talin1 and talin2), tight junction proteins (ZO-1, ZO-2, and ZO-3), transcriptional mediators of epithelial-mesenchymal transition (EMT) (Snail1 and Snail2), and anoikis-related protein, such as Mcl-1 (L). Interestingly, Caki/ZO-2 and Caki/α6 are significantly suppressed the FPDHP-mediated cell detachment, and the constitutive active form of Akt and overexpression of Mcl-1 (L) partially inhibited the cellular detachment induced by FPDHP. On the other hand, when FPDHP was treated for more than 12 h, FPDHP induced caspase-dependent apoptosis and release of AIF and cytochrome c from mitochondria. Furthermore, FPDHP down regulated Mcl-1 (L) at post-transcriptional level, and overexpression of Mcl-1 (L) partially attenuated the apoptosis induced by FPDHP. Additionally, PD150606, a calpain inhibitor, attenuated FPDHP-mediated cell detachment and apoptosis. Taken together, these results suggest that FPDHP possesses anoikis-inducing activity or potential making cancer cells susceptible to anoikis, and may be developed as a novel active compound for cancer treatment.

Chen X, Zhao M, Huang J, et al.
microRNA-130a suppresses breast cancer cell migration and invasion by targeting FOSL1 and upregulating ZO-1.
J Cell Biochem. 2018; 119(6):4945-4956 [PubMed] Related Publications
FOSL1 is frequently overexpressed in multiple types of human cancers including invasive breast cancers and implicated in cancer invasion and metastasis. However, how FOSL1 is overexpressed in cancers remains to be elucidated. Several microRNAs (miRNAs) have been shown to target FOSL1 and are downregulated in human cancers. Here, we report that miR-130a is a novel FOSL1 targeting miRNA. Using gene expression microarray analysis, we found that FOSL1 is among the most up-regulated genes in cells transfected with miR-130a inhibitors. Transient transfection-immunoblot, RNA-immunoprecipitation, and luciferase reporter assays revealed that miR-130a directly targets FOSL1 mRNA at its 3'-UTR. Overexpression of miR-130a significantly reduced the levels of FOSL1 in invasive breast cancer MDA-MB-231 and Hs578T cell lines and suppresses their migration and invasion. This inhibition can be rescued by ectopic expression of miR-130a-resistant FOSL1. Interestingly, we show that overexpression of miR-130a increased the levels of tight-junction protein ZO-1 while inhibition of miR-130a reduced the levels of ZO-1. We further show that miR-130a expression is significantly reduced in cancer tissues from triple-negative breast cancer (TNBC) patients, correlating significantly with the upregulation of FOSL1 expression, compared to non-TNBC tissues. Together, our results reveal that miR-130a directly targets FOSL1 and suppresses the inhibition of ZO-1, thus inhibiting cancer cell migration and invasion, in TNBCs.

Weingarten C, Jenudi Y, Tshuva RY, et al.
The Interplay Between Epithelial-Mesenchymal Transition (EMT) and the Thyroid Hormones-αvβ3 Axis in Ovarian Cancer.
Horm Cancer. 2018; 9(1):22-32 [PubMed] Related Publications
Ovarian cancer is a highly metastatic disease. The metastatic potential is enhanced by epithelial to mesenchymal transition (EMT) in which αvβ3 integrin plays a role. Thyroid hormones (L-thyroxine, T4, and 3,5,3'-triiodo-L-thyronine, T3) bind this integrin, and we hypothesized that the thyroid hormone-αvβ3 axis may be involved in EMT activity in ovarian cancer. The transcription (mRNA), protein abundance (westerns), and protein localization (fluorescence microscopy) of several EMT markers were studied in ovarian cancer cells (OVCAR-3, A2780, and SKOV-3) treated with 1 nM T3 or 100 nM T4 for 1-24 h. The protein levels of β-catenin, and its downstream targets, zeb-1, slug, and vimentin, were significantly induced by both hormones, while the effect on transcription was limited. The pre-incubation of the cells overnight with two integrin inhibitors, RGD (0.1-10 μM) or αvβ3 blocking antibody (1-100 ng/mL), prevented the induction of β-catenin by T3 and zeb-1 by T4, indicating direct integrin involvement. The transcription of the mesenchymal markers, β-catenin, zeb-1, slug/snail, vimentin, and n-cadherin was hardly affected by T3 and T4, while that of the epithelial markers, e-cadherin and zo-1, was inhibited. Our results suggest a novel role for the thyroid hormone-αvβ3 axis in EMT, with possible implications for ovarian cancer metastasis.

Liang G, Fang X, Yang Y, Song Y
Silencing of CEMIP suppresses Wnt/β-catenin/Snail signaling transduction and inhibits EMT program of colorectal cancer cells.
Acta Histochem. 2018; 120(1):56-63 [PubMed] Related Publications
Cell migration inducing hyaluronan binding protein (CEMIP) is a hyaluronic acid binding protein, the abnormal elevation of which is suggested as a contributor in the carcinogenesis of colorectal cancer (CRC). Cancer cells lose their adhesive properties and acquire an enhanced mobility by undergoing epithelial-mesenchymal transition (EMT). This study is performed to investigate whether and how CEMIP orchestrates the EMT process of CRC cells. To avoid the unexpected off-target effects possibly caused by one single shRNA, two shRNAs targeting different mRNA regions of CEMIP gene were used to knock down the mRNA and protein expression of CEMIP. Our data showed that the proliferation, migration and invasion of two CRC cell lines, HCT116 and SW480 cells, were inhibited by CEMIP shRNA. We here defined EMT as the complete or partial loss of E-cadherin and zona occludens protein 1 (ZO-1) (epithelial markers) and the gain of Vimentin and N-cadherin (mesenchymal markers), and found that the EMT process was attenuated in CEMIP-silenced SW480 cells. Snail, a direct target of β-catenin/T cell factor complex, is known to activate the EMT program during cancer metastasis. CEMIP shRNA was further found to suppress the Wnt/β-catenin/Snail signaling transduction in CRC cells as manifested by the decreased nuclear β-catenin and Snail. Collectively, our work demonstrates that CEMIP contributes to metastatic phenotype of CRC cells in vitro.

Wan L, Yu W, Shen E, et al.
SRSF6-regulated alternative splicing that promotes tumour progression offers a therapy target for colorectal cancer.
Gut. 2019; 68(1):118-129 [PubMed] Related Publications
OBJECTIVE: To investigate the molecular function of splicing factor SRSF6 in colorectal cancer (CRC) progression and discover candidate chemicals for cancer therapy through targeting SRSF6.
DESIGN: We performed comprehensive analysis for the expression of SRSF6 in 311 CRC samples, The Cancer Genome Atlas and Gene Expression Omnibus (GEO) database. Functional analysis of SRSF6 in CRC was performed
RESULTS: SRSF6 was frequently upregulated in CRC samples and associated with poor prognosis, which promoted proliferation and metastasis
CONCLUSIONS: SRSF6 functions the important roles in mediating CRC progression through regulating AS, and indacaterol is repositioned as an antitumour drug through targeting SRSF6.
ACCESSION NUMBERS: The accession numbers for sequencing data are SRP111763 and SRP111797.

Xiong J, Wang D, Wei A, et al.
Deregulated expression of miR-107 inhibits metastasis of PDAC through inhibition PI3K/Akt signaling via caveolin-1 and PTEN.
Exp Cell Res. 2017; 361(2):316-323 [PubMed] Related Publications
Pancreatic ductal adenocarcinoma (PDAC) displays a highly aggressive malignancy and is considered to be an incurable and rapidly lethal disease. MicroRNAs (miRNAs) are small non-coding RNAs of approximately nucleotides that regulate several aspects of tumors pathogenesis, including migration, invasion, metastasis and epithelial-mesenchymal transition. We have found that miR-107 was significantly high expression in PDAC tissues and cells. High miR-107 expression is associated with poor clinicopathological parameters and prognosis in PDAC patients. Deregulated expression of miR-107 in PDAC cells (AsPC-1 and Panc-1) is sufficient to reduce cell migration and invasion, and to induce upregulation of epithelial markers (β-catenin, ZO-1 and E-cadherin) and a decrease of mesenchymal marker expression (ZEB-1 and vimentin). We also found that the caveolin-1, PTEN and p-Akt expression are modulated by miR-107 in PDAC cells. Moreover, our study clearly demonstrated that deregulated expression of miR-107 inhibited cell migration and invasion and EMT by up-regulation of caveolin-1 and PTEN, and inhibition of PI3K/Akt signaling in PDAC cells. Our study suggested that miR‑107 expression might both be a useful indicator of the metastatic potential and provided a new potential therapeutic target in PDAC.

Nagaraja SS, Krishnamoorthy V, Raviraj R, et al.
Effect of Trichostatin A on radiation induced epithelial-mesenchymal transition in A549 cells.
Biochem Biophys Res Commun. 2017; 493(4):1534-1541 [PubMed] Related Publications
Radiotherapy is used to treat tumors of different origins and nature, but often lead to development of radioresistance and metastasis of cells. Interestingly, radiation induces epithelial-mesenchymal transition (EMT), a process by which epithelial cells undergo mesenchymal phenotype and stimulates tumor progression capability. Our study investigated the effect of Trichostatin A (TSA), a natural derivate isolated from Streptomyces, upon radiation-induced lung EMT and we tried to understand the role of signaling molecules in irradiated lung cancer cells (A549). The cells were categorized into four groups: untreated control, radiation alone (R; 8Gy, X-ray), radiation combined with TSA (R + T) and TSA (100nM). Radiation-induced lung EMT were evidenced by decreased expression of epithelial marker like E-cadherin, Zona occluden1 (ZO-1) and increased expression of N-cadherin and Vimentin. The Snail protein, a master regulator of EMT, was observed to be elevated after radiation treatment. In addition, TGF-β1 signaling (smad2, 3, and 4) proteins were activated upon irradiation. Western blot data were supported by the altered m-RNA expression of E-cadherin, TGF-β and Snail genes and this effect were reversed by TSA treatment. In addition to this, as supportive evidence, we performed docking studies between snail protein and TSA using Auto docking software and results suggested that less binding energy was needed for the putative binding of TSA on C-terminal domain of Snail protein. Based on our report, we suggest that TSA can effectively inhibit radiation-induced EMT (i) by altering epithelial and mesenchymal markers (ii) by modulating signaling molecules of TGFβ1 pathway (iii) by inhibiting cancer cell migratory potential in A549 cells (iv)by effectively binding to Snail which is an enhancer of EMT.

Wallesch M, Pachow D, Blücher C, et al.
Altered expression of E-Cadherin-related transcription factors indicates partial epithelial-mesenchymal transition in aggressive meningiomas.
J Neurol Sci. 2017; 380:112-121 [PubMed] Related Publications
E-Cadherin has been suggested to be involved in meningioma progression but is also known as a key player of epithelial to mesenchymal transition (EMT). We wondered whether the adherens junction protein E-Cadherin, the tight junction protein Zo-1, and transcription factors suppressing E-Cadherin expression (Slug, Snail, Twist, Zeb-1) are differentially expressed between histopathological subtypes of meningioma, and if the expression of these factors is related to biological features of meningiomas. Analyzing 85 meningiomas of various histopathological subtypes and grades of malignancy by immunohistochemistry and 50 of them in addition by real-Time-PCR, we observed significantly reduced expression of Zeb-1, Twist and Slug, together with slightly increased expression levels for E-Cadherin and Zo- 1 in fibroblastic WHO-grade I tumors compared to meningothelial WHO grade I tumors, contradicting the hypothesis of EMT in the fibroblastic meningiomas characterized by mesenchymal appearance. However, comparing aggressive WHO grade II or III meningiomas with WHO-grade I tumors, we observed altered expression levels (loss of E-Cadherin and Zo-1, increased expression of Zeb-1 and Slug) indicating molecular features of EMT in aggressive meningiomas. This was supported by reduced E-Cadherin and increased Slug levels in recurrent compared to non-recurrent meningiomas. The expression levels of E-cadherin and Zo-1 were positively correlated with expression of NF2 mRNA. In primary meningioma cultures and IOMM-Lee meningioma cells, EMT induction by TGF-ß resulted in altered morphology and increased expression of EMT associated transcription factors. Meningioma cells with allelic losses of NF2 showed generally higher levels of various EMT relevant proteins, but were unresponsive to TGF-ß treatment. Our data indicate that aggressive meningiomas of WHO grade II/III are characterized by molecular alterations indicating partial EMT. This might contribute to the aggressive biology of these tumors.

Wu J, Zhou XJ, Sun X, et al.
RBM38 is involved in TGF-β-induced epithelial-to-mesenchymal transition by stabilising zonula occludens-1 mRNA in breast cancer.
Br J Cancer. 2017; 117(5):675-684 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The transforming growth factor-β (TGF-β) pathway plays a vital role in driving cancer cell epithelial-mesenchymal transition (EMT). Zonula occludens-1 (ZO-1), which is downregulated in response to TGF-β, is able to control endothelial cell-cell tension, cell migration, and barrier formation. However, the molecular mechanism of how TGF-β regulates ZO-1 expression remains unclear.
METHODS: Breast cancer cells were treated with TGF-β to induce an EMT progress. Chromatin immunoprecipitation and dual-luciferase reporter assay were performed to investigate direct relationship between Snail and RNA binding motif protein 38 (RBM38). The RNA immunoprecipitation combined with RNA electrophoretic mobility shift assay and dual-luciferase reporter assay were conducted to testify direct relationship between RBM38 and ZO-1. The ZO-1 siRNA was transfected to breast cancer cells that overexpress RBM38 and the control, followed by transwell and Matrigel invasion assays to examine cell migratory and invasive ability.
RESULTS: Transforming growth factor-β induced a remarkable downregulation of RBM38 in breast cancer that was directly regulated by transcription repressor Snail targeting the E-box elements in promoter region of RBM38 gene. Additionally, RBM38 positively regulated ZO-1 transcript via directly binding to AU/U-rich elements in its mRNA 3'-UTR. Moreover, by magnifying RBM38 expression, cell migration and invasion mediated by knockdown of ZO-1 in breast cancer were reversed.
CONCLUSIONS: All the results clarified a linear regulation relationship among Snail, RBM38, and ZO-1, implicating RBM38 as a pivotal mediator in TGF-β-induced EMT in breast cancer.

Park JM, Han YM, Jeong M, et al.
Synthetic 8-hydroxydeoxyguanosine inhibited metastasis of pancreatic cancer through concerted inhibitions of ERM and Rho-GTPase.
Free Radic Biol Med. 2017; 110:151-161 [PubMed] Related Publications
8-hydroxydeoxyguanosine (8-OHdG) is generated consequent to oxidative stress, but its paradoxical anti-oxidative, anti-inflammatory, and anti-mutagenic effects via Rho-GTPase inhibition were noted in various models of inflammation and cancer. Metastasis occurs through cell detachment, epithelial-mesenchymal transition (EMT), and cell migration; during these processes, changes in cell morphology are initiated through Rho-GTPase-dependent actin cytoskeleton polymerization. In this study, we explored the anti-metastatic mechanisms of 8-OHdG in Panc-1 pancreatic cancer cells. 8-OHdG inhibits cell migration by inactivating ERM and Rho-GTPase proteins, and inhibiting focal adhesion kinase (FAK) and matrix metalloproteinases (MMPs). At 15min, 8-OHdG significantly inactivated ERM (p < 0.05) and led to a significant retardation of wound healing; siERM and H1152 (ROCK inhibitor) had similar effects (p < 0.05). However, FAK inhibitor 14, DPI (NOX inhibitor), and NAC (antioxidant) significantly delayed wound healing without inhibiting ERM or CD44 (p < 0.05). In the experiments on cell migration, siERM, siCD44, DPI, and 8-OHdG significantly inhibited MMPs. 8-OHdG significantly decreased DCF-DA activation in Panc-1 pancreatic cancer cells and down-regulated NOXs (nox-1, nox-2, and nox-3). Finally, all of these anti-migration actions of 8-OHdG resulted in significant inhibition of EMT, as evidenced by the up-regulation of ZO-1 and claudin-1 and down-regulation of vimentin. We found significant inhibition of lung metastasis of Panc-1 cells by 8-OHdG. In conclusion, exogenous 8-OHdG had potent anti-metastasis effects mediated by either ERM or Rho GTPase inhibition in metastasis-prone pancreatic cancer cells.

Zhang X, Zhou H, Zhang Y, et al.
ZNF452 facilitates tumor proliferation and invasion via activating AKT-GSK3β signaling pathway and predicts poor prognosis of non-small cell lung cancer patients.
Oncotarget. 2017; 8(24):38863-38875 [PubMed] Free Access to Full Article Related Publications
ZNF452 is a zinc-finger protein family member which contains an isolated SCAN (SRE-ZBP, CTfin51, AW-1 and Number 18 cDNA) zinc-finger domain. Despite the SCAN N-terminus domain is known to play a role in transcriptional regulation of genes involved in cell survival and differentiation, there are no precise cellular functions that have been assigned to ZNF452. In the present study, we found that either endogenous or exogenous ZNF452 was overexpressed in the cytoplasm of NSCLC cells and positive ratio of ZNF452 in NSCLC samples (50.8%, 93/183) was significantly higher than that in normal lung tissues (22.4%, 13/58, P<0.001). ZNF452 overexpression was correlated with advanced TNM stage (P=0.033), positive lymph node metastasis (P=0.002) and predicted poor overall survival of NSCLC patients (P<0.001). ZNF452 facilitated tumor growth, colony formation, G1-S phase arrest, migration and invasion through upregulating the levels of CyclinD1, CyclinE1, p-Rb, or Snail, and downregulating the expression of Zo-1. In nude mice xenografts, overexpressing ZNF452 also promoted tumor proliferation and metastasis. Subsequently, we found that the effect of ZNF452 on facilitating tumor proliferation and invasion was through activating its downstream AKT-GSK3β signaling pathway. Treatment of AKT inhibitor markedly prevented the phosphorylation of AKT and GSK3β which subsequently counteracted increasing expression of CyclinD1, CyclinE1 or Snail and restored the decreasing expression of Zo-1, as well as the upregulation of tumor proliferation and invasion, caused by ZNF452 overexpression.Taken together, the present study indicated that ZNF452 may be an upstream regulator of AKT-GSK3β signaling pathway and facilitates proliferation and invasion of NSCLC.

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