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Verteporfin inhibits gastric cancer cell growth by suppressing adhesion molecule FAT1.

ABSTRACT: Gastric cancer (GC) is a leading cause of death worldwide and in urgent need of targeted drug development. In the current, we investigated the ability of a repositioned drug verteporfin (VP), originally a treatment for macular degeneration, to inhibit GC cell growth. VP inhibited growth of various GC cell lines. Gene expression profiling of GC cell lines treated with VP revealed that migration-related genes and those with oncogenic potential were down-regulated. Of these genes, we found that FAT1, an adhesion molecule promoting cell invasion, was highly suppressed by VP. Silencing of FAT1 suppressed cell migration and invasion as VP did. FAT1 expression was up-regulated in tumors, and patients with high FAT1-expressing tumors had a worse prognosis. We propose that VP- targeting FAT1 to suppress metastatic potential is a promising therapeutic strategy against GC.

SUBMITTER: Kang MH

PROVIDER: S-EPMC5716775 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Verteporfin inhibits gastric cancer cell growth by suppressing adhesion molecule FAT1.

Kang Myoung-Hee MH Jeong Gi Seok GS Smoot Duane T DT Ashktorab Hassan H Hwang Chang Mo CM Kim Byung Sik BS Kim Hee Sung HS Park Yun-Yong YY

Oncotarget 20171019 58

Gastric cancer (GC) is a leading cause of death worldwide and in urgent need of targeted drug development. In the current, we investigated the ability of a repositioned drug verteporfin (VP), originally a treatment for macular degeneration, to inhibit GC cell growth. VP inhibited growth of various GC cell lines. Gene expression profiling of GC cell lines treated with VP revealed that migration-related genes and those with oncogenic potential were down-regulated. Of these genes, we found that FAT ...[more]

PMID: 29228735

Similar Datasets

Correction: Verteporfin inhibits gastric cancer cell growth by suppressing adhesion molecule FAT1.

Project description:[This corrects the article DOI: 10.18632/oncotarget.21946.].

| S-EPMC6324691 | biostudies-literature

Photosensitizer verteporfin inhibits the growth of YAP- and TAZ-dominant gastric cancer cells by suppressing the anti-apoptotic protein Survivin in a light-independent manner.

Project description:Yes-associated protein (YAP) positivity indicates a poor prognosis in gastric cancer. Transcriptional co-activator with a PDZ-binding domain (TAZ), a YAP paralog, is highly expressed in gastric signet ring cell carcinoma. Verteporfin (VP), a clinical photosensitizer, was recently shown to inhibit YAP/TAZ. In the present study, the therapeutic potential of VP treatment was explored using two gastric cancer cell lines: MKN-45 (TAZ-dominant) and MKN-74 (YAP-dominant). Cell proliferation was evaluated by MTS assay. Vascular mimicry was evaluated by the tube formation assay. Gene and protein expression levels of YAP/TAZ downstream effectors [such as Survivin, Cysteine-rich angiogenic inducer 61 (CYR61), and connective tissue growth factor (CTGF)] were measured. YAP or TAZ localization was evaluated by immunofluorescence. Cell death was assessed by immunofluorescent staining of Annexin V. YAP and TAZ expression were knocked down by small interfering RNA. The current results demonstrate that MKN-45, a poorly differentiated TAZ-dominant gastric cancer cell line, was more sensitive to VP than MKN-74, a moderately differentiated YAP-dominant gastric cancer cell line. VP changed the localization of YAP/TAZ, promoted its degradation and significantly decreased the protein level of Survivin in both cell lines. Cell death was induced by VP treatment in a dose-dependent manner. Vascular mimicry was inhibited in both cell lines. Proliferation in both cell lines decreased in response to YAP/TAZ knockdown. The present study indicated that VP has potential as a therapeutic agent in YAP- and TAZ-dominant gastric cancers due to its ability to suppress the anti-apoptotic protein Survivin via inhibition of YAP and TAZ.

| S-EPMC8358589 | biostudies-literature

Verteporfin inhibits YAP-induced bladder cancer cell growth and invasion via Hippo signaling pathway.

Project description:The highly conserved Hippo signaling pathway is one of the most important pathways involved in tumorigenesis and progress. Previous studies show that YAP, the transcriptional coactivator of Hippo pathway, is expressed highly in many clinical bladder cancer tissues and plays crucial role on bladder cancer progress. To find the YAP-specific target drug and its molecular mechanism in bladder cancer, we apply Verteporfin (VP), a YAP specific inhibitor to function as anti-bladder cancer drug and discover that VP is able to inhibit bladder cancer cell growth and invasion in a dosage dependent manner. Moreover, we demonstrate that VP may inhibit bladder cancer cell growth and invasion via repressing target genes' expression of the Hippo signaling pathway. In further study, we provide evidence that VP is able to inhibit excessive YAP induced bladder cancer cell growth and invasion. To address the repressive function of VP against YAP in bladder cancer, we check the target genes' expression and find VP can dramatically repress YAP overexpression induced Hippo pathway target genes' expression. Taken together, we discover that VP inhibits YAP-induced bladder cancer cell growth and invasion via repressing the target genes' expression of Hippo signaling pathway.

| S-EPMC5930467 | biostudies-literature

Cryptotanshinone inhibits breast cancer cell growth by suppressing estrogen receptor signaling.

Project description:Estrogen receptor (ER) is a major therapeutic target for the treatment of breast cancer, because of the crucial role of estrogen signaling deregulation in the development and progression of breast cancer. In this study, we report the identification of a novel ER? binding compound, cryptotanshinone (CPT), by screening the CADD database. We also show that CPT effectively inhibits estrogen-induced ER transactivation and gene expression of ER target genes. Furthermore, we showed that CPT suppressed breast cancer cell growth mainly in an ER? dependent manner. Finally, we confirmed the potential therapeutic efficiency of CPT using xenograft experiments in vivo. Taken together, our results describe a novel mechanism for the anticancer activity of CPT and provide supporting evidence for its use as a potential therapeutic agent to treat patients with ER? positive breast cancer.

| S-EPMC4622426 | biostudies-literature

Clinical significance and biological role of L1 cell adhesion molecule in gastric cancer.

Project description:BackgroundL1 cell adhesion molecule (L1CAM) is highly expressed in malignant tumours and might play a pivotal role in tumour progression.MethodsWe analysed by immunohistochemistry L1CAM protein expression in formalin-fixed, paraffin-embedded specimens from 309 GC patients. We performed propensity score matching (PSM) analysis to clarify the prognostic impact of L1CAM in GC patients. We evaluated L1CAM gene expression in fresh frozen specimens from another group of 131 GC patients to establish its clinical relevance. The effects of changes in L1CAM were investigated in vitro and in vivo.ResultsL1CAM was mainly expressed in tumour cells of GC tissues. Elevated L1CAM expression was an independent prognostic factor for overall and disease-free survival, and an independent risk factor for distant metastasis in GC patients. PSM analysis showed that high L1CAM expression was significantly associated with poor prognosis. L1CAM gene expression using fresh frozen specimens successfully validated all of these findings in an independent cohort. Inhibition of L1CAM suppressed cell proliferation, cycle progress, invasion, migration and anoikis resistance in GC cells. Furthermore, L1CAM inhibition suppressed the growth of peritoneal metastasis.ConclusionL1CAM may serve as a feasible biomarker for identification of patients who have a high risk of recurrence of GC.

| S-EPMC6964673 | biostudies-literature

ERp29 inhibits tumorigenicity by suppressing epithelial mesenchymal transition in gastric cancer.

Project description:ERp29 is a novel endoplasmic reticulum (ER) protein that plays an important role in protein unfolding and secretion. Recently, it has been reported to be widely implicated in control of tumorigenesis in some tumors. However, the potential function of ERp29 in gastric cancer remains poorly understood. In this study, we found that the positive rate of ERp29 in gastric cancer tissues was significantly lower than that in adjacent non-tumor tissues. And tumor with high ERp29 expression had inclinations towards smaller tumor size and earlier TNM stage. The in vitro experiments indicated that over-expression of ERp29 in gastric cancer cells significantly suppressed the proliferation and migration of tumor cells, which is consistent with the result of the in vivo animal experiments. Furthermore, our mechanistic investigations revealed that ERp29 reversed EMT process in gastric carcinoma, and its effect was related to the inactivation of ERK1/2 and AKT phosphorylation. Thus, we conclude that ERp29 acts as a tumor suppressor gene in gastric cancer, and is expected to become a novel target of the treatment of GC.

| S-EPMC5667996 | biostudies-literature

ZiYinHuaTan Recipe Inhibits Cell Proliferation and Promotes Apoptosis in Gastric Cancer by Suppressing PI3K/AKT Pathway.

Project description:In recent years, traditional Chinese medicine has played an important role in the treatment of gastric cancer in China. ZiYinHuaTan (ZYHT) recipe was developed for advanced gastric cancer and had shown its promising value in the clinic. In this study, we explore the effect of ZYHT on gastric cancer in vitro and in vivo. ZYHT can inhibit tumor growth and improve the general condition of mice in subcutaneous transplantation nude mice models of gastric cancer. And ZYHT can also inhibit cell proliferation and blocked the cells in G0/G1 to induce cell apoptosis in HGC27 and MGC803 cells. Then, network pharmacology analysis showed that ZYHT may exert antitumor effect mainly through PI3K/AKT signaling pathway. Furthermore, the expression of PI3K, p-Akt, CyclinD1, and Bcl-2 was detected in vitro and in vivo. The results showed that ZYHT could decrease the expression of PI3K, CyclinD1, and Bcl-2 both in vitro and in vivo. These results suggested that ZYHT could be used as a method for the treatment of developed gastric cancer.

| S-EPMC7193275 | biostudies-literature

miRNA-194 predicts favorable prognosis in gastric cancer and inhibits gastric cancer cell growth by targeting CCND1.

Project description:MicroRNAs (MiRNAs) play critical roles in regulating target gene expression and multiple cellular processes in human cancer malignant progression. However, the function of miR-194 in gastric cancer (GC) remains unclear and controversial. In this study, we identified a series of miRNAs that can serve as prognostic biomarkers for GC by analysis of miRNA expression using The Cancer Genome Atlas data. Among them, miR-100, miR-125b, miR-199a, and miR-194 were the four most promising prognostic biomarkers in GC due to their significant associations with various clinical characteristics of patients. miR-100, miR-125b, and miR-199a predicted poor prognosis in GC, while miR-194 predicted favorable prognosis in GC. We also provide the first comprehensive transcriptome analysis of miR-194 in GC. Our data suggest that miR-194 tends to regulate target genes by binding to their 3' UTRs in a 7-mer-A1, 7-mer-m8, or 8-mer manner. KEGG pathway analysis showed that the cell cycle was one of the pathways most affected by miR-194 in GC. Moreover, CCND1 was shown to be a novel target gene of miR-194 in GC. Additionally, downregulation of CCND1 by miR-194 in GC further led to cell growth inhibition and cell cycle arrest. In conclusion, miR-100, miR-125b, miR-199a, and miR-194 may have potential as prognostic and diagnostic biomarkers for GC. miR-194 suppresses GC cell growth mainly through targeting CCND1 and induction of cell cycle arrest.

| S-EPMC8255842 | biostudies-literature

miR-6745-TIMP1 axis inhibits cell growth and metastasis in gastric cancer.

Project description:Tissue inhibitor matrix metalloproteinase 1 (TIMP1) has been reported to act as a tumor oncogene in colon cancer. However, little is known about the biological role of TIMP1 in gastric cancer. In this study, we found that the expression of TIMP1 in GC tissues was upregulated compared with the normal gastric tissues. TIMP1 was confirmed as a direct target of miR-6745 and silencing TIMP1 mimicked the effects of miR-6745 in GC cells. Further mechanism studies have shown that miR-6745 inhibits the Wnt/β-catenin pathway by targeting TIMP1, thereby inhibiting cell proliferation, migration and invasion. In addition, through the analysis of GC tissues, a negative correlation between miR-6745 and TIMP1 was found in 42 GC tissues. Our findings indicate that the miR-6745-TIMP1 axis regulates Wnt/βcatenin signaling and participates in GC tumorigenesis and provide a potential therapeutic target for preventing GC progression.

| S-EPMC8610132 | biostudies-literature

Synthetic miR-143 Inhibits Growth of HER2-Positive Gastric Cancer Cells by Suppressing KRAS Networks Including DDX6 RNA Helicase.

Project description:Gastric cancer (GC) is one of the most common cancers worldwide. In the clinical setting, the identification of HER2 overexpression in GC was a significant finding, as trastuzumab, an anti-HER2 drug, provides a survival advantage to HER2-positive GC patients. In HER2-postive GC, the dysregulation of PI3K/AKT and MAPK/ERK signaling pathways has been reported, and inhibition of these pathways is an important therapeutic strategy. MiR-143 is known to act as a tumor suppressor in several cancers, such as bladder cancer, breast cancer, colorectal cancer, and gastric cancer. In the current study, we developed a novel chemically-modified miR-143 and explored the functions of this synthetic miR-143 (syn-miR-143) in HER2-positive gastric cancer. The expression level of miR-143 was down-regulated in GC cell lines, including HER2-positive GC cell lines, MKN7, and KATO-III. The ectopic expression of miR-143 in those cell lines suppressed cell growth through systemic silencing of KRAS and its effector signaling molecules, AKT and ERK. Furthermore, syn-miR-143 indirectly down-regulated the expression of HER2, an upstream molecule of KRAS, through silencing DEAD/H-box RNA helicase 6 (DDX6), RNA helicase, which enhanced HER2 protein expression at the translational step in HER2-positive GC cells. These findings suggested that syn-miR-143 acted as a tumor suppressor through the impairment of KRAS networks including the DDX6.

| S-EPMC6479539 | biostudies-literature

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