Tepotinib inhibits the epithelial-mesenchymal transition and tumour growth of gastric cancers via decreasing MUC5B, MMP7, and COX2

The expression of leucine-rich repeat and immunoglobulin-like domain-containing nogo receptor-interacting protein 2 (LINGO2) has been reported in Parkinson’s disease; however, its role in other diseases is unknown. Gastric cancer is the second leading cause of cancer death. Cancer stem cells (CSC) are a subpopulation of cancer cells that contribute to the initiation and invasion of cancer. We identified LINGO2 as a CSC-associated protein in gastric cancers both in vitro and in patient-derived tissues. We studied the effect of LINGO2 on cell motility, stemness, tumorigenicity, and angiogenic capacity using cells sorted based on LINGO2 expression and LINGO2-silenced cells. Tissue microarray analysis showed that LINGO2 expression was significantly elevated in advanced gastric cancers. The overall survival of patients expressing high LINGO2 was significantly shorter than that of patients with low LINGO2. Cells expressing high LINGO2 showed elevated cell motility, angiogenic capacity, and tumorigenicity, while LINGO2 silencing reversed these properties. Silencing LINGO2 reduced kinase B (AKT)/extracellular signal-regulated kinase (ERK)/ERK kinase (MEK) phosphorylation and decreased epithelial-mesenchymal transition (EMT)-associated markers—N-Cadherin and Vimentin and stemness-associated markers— POU class 5 homeobox 1 (OCT4) and Indian hedgehog (IHH), and markedly decreased the CD44+ population. These indicate the involvement of LINGO2 in gastric cancer initiation and progression by altering cell motility, stemness, and tumorigenicity, suggesting LINGO2 as a putative target for gastric cancer treatment.

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Molecular Signatures of the Insulin-like Growth Factor 1-mediated Epithelial-Mesenchymal Transition in Breast, Lung and Gastric Cancers

International Journal of Molecular Sciences ◽

10.3390/ijms19082411 ◽

2018 ◽

Vol 19 (8) ◽

pp. 2411 ◽

Cited By ~ 20

Author(s):

Armando Cevenini ◽

Stefania Orrù ◽

Annamaria Mancini ◽

Andreina Alfieri ◽

Pasqualina Buono ◽

...

Keyword(s):

Growth Factor ◽

Epithelial Mesenchymal Transition ◽

Molecular Signatures ◽

Insulin Like Growth Factor ◽

Cancer Proliferation ◽

Igf Binding Proteins ◽

Mesenchymal Transition ◽

Gastric Cancers ◽

Igf System ◽

Igf Binding

The insulin-like growth factor (IGF) system, which is constituted by the IGF-1 and IGF-2 peptide hormones, their corresponding receptors and several IGF binding proteins, is involved in physiological and pathophysiological processes. The IGF system promotes cancer proliferation/survival and its signaling induces the epithelial-mesenchymal transition (EMT) phenotype, which contributes to the migration, invasiveness, and metastasis of epithelial tumors. These cancers share two major IGF-1R signaling transduction pathways, PI3K/AKT and RAS/MEK/ERK. However, as far as we could review at this time, each type of cancer cell undergoes EMT through tumor-specific routes. Here, we review the tumor-specific molecular signatures of IGF-1-mediated EMT in breast, lung, and gastric cancers.

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Cross talk between hedgehog and epithelial–mesenchymal transition pathways in gastric pit cells and in diffuse-type gastric cancers

British Journal of Cancer ◽

10.1038/sj.bjc.6604846 ◽

2008 ◽

Vol 100 (2) ◽

pp. 389-398 ◽

Cited By ~ 69

Author(s):

H Ohta ◽

K Aoyagi ◽

M Fukaya ◽

I Danjoh ◽

A Ohta ◽

...

Keyword(s):

Cross Talk ◽

Epithelial Mesenchymal Transition ◽

Diffuse Type ◽

Mesenchymal Transition ◽

Gastric Cancers ◽

Transition Pathways ◽

Pit Cells

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Gastrokine 1 functions as a tumor suppressor by inhibition of epithelial–mesenchymal transition in gastric cancers

Journal of Cancer Research and Clinical Oncology ◽

10.1007/s00432-011-1051-8 ◽

2011 ◽

Vol 137 (11) ◽

pp. 1697-1704 ◽

Cited By ~ 37

Author(s):

Jung Hwan Yoon ◽

Young Hwi Kang ◽

Yoo Jin Choi ◽

In Soo Park ◽

Suk Woo Nam ◽

...

Keyword(s):

Tumor Suppressor ◽

Epithelial Mesenchymal Transition ◽

Mesenchymal Transition ◽

Gastric Cancers ◽

Gastrokine 1

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S-Allylcysteine inhibits tumour progression and the epithelial–mesenchymal transition in a mouse xenograft model of oral cancer

British Journal Of Nutrition ◽

10.1017/s0007114511005307 ◽

2011 ◽

Vol 108 (1) ◽

pp. 28-38 ◽

Cited By ~ 17

Author(s):

Man-Hui Pai ◽

Yueh-Hsiung Kuo ◽

En-Pei Isabel Chiang ◽

Feng-Yao Tang

Keyword(s):

Oral Cancer ◽

Tumour Growth ◽

Epithelial Mesenchymal Transition ◽

Tumour Progression ◽

D1 Protein ◽

Xenograft Model ◽

Mesenchymal Transition ◽

Mouse Xenograft ◽

Mouse Xenograft Model

Oral cancer is prevalent worldwide. Studies have indicated that an increase in the osteopontin (OPN) plasma level is correlated with the progression of oral cancer. Our previous report showed that the aqueous garlic extract S-allylcysteine (SAC) inhibited the epithelial–mesenchymal transition (EMT) of human oral cancer CAL-27 cells in vitro. Therefore, the present study investigated whether SAC consumption would help prevent tumour growth and progression, including the EMT, in a mouse xenograft model of oral cancer. The results demonstrated that SAC dose-dependently inhibited the growth of oral cancer in tumour-bearing mice. The histopathological and immunohistochemical staining results indicated that SAC was able to effectively suppress the tumour growth and progression of oral cancer in vivo. The chemopreventive effect of SAC was associated with the suppression of carcinogenesis factors such as N-methylpurine DNA glycosylase and OPN. SAC significantly suppressed the phosphorylation of Akt, mammalian target of rapamycin, inhibitor of κBα and extracellular signal-regulated kinase 1/2 in tumour tissues. The results demonstrated that the SAC-mediated suppression of cyclin D1 protein was associated with an augmented expression of the cell-cycle inhibitor p16Ink4. Furthermore, SAC inhibited the expression of cyclo-oxygenase-2, vimentin and NF-κB p65 (RelA). These results show that SAC has potential as an agent against tumour growth and the progression of oral cancer in a mouse xenograft model.

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Long Noncoding RNA HOTAIR Promotes Epithelial-Mesenchymal Transition and Is a Suitable Target to Inhibit Peritoneal Dissemination in Human Scirrhous Gastric Cancers

Pathobiology ◽

10.1159/000508350 ◽

2020 ◽

Vol 87 (5) ◽

pp. 277-290

Author(s):

Yoshifumi Takei ◽

Toshifumi Hara ◽

Akiko Suzuki ◽

Keichiro Mihara ◽

Kazuyoshi Yanagihara

Keyword(s):

Gastric Cancer ◽

Cell Line ◽

Noncoding Rna ◽

Epithelial Mesenchymal Transition ◽

Peritoneal Dissemination ◽

Luciferase Assay ◽

Scirrhous Gastric Cancer ◽

Mesenchymal Transition ◽

Gastric Cancers ◽

Original Cell

Objectives: Scirrhous gastric cancer, which accounts for approximately 10% of all gastric cancers, often disseminates to the peritoneum, leading to intractable cases with poor prognosis. There is an urgent need for new treatment approaches for this difficult cancer. Methods: We previously established an original cell line, HSC-60, from a scirrhous gastric cancer patient and isolated a peritoneal-metastatic cell line, 60As6, in nude mice following orthotopic inoculations. In the present study, we focused on the expression of long noncoding ribonucleic acid (RNA) (lncRNA) in the cell lines and investigated the mechanism on peritoneal dissemination. Results: We demonstrated that an lncRNA, HOX transcript antisense RNA (HOTAIR), is expressed significantly more highly in 60As6 than HSC-60 cells. Then, using both HOTAIR knockdown and overexpression experiments, we showed that high-level expression of HOTAIR promotes epithelial-mesenchymal transition (EMT) in 60As6 cells. By luciferase assay, we found that HOTAIR directly targets and binds to miR-217, and that miR-217 directly binds to Zinc finger E-box-binding homeobox 1 (ZEB1). The knockdown of HOTAIR in 60As6 cells significantly reduced the invasion activity and peritoneal dissemination – and significantly prolonged the survival – in the orthotopic tumor mouse model. Conclusion: An EMT-associated pathway (the HOTAIR-miR-217-ZEB1 axis) appears to inhibit peritoneal dissemination and could lead to a novel therapeutic strategy against scirrhous gastric cancer in humans.

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