Role of Rac1 Pathway in Epithelial-to-Mesenchymal Transition and Cancer Stem-like Cell Phenotypes in Gastric Adenocarcinoma

Yoon, Changhwan; Cho, Soo‐Jeong; Chang, K. C.; Park, Do Joong; Ryeom, Sandra; Yoon, Sam S.

doi:10.1158/1541-7786.mcr-17-0053

Cited by 68 publications

(54 citation statements)

References 40 publications

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“…2A). Epithelial-mesenchymal transition (EMT) is essential for initiation of metastasis for cancer progression 23 and is driven by the transcription factors SNAI1, SLUG, ZEB1/2, or TWIST1/2 24 . CD44(+)-HNSCC cells showed decreased expression of E-cadherin and increased Snail expression as EMT-related protein (Suppl.…”

Section: Resultsmentioning

confidence: 99%

“…For IHC, formalin fixed, paraffin-embedded sections were deparaffinized by xylene and rehydrated. Sections were either stained with H&E or immunostained using the VECTASTAIN Elite ABC kit (Vector Laboratories Inc.) following manufacturer's instructions and standard protocols 23 . Antibodies included CD44 (#3570, Cell Signaling Technology), CD24 (sc-11406, Santa Cruz Biotechnology), CD133 (MBS462020; MyBioSource), Musashi-1 (ab21628; abcam), Sox2 (#4900; Cell Signaling Technology), Oct-4 (#2750; Cell Signaling Technology), Nanog (#4893; Cell Signaling Technology), c-Myc (sc-40; Santa Cruz Biotechnology), Ki-67 (ab197234; abcam), cleaved caspase-3 (#9661; Cell Signaling Technology), ɣH2AX (Millipore 05-636), and Snail (sc-271977; Santa Cruz Biotechnology).…”

Section: Immunohistochemistry and Immunofluorescencementioning

confidence: 99%

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RETRACTED ARTICLE: ERK1/2-Nanog signaling pathway enhances CD44(+) cancer stem-like cell phenotypes and epithelial-to-mesenchymal transition in head and neck squamous cell carcinomas

et al. 2020

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Head and neck squamous cell carcinomas (HNSCCs) harbor a subset of cells that are CD44(+) and present with malignancy and radiotherapy resistance. As a key regulator of self-renewal, Nanog expression not only determines cell fate in pluripotent cells but also mediates tumorigenesis in cancer cells; thus, we examined the role of Nanog in CD44 (+) HNSCC. Three HNSCC cell lines, tumor xenografts, and patient tumors were examined. Nanog levels were significantly higher in CD44(+) HNSCC spheroids than in CD44(−) spheroids, and further increased when grown as spheroids to enrich for CSCs. CD44(+) spheroids showed a 3.4-7.5-fold increase in migration and invasion compared with CD44(−) spheroids and were resistant to radiation therapy, which was reversed by inhibiting Nanog. Nanog knockdown also decreased spheroid formation by 66.5-68.8%. Moreover, a phosphokinase array identified upregulated ERK1/2 signaling in CD44(+) HNSCC cells compared with that in CD44(−) cells. ERK1/2 signaling was found to regulate Nanog expression, aiding tumor progression, metastasis, and radiotherapy resistance. In xenograft models, the combination of radiation and Nanog or ERK1/2 inhibition inhibited tumor growth by 75.6% and 79.1%, respectively. In lung metastasis models, CD44(+) cells injected into the tail vein of mice led to significantly more lung metastases and higher Nanog expression level compared with that by ERK1/2-knockdown CD44(+) cells. Finally, in tumor tissues, CD44 and Nanog expression levels were correlated with tumorigenesis in HNSCC patients. Thus, targeting Nanog and the ERK1/2 signaling pathway may prevent or reverse CSC phenotypes and epithelial-mesenchymal transition that drive tumor progression, metastasis, and radiotherapy resistance in HNSCC.

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Section: Resultsmentioning

confidence: 99%

Section: Immunohistochemistry and Immunofluorescencementioning

confidence: 99%

RETRACTED ARTICLE: ERK1/2-Nanog signaling pathway enhances CD44(+) cancer stem-like cell phenotypes and epithelial-to-mesenchymal transition in head and neck squamous cell carcinomas

et al. 2020

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“…Rac1 promotes the EMT program in gastric adenocarcinomas and the acquisition of a cancer stem cell state. Rac1 inhibition in gastric adenocarcinoma cells blocks EMT and CSC phenotypes and thus prevents metastasis and may augment chemotherapy (Yoon et al, ). These studies and our experimental data provide theoretical support for the mechanism by which NKCC1 promotes EMT.…”

Section: Discussionmentioning

confidence: 99%

NKCC1 promotes EMT‐like process in GBM via RhoA and Rac1 signaling pathways

Tao

et al. 2018

Journal Cellular Physiology

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Glioblastoma is the most common and lethal primary intracranial tumor. As the key regulator of tumor cell volume, sodium‐potassium‐chloride cotransporter 1 (NKCC1) expression increases along with the malignancy of the glioma, and NKCC1 has been implicated in glioblastoma invasion. However, little is known about the role of NKCC1 in the epithelial‐mesenchymal transition‐like process in gliomas. We noticed that aberrantly elevated expression of NKCC1 leads to changes in the shape, polarity, and adhesion of cells in glioma. Here, we investigated whether NKCC1 promotes an epithelial–mesenchymal transition (EMT)‐like process in gliomas via the RhoA and Rac1 signaling pathways. Pharmacological inhibition and knockdown of NKCC1 both decrease the expressions of mesenchymal markers, such as N‐cadherin, vimentin, and snail, whereas these treatments increase the expression of the epithelial marker E‐cadherin. These findings indicate that NKCC1 promotes an EMT‐like process in gliomas. The underlying mechanism is the facilitation of the binding of Rac1 and RhoA to GTP by NKCC1, which results in a significant enhancement of the EMT‐like process. Specific inhibition or knockdown of NKCC1 both attenuate activated Rac1 and RhoA, and the pharmacological inhibitions of Rac1 and RhoA both impair the invasion and migration abilities of gliomas. Furthermore, we illustrated that NKCC1 knockdown abolished the dissemination and spread of glioma cells in a nude mouse intracranial model. These findings suggest that elevated NKCC1 activity acts in the regulation of an EMT‐like process in gliomas, and thus provides a novel therapeutic strategy for targeting the invasiveness of gliomas, which might help to inhibit the spread of malignant intracranial tumors.

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“…It was hypothesized that overexpression of the regulator of G-protein signaling pathway 1 (RGS1) might promote the transition of stem cells into CSCs [308]. Besides, CSCs are involved in EMT progression via a vast number of mechanisms, including an overactivation of KRAS, STAT3, Rac1, Wnt, Notch, PTEN, ERK, NF-κB signaling pathways, or hypoxic microenvironment [309][310][311][312][313][314][315][316][317][318]. Recently, researchers have proposed the role of CSC-associated protein, leucine-rich repeat and immunoglobulin-like domain-containing nogo receptor-interacting protein 2 (LINGO2), in gastric cancer and EMT initiation [319].…”

Section: Stem Cellsmentioning

confidence: 99%

Mechanisms of the Epithelial–Mesenchymal Transition and Tumor Microenvironment in Helicobacter pylori-Induced Gastric Cancer

Baj

Korona-Głowniak

Forma

et al. 2020

Cells

112

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Helicobacter pylori (H. pylori) is one of the most common human pathogens, affecting half of the world's population. Approximately 20% of the infected patients develop gastric ulcers or neoplastic changes in the gastric stroma. An infection also leads to the progression of epithelial-mesenchymal transition within gastric tissue, increasing the probability of gastric cancer development. This paper aims to review the role of H. pylori and its virulence factors in epithelial-mesenchymal transition associated with malignant transformation within the gastric stroma. The reviewed factors included: CagA (cytotoxin-associated gene A) along with induction of cancer stem-cell properties and interaction with YAP (Yes-associated protein pathway), tumor necrosis factor α-inducing protein, Lpp20 lipoprotein, Afadin protein, penicillin-binding protein 1A, microRNA-29a-3p, programmed cell death protein 4, lysosomal-associated protein transmembrane 4β, cancer-associated fibroblasts, heparin-binding epidermal growth factor (HB-EGF), matrix metalloproteinase-7 (MMP-7), and cancer stem cells (CSCs). The review summarizes the most recent findings, providing insight into potential molecular targets and new treatment strategies for gastric cancer.

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Role of Rac1 Pathway in Epithelial-to-Mesenchymal Transition and Cancer Stem-like Cell Phenotypes in Gastric Adenocarcinoma

Cited by 68 publications

References 40 publications

RETRACTED ARTICLE: ERK1/2-Nanog signaling pathway enhances CD44(+) cancer stem-like cell phenotypes and epithelial-to-mesenchymal transition in head and neck squamous cell carcinomas

RETRACTED ARTICLE: ERK1/2-Nanog signaling pathway enhances CD44(+) cancer stem-like cell phenotypes and epithelial-to-mesenchymal transition in head and neck squamous cell carcinomas

NKCC1 promotes EMT‐like process in GBM via RhoA and Rac1 signaling pathways

Mechanisms of the Epithelial–Mesenchymal Transition and Tumor Microenvironment in Helicobacter pylori-Induced Gastric Cancer

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