Transforming growth factor-β decreases the cancer-initiating cell population within diffuse-type gastric carcinoma cells

Ehata, Shogo; Johansson, Erik; Katayama, Ryohei; Koike, Sumie; Watanabe, Akira; Hoshino, Yoichi; Katsuno, Yoko; Komuro, Akiyoshi; Koinuma, Daizo; Kano, Mitsunobu R.; Yashiro, Masakazu; Hirakawa, Kosei; Aburatani, Hiroyuki; Fujita, Naoya; Miyazono, Kohei

doi:10.1038/onc.2010.546

Cited by 75 publications

(71 citation statements)

References 52 publications

(52 reference statements)

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“…Disruption in TGFb signaling facilitates the growth of diffuse-type GC (Komuro et al, 2009). Furthermore, TGFb suppresses the progression of diffuse-type GC by inducing the differentiation of cancer-initiating cell sub-population (Ehata et al, 2011). This study provided another line of evidence delineating the downregulation of TGFb-RII by miR-370 targeting in GC cells; interestingly, this was found to be associated with an increased GC cell mobility through modulation of TGFb signal.…”

Section: Discussionsupporting

confidence: 51%

“…The potential impacts of miR-370 expression on apoptosis, differentiation, drug resistance and survival in hypoxia situation require further elucidation (Petrocca et al, 2008;Komuro et al, 2009;Ehata et al, 2011). The role of TGFb pathway in xenografic tumor growth also needs clarification.…”

Section: Discussionmentioning

confidence: 99%

“…Transforming growth factor-b (TGFb) has pluripotent roles in regulating biological and pathological processes (van den Brink and Offerhaus, 2007;Massague, 2008). On ligand binding, the TGFb receptor II (TGFb-RII) activates TGFb-RI and transduces signals through a cascade of elements including Smad signaling molecules (Massague, 2008;Ehata et al, 2011). SB431542 blocks Smad signaling by inactivating TGFb1-RI receptor kinase (Inman et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

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Overexpression of miR-370 and downregulation of its novel target TGFβ-RII contribute to the progression of gastric carcinoma

et al. 2011

Oncogene

101

100

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MicroRNAs (miRNAs) are endogenous non-coding RNAs that are known to be involved in the pathogenesis of tumors. Gastric carcinoma (GC) is a common malignancy worldwide. The aim of this study was the identification of the expression signature and functional roles of aberrant miRNAs in GC. Initial screening established a profile of aberrantly expressed miRNAs in tumors. miR-370 was confirmed to be overexpressed in GC tissues. Higher expression of miR-370 in GC tissues was associated with more advanced nodal metastasis and a higher clinical stage compared with controls. In addition, significantly higher level of miR-370 was noted in the plasma of GC patients compared with controls. Patients having more invasive or advanced tumors also exhibited a higher plasma level of miR-370. In vitro assays indicated that exogenous miR-370 expression enhanced the oncogenic potential of GC cells. The AGS-GFPM2 cells with exogenous miR-370 expression also exhibited enhanced abdominal metastatic dissemination in nude mice. Reporter assays confirmed that miR-370 targeted predicted sites in 3 0 UTR of transforming growth factor-b receptor II (TGFb-RII) gene. The exogenous miR-370 expression decreased TGFb-RII expression and the phosphorylation of Smad3 elicited by TGFb1. The TGFb1-mediated repression in cell migration was reverted by exogenous miR-370 expression. A reverse correlation between miR-370 and TGFb-RII expression was noted in GC tissues. This study concludes that miR-370 is a miRNA that is associated with GC progression by downregulating TGFb-RII. The miRNA expression profile described in this study should contribute to future studies on the role of miRNAs in GC.

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Section: Discussionsupporting

confidence: 51%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Overexpression of miR-370 and downregulation of its novel target TGFβ-RII contribute to the progression of gastric carcinoma

et al. 2011

Oncogene

101

100

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“…In support of this postulate, decreased expression of CSC markers was also detected in tumor cells of a single glioblastoma patient undergoing the first clinical trial of the small molecule TbRI inhibitor, galunisertib (Anido et al 2010). However, others made contrary findings in gastric carcinoma cells in culture and in a breast carcinoma xenograft model (Tang et al 2007;Ehata et al 2011). TbRISmad2 signaling has been implicated in maintaining epigenetic silencing that promotes and sustains EMT and the CSC phenotype (Papageorgis et al 2010).…”

Section: Tgf-b Action In Cancer Stem-cell Maintenancementioning

confidence: 99%

Targeting TGF-β Signaling for Therapeutic Gain

Akhurst

2017

Cold Spring Harb Perspect Biol

168

139

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Transforming growth factor bs (TGF-bs) are closely related ligands that have pleiotropic activity on most cell types of the body. They act through common heterotetrameric TGF-b type II and type I transmembrane dual specificity kinase receptor complexes, and the outcome of signaling is context-dependent. In normal tissue, they serve a role in maintaining homeostasis. In many diseased states, particularly fibrosis and cancer, TGF-b ligands are overexpressed and the outcome of signaling is diverted toward disease progression. There has therefore been a concerted effort to develop drugs that block TGF-b signaling for therapeutic benefit. This review will cover the basics of TGF-b signaling and its biological activities relevant to oncology, present a summary of pharmacological TGF-b blockade strategies, and give an update on preclinical and clinical trials for TGF-b blockade in a variety of solid tumor types.

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“…CSCs have been identified in several types of tumors, and biomarkers have been established, such as those identified by SP assay (13)(14)(15): CD44 in breast CSCs (16); and CD133 in hematopoietic CSCs, (17) neural stem cells (18) and colon cancer cells (19,20). These biomarkers are sometimes related with the prognosis of tumors.…”

Section: Methods For Identifying Cscs: Biomarkersmentioning

confidence: 99%

Cancer stem cells: The potential of carbon ion beam radiation and new radiosensitizers (Review)

et al. 2015

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Abstract. Cancer stem cells (CSCs) are a small population of cells in cancer with stem-like properties such as cell proliferation, multiple differentiation and tumor initiation capacities. CSCs are therapy-resistant and cause cancer metastasis and recurrence. One key issue in cancer therapy is how to target and eliminate CSCs, in order to cure cancer completely without relapse and metastasis. To target CSCs, many cell surface markers, DNAs and microRNAs are considered as CSC markers. To date, the majority of the reported markers are not very specific to CSCs and are also present in nonCSCs. However, the combination of several markers is quite valuable for identifying and targeting CSCs, although more specific identification methods are needed. While CSCs are considered as critical therapeutic targets, useful treatment methods remain to be established. Epigenetic gene regulators, microRNAs, are associated with tumor initiation and progression. MicroRNAs have been recently considered as promising therapeutic targets, which can alter the therapeutic resistance of CSCs through epigenetic modification. Moreover, carbon ion beam radiotherapy is a promising treatment for CSCs. Evidence indicates that the carbon ion beam is more effective against CSCs than the conventional X-ray beam. Combination therapies of radiosensitizing microRNAs and carbon ion beam radiotherapy may be a promising cancer strategy. This review focuses on the identification and treatment resistance of CSCs and the potential of microRNAs as new radiosensitizers and carbon ion beam radiotherapy as a promising therapeutic strategy against CSCs.

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Transforming growth factor-β decreases the cancer-initiating cell population within diffuse-type gastric carcinoma cells

Cited by 75 publications

References 52 publications

Overexpression of miR-370 and downregulation of its novel target TGFβ-RII contribute to the progression of gastric carcinoma

Overexpression of miR-370 and downregulation of its novel target TGFβ-RII contribute to the progression of gastric carcinoma

Targeting TGF-β Signaling for Therapeutic Gain

Cancer stem cells: The potential of carbon ion beam radiation and new radiosensitizers (Review)

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