Inhibitory effect of a TGFβ receptor type-I inhibitor, Ki26894, on invasiveness of scirrhous gastric cancer cells

Shinto, Osamu; Yashiro, Masakazu; Kawajiri, Hidemi; Shimizu, Kiyoshí; Shimizu, Toshiyuki; Miwa, Atsushi; Hirakawa, Kosei

doi:10.1038/sj.bjc.6605561

Cited by 89 publications

(85 citation statements)

References 35 publications

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“…Thereafter, the cells were washed and resuspended in serum-free DMEM. Then, 1.5x10 6 of cells mixed with Matrigel (1:1) were subcutaneously injected into the right flank area of athymic nude mice, the growth of which was monitored regularly. After 16 days of xenograft implantation, tumors were selected for implantation to other nude mice using a 20-inoculating needle at an average size of 1 cm 3 .…”

Section: Methodsmentioning

confidence: 99%

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Pien Tze Huang inhibits liver metastasis by targeting TGF-β signaling in an orthotopic model of colorectal cancer

et al. 2015

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Abstract.Metastasis is the leading cause of cancer-related mortality in almost all types of cancers, including colorectal cancer (CRC). Epithelial-mesenchymal transition (EMT) is a critical process during the metastatic cascade. This process may be a potential target for the diagnosis and treatment of CRC. Pien Tze Huang (PZH), a well-known traditional Chinese formula, has been demonstrated to be clinically effective in treating various types of human malignancies, including CRC. Our published data suggest that PZH can induce apoptosis, as well as inhibit cell proliferation and tumor angiogenesis, thus suppressing CRC growth in vitro and in vivo. We evaluated the therapeutic efficacy of PZH against CRC metastasis using a CRC liver metastasis mouse model to further explore the mechanisms underlying the antitumor action of PZH. MTT, migration, and Matrigel invasion assays were used to assess the effect of PZH on cell viability, migration and invasion. We then established an orthotopic liver metastasis model of colon cancer using microsurgical techniques. Mice were intragastrically administered 234 mg/kg/day dose of either PZH or saline for 14 days. The body and tumor weights of the mice were measured after they were sacrificed. Moreover, we examined the effect of PZH inhibition on liver metastasis. Finally, EMT-related proteins and the TGF-β signaling pathway were assessed using immunohistochemical staining (IHS). The present data revealed that PZH significantly inhibited the migration and invasion of CT-26 cells in a dose-dependent manner, which affirmed the inhibitory effect of PZH on CRC cell metastasis. No significant change was observed between the in vivo primary tumor growth and body weight. However, the control group had five cases of liver metastasis (5/6), whereas one case was found in the PZH group (1/6). Thus, PZH exhibited therapeutic efficacy against CRC metastasis without apparent toxicity. The inhibitory effect of PZH on EMT resulted in an increase in E-cadherin expression, as well as a decrease in N-cadherin expression. In addition, PZH significantly inhibited TGF-β, as well as the phosphorylation of Smad2/3 and Smad4 in the tumor tissues, indicating its suppressive action on TGF-β signaling. These molecular effects ultimately resulted in the inhibition of cancer cell EMT and tumor metastasis.

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Section: Methodsmentioning

confidence: 99%

“…EMT refers to the morphological and molecular changes that occur when epithelial cells lose their characteristics, gain mesenchymal properties and become motile, which makes EMT a key event in tumor invasion and metastasis (5)(6)(7). EMT could thus be a potential target for CRC therapy.…”

Section: Introductionmentioning

confidence: 99%

Pien Tze Huang inhibits liver metastasis by targeting TGF-β signaling in an orthotopic model of colorectal cancer

et al. 2015

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“…Scirrhous type GC secretes a larger amount of the active form of TGF-β than non-scirrhous type GC (34), and TGF-β has important pathological and biological roles in scirrhous type GC (3,5,35,36). To investigate the effects of TGF-β1 on miR-145 and α-SMA expression, NF-38 and CaF-38 were treated with TGF-β1, and their expression levels of miR-145 and α-SMA were monitored by qRT-PCR.…”

Section: Tgf-β Regulates α-Sma Expression Via Mir-145mentioning

confidence: 99%

MicroRNA-145 is a potential prognostic factor of scirrhous type gastric cancer

et al. 2014

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Abstract. Gastric cancer (GC) is one of the most common malignancies worldwide. In particular, scirrhous type GC is highly metastatic and is characterized clinically by rapid disease progression and poor prognosis. MicroRNAs (miRNAs) play crucial roles in cancer development and progression. We previously demonstrated by microarray analysis that microRNA-145 (miR-145) is one of the more highly expressed miRNAs in scirrhous type GC vs. non-scirrhous types of GC. In the present study, we investigated the role of miR-145 in scirrhous type GC. The expression levels of miR-145 assessed by quantitative RT-PCR were higher in scirrhous type GC tissue samples than in non-scirrhous type GC and corresponding normal tissues. GC patients with high miR-145 expression were at a more advanced tumor stage (P=0.0156) and had more scirrhous type histology (P=0.0054) than those with low miR-145 expression. Furthermore, miR-145 expression was significantly associated with poor prognosis in GC patients (P=0.0438). miR-145 expression was localized in stromal fibroblasts of scirrhous type GC but not in cancer cells. miR-145 was induced by treatment by transforming growth factor-β, and it enhanced the expression of α-smooth muscle actin, a marker of myofibroblasts, in both normal gastric fibroblasts and cancer-associated fibroblasts. These data suggest that miR-145 may contribute to the progression of scirrhous type GC by regulating activation of peri-tumoral fibroblasts.

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“…This signalling cascade initiates broad cellular and noncellular processes including proliferation and differentiation, migration and motility, and deposition of extracellular matrix, as well as induces the production of cytokines contributing to tumorigenesis, metastasis, and angiogenesis (Ge, et al, 2006;Petersen, et al, 2010). Due to its central role in TGFsignalling, T RI is emerging as a novel target for the blockade of the tumor-promoting and metastasis activities of the TGF-pathway (Shinto, et al, 2010). Consequently, the TGF- signal becomes a bone metastasis-promoting one (Kang Y, et al, 2005;Kominsky SL, et al, 2007;Yin JJ, et al, 1999).…”

Section: Transforming Growth Factor- (Tgf-) and Ccn2mentioning

confidence: 99%

Role of Connective Tissue Growth Factor (CTGF/CCN2) in Oral Squamous Cell Carcinoma-Induced Bone Destruction

Shimo¹,

Sasaki²

2012

Squamous Cell Carcinoma

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Inhibitory effect of a TGFβ receptor type-I inhibitor, Ki26894, on invasiveness of scirrhous gastric cancer cells

Cited by 89 publications

References 35 publications

Pien Tze Huang inhibits liver metastasis by targeting TGF-β signaling in an orthotopic model of colorectal cancer

Pien Tze Huang inhibits liver metastasis by targeting TGF-β signaling in an orthotopic model of colorectal cancer

MicroRNA-145 is a potential prognostic factor of scirrhous type gastric cancer

Role of Connective Tissue Growth Factor (CTGF/CCN2) in Oral Squamous Cell Carcinoma-Induced Bone Destruction

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