Identification of novel small compounds that restore E-cadherin expression and inhibit tumor cell motility and invasiveness

Hirano, Tamaki; Satow, Reiko; Kato, Asami; Tamura, Mana; Murayama, Yumi; Saya, Hideyuki; Kojima, Hirotatsu; Nagano, Tetsuo; Okabe, Takayoshi; Fukami, Kiyoko

doi:10.1016/j.bcp.2013.09.001

Cited by 19 publications

(11 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Several molecules, for example, IFN-gamma, SMAD-7 and E-cadherin confer inhibition of EMT to B16F10 cells [28,29,33,34]. It was reported that IFN-γ and TGF-β have opposite effects on diverse cellular functions.…”

Section: Discussionmentioning

confidence: 99%

Regulation gene expression of miR200c and ZEB1 positively enhances effect of tumor vaccine B16F10/GPI-IL-21 on inhibition of melanoma growth and metastasis

Wang

Zhao

et al. 2014

J Transl Med

View full text Add to dashboard Cite

BackgroundGenetically modified cells have been shown to be one of the most effective tumor vaccine strategies. However, in many cases, such as in melanoma, induction of a potent immune responses against the disease still remains a major challenge. Thus, novel strategies to reinforce tumor vaccine efficacy are needed. Using microRNA (miR) and Zinc-finger E-box binding homeobox (ZEB) have received much attention for potentially regulating tumor progression. To elicit a potent antitumor efficacy against melanoma, we used tumor vaccine in combination with miR200c overexpression or ZEB1 knockdown to assess the efficacy of treatment of murine melanoma.MethodsB16F10 cell vaccine expressing interleukin 21 (IL-21) in the glycosylpho- sphatidylinositol (GPI)-anchored form (B16F10/GPI-IL-21) were developed. The vaccine was immunized into mice challenged by B16F10 cells or B16F10 cells stably transduced with lentiviral-miR200c (B16F10/miR200c) or transfected with the ZEB1-shRNA recombinant (B16F10/shZEB1) or the B16F10/GPI-IL-21 vaccine. The immune responses, tumorigenicity and lung metastasis in mice were evaluated, respectively.ResultsThe vaccination with B16F10/GPI-IL-21 markedly increased the serum cytokine levels of IFN-γ, TNF-α, IL-4 and decreased TGF-β level as well as augmented the cytotoxicity of splenocytes in immunized mice compared with control mice. In addition, the tumor vaccine B16F10/GPI-IL-21 significantly inhibited the tumor growth and reduced counts of lung metastases in mice challenged by B16F10/GPI-IL-21, B16F10/shZEB1 and B16F10/miR200c respectively compared with the control mice challenged by B16F10 cells. The efficacy mechanisms may involve in reinforcing immune responses, increasing expression of miR200c, E-cadherin and SMAD-7 and decreasing expression of TGF-β, ZEB1, Vimentin and N-cadherin in tumor tissues from the immunized mice.ConclusionsThese results indicate that the tumor vaccine B16F10/GPI-IL-21 in combination with miR200c overexpression or ZEB1 knockdown effectively inhibited melanoma growth and metastasis a murine model. Such a strategy may, therefore, be used for the clinical trials.

show abstract

Section: Discussionmentioning

confidence: 99%

Regulation gene expression of miR200c and ZEB1 positively enhances effect of tumor vaccine B16F10/GPI-IL-21 on inhibition of melanoma growth and metastasis

Wang

Zhao

et al. 2014

J Transl Med

View full text Add to dashboard Cite

show abstract

“…Migration assays were performed using cell culture insert with 8-μm-sized pores (BD Biosciences) in a 24-well plate with RPMI Medium 1640 containing 10% (vol/vol) FBS. For invasion assays, the cell culture inserts were added with 60 μL (2.5 mg/mL) BD Matrigel Basement Membrane Matrix Growth Factor Reduced (BD Biosciences) as described previously (31). Materials and methods for plasmids; siRNA and transfection; immunofluorescence microscopy; RNA isolation, cDNA synthesis, and qRT-PCR; luciferase reporter assay; cell proliferation assay; soft agar colony formation assay; animal experiments; and statistical analysis are provided in SI Materials and Methods.…”

Section: Methodsmentioning

confidence: 99%

Phospholipase Cδ1 induces E-cadherin expression and suppresses malignancy in colorectal cancer cells

Satow

Hirano

Batori

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

Colorectal cancer (CRC) is one of the most common causes of cancer-related deaths worldwide, and Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations in CRC predict the ineffectiveness of EGF receptor-targeted therapy. Previous transcriptional microarray analysis suggests the association between phospholipase Cδ1 (PLCδ1) expression and KRAS mutation status in CRC. However, both the roles and the regulatory mechanisms of PLCδ1 in CRC are not known. Here, we found that the expression of PLCδ1, one of the most basal PLCs, is down-regulated in CRC specimens compared with normal colon epithelium by immunohistochemistry. Furthermore, we examined the roles of PLCδ1 in CRC cell lines that harbor an activating KRAS mutation. Ectopic expression of PLCδ1 in CRC cells induced the expression of E-cadherin, whereas knockdown of PLCδ1 repressed the expression of E-cadherin. Moreover, the overexpression of PLCδ1 suppressed the expression of several mesenchymal genes and reduced cell motility, invasiveness, and in vivo tumorigenicity of SW620 CRC cells. We also showed that PLCδ1 expression is repressed by the KRAS/mitogen-activated protein kinase kinase (MEK) pathway. Furthermore, PLCδ1 suppressed the phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 through E-cadherin induction in CRC cells, suggesting the presence of a negative regulatory loop between KRAS/MEK/ERK signaling and PLCδ1. These data indicate that PLCδ1 has tumor-suppressive functions in CRC through E-cadherin induction and KRAS/MEK/ERK signal attenuation.phospholipase C delta 1 | epithelial-to-mesenchymal transition | tumor suppressor C olorectal cancer (CRC) is one of the most common cancers and causes of cancer-related deaths worldwide. Although CRC patients with unresectable tumors and metastasis have been treated with chemotherapy, recent advances in molecular research about CRC have resulted in the development of molecular targeted therapies, such as cetuximab and panitumumab. Chemotherapy combined with these targeted therapies improves the prognosis of CRC patients with unresectable tumors to some extent (1, 2). However, some CRC patients with activating Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are unable to benefit from such drugs, because both cetuximab and panitumumab are epidermal growth factor (EGF) receptor-targeting agents and mutant KRAS constitutively activates the downstream signaling of EGF receptor (3). A more vigorous study using KRAS-mutant CRC is needed to identify novel molecular targets for drugs that will improve the prognosis of CRC patients with unresectable tumors, especially those with KRAS mutations.Mutations in KRAS are found in about 40% of CRC patients. Constitutively active KRAS mutations lead to the hyperactivation of mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) [mitogen-activated protein kinase (MAPK)] signaling and/or phosphatidylinositol-3 kinase (PI3K) pathways (4). Activation of MEK/ERK (MAPK) signaling results in increased phosphorylation...

show abstract

“…Although MTX is not used in CRC therapy, extensive clinical trials might improve the outcomes. The other two leading drug candidates have high potential as novel cancer drugs aimed at preventing metastasis [186]. Further work should be performed to elucidate their mechanisms of action and to optimize them as new therapeutic agents.…”

Section: Cancer Therapeutics Targeting Emtmentioning

confidence: 99%

Epithelial–mesenchymal transition in colorectal cancer metastasis: A system review

Cao

Liu

et al. 2015

Pathology - Research and Practice

321

240

View full text Add to dashboard Cite

Identification of novel small compounds that restore E-cadherin expression and inhibit tumor cell motility and invasiveness

Cited by 19 publications

References 28 publications

Regulation gene expression of miR200c and ZEB1 positively enhances effect of tumor vaccine B16F10/GPI-IL-21 on inhibition of melanoma growth and metastasis

Regulation gene expression of miR200c and ZEB1 positively enhances effect of tumor vaccine B16F10/GPI-IL-21 on inhibition of melanoma growth and metastasis

Phospholipase Cδ1 induces E-cadherin expression and suppresses malignancy in colorectal cancer cells

Epithelial–mesenchymal transition in colorectal cancer metastasis: A system review

Contact Info

Product

Resources

About