Heterogeneities in the biological and biochemical functions of Smad2 and Smad4 mutants naturally occurring in human lung cancers

Yanagisawa, Kiyoshi; Uchida, Kosaku; Nagatake, Masaaki; Masuda, Akira; Sugiyama, Miyabi; Saito, Toshiko; Yamaki, Kenichi; Takahashi, Takashi; Osada, Hiroyuki

doi:10.1038/sj.onc.1203591

Cited by 45 publications

(36 citation statements)

References 29 publications

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“…There is a strong correlation between progressive malignancy and loss in sensitivity towards the negative regulation of cellular proliferation TGF-b in tumour cells, which is often due to mutational inactivation or decreased TGF-b receptor function (de Caestecker et al, 2000;Kim et al, 2000). In addition tumour cells often escape from the anti-proliferative effects of TGF-b by mutation or disregulated expression of components in its signalling pathway (Yanagisawa et al, 2000). These publications suggest that TGF-b2 could be given safely during anti-tumour therapy.…”

Section: Discussionmentioning

confidence: 99%

Transforming Growth Factor-β2 protects the small intestine during methotrexate treatment in rats possibly by reducing stem cell cycling

Land¹,

Meijer²,

Frerichs³

et al. 2002

Br J Cancer

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During chemo-and radiation therapy, the balance between epithelial cell proliferation, differentiation, and cell death at the villus tip is disrupted by premature death of dividing epithelial cells. This will subsequently lead to the onset of mucosal barrier injury in the whole gastrointestinal tract. Up till now there is no validated method to treat side effects occurring due to therapy. An approach to manage this side effect might be to reversibly arrest growth of epithelial stem cells during therapy using Transforming Growth Factor-b2. A Transforming Growth Factor-b2 enriched fraction prepared from bovine milk was shown to protect small intestinal epithelial cells against cell cycle specific chemotherapeutic agents by arresting the cells in G1-phase. Secondly, in a rat model for induced small intestinal damage, oral supplementation of rats exposed to methotrexate with the Transforming Growth Factor-b2 enriched fraction significantly reduced the chemotherapy-associated weight loss and ileal villus atrophy by reducing cell proliferation in the normal stem cell population. Thus oral supplementation with a bovine milk fraction enriched for Transforming Growth Factor-b2 attenuated the side effects of chemotherapy in the small intestine in rats.

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Section: Discussionmentioning

confidence: 99%

Transforming Growth Factor-β2 protects the small intestine during methotrexate treatment in rats possibly by reducing stem cell cycling

Land¹,

Meijer²,

Frerichs³

et al. 2002

Br J Cancer

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“…(1999) found decreased TGF-beta RII expression in NSCLC tissues, suggesting that decreased TβRII expression plays an important role in the carcinogenesis of lung cancer. Study (Yanagisawa et al, 2000) have shown that high frequent absence of Smad2 and Smad4 mutants changed the TGF-β signal transduction pathways and lead to the initiation of lung tumor.…”

Section: Discussionmentioning

confidence: 99%

TGF-β1 Protein Expression in Non-Small Cell Lung Cancers is Correlated with Prognosis

Huang¹,

Liu²,

Qi³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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To investigate the expression intensity and prognostic significance of TGF-β1 protein in non-small cell lung cancer (NSCLC), immunohistochemistry was carried out in 194 cases of NSCLC and 24 cases of normal lung tissues by SP methods. The PU (positive unit) value was used to assess the TGF-β1 protein expression in systematically selected fields under the microscope with Leica Q500MC image analysis. We found that the TGF-β1 PU value was nearly two-fold higher in NSCLC than in normal lung tissues (p=0.000), being associated with TNM stages (p=0.000) and lymph node metastases (p=0.000), but not to patient age, gender, smoking history, tumor differentiation, histological subtype and tumor location (P>0.05). Univariate analysis indicated that patients with high TGF-β1 protein expression and lymph node metastases demonstrated a poor prognosis (both p=0.000, ). Multivariate analysis showed that TGF-β1 protein expression (RR = 2.565, p=0.002) and lymph node metastases (RR=1.874, p= 0.030) were also independent prognostic factors. Thus, TGF-β1 protein expression may be correlated to oncogenesis and serve as an independent prognostic biomarker for NSCLC.

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“…However, the 130-kDa band was only moderately restored with CLCP1-SEMA4B co-transfection (Figure 4b, lane 6) and not recovered at all with CLCP1-SEMA4B-Fc co-transfection (Figure 4b, lane 8). In Figure 4c, the size of the co-immunoprecipitated CLCP1 isoform was compared with that of CLCP1 proteins in cell lysates derived from transfectants treated with or without MG-132 or another proteasome inhibitor, lactacystin, which was effective for a Smad4 mutant (Yanagisawa et al, 2000) ( Supplementary Figures 1 and 2). The main co-precipitated CLCP1 isoform appeared to be a 110-kDa isoform, even in samples treated with proteasome inhibitors.…”

Section: Clcp1 Regulates Lung Cancer Cell Motility With Sema4bmentioning

confidence: 99%

CLCP1 interacts with semaphorin 4B and regulates motility of lung cancer cells

et al. 2007

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We previously established a highly metastatic subline, LNM35, from the NCI-H460 lung cancer cell line, and demonstrated upregulation of a novel gene, CLCP1 (CUB, LCCL-homology, coagulation factor V/VIII homology domains protein), in LNM35 and lung cancer specimens. In this study, we focused on the potential roles of that gene in cancer metastasis. First, we established stable LNM35 RNAi clones, in which CLCP1 expression was suppressed by RNAi, and found that their motility was significantly reduced, although growth rates were not changed. Next, in vitro selection of a phage display library demonstrated that a phage clone displaying a peptide similar to a sequence within the Sema domain of semaphorin 4B (SEMA4B) interacted with LNM35. Immunoprecipitation experiments confirmed interaction of CLCP1 with SEMA4B, regulation of CLCP1 protein by ubiquitination and proteasome degradation enhanced in the presence of SEMA4B. These results are the first to indicate that CLCP1 plays a role in cell motility, whereas they also showed that at least one of its ligands is SEMA4B and that their interaction mediates proteasome degradation by CLCP1. Although the physiological role of the interaction between CLCP1 and SEMA4B remains to be investigated, this novel gene may become a target of therapy to inhibit metastasis of lung cancers.

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Heterogeneities in the biological and biochemical functions of Smad2 and Smad4 mutants naturally occurring in human lung cancers

Cited by 45 publications

References 29 publications

Transforming Growth Factor-β2 protects the small intestine during methotrexate treatment in rats possibly by reducing stem cell cycling

Transforming Growth Factor-β2 protects the small intestine during methotrexate treatment in rats possibly by reducing stem cell cycling

TGF-β1 Protein Expression in Non-Small Cell Lung Cancers is Correlated with Prognosis

CLCP1 interacts with semaphorin 4B and regulates motility of lung cancer cells

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