BCL6 degradation caused by the interaction with the C-terminus of pro-HB-EGF induces cyclin D2 expression in gastric cancers

Hirata, Yoshikazu; Ogasawara, Nagahisa; Sasaki, Makoto; Mizushima, Takashi; Shimura, Takaya; Mizoshita, Tsutomu; Mori, Yoshinori; Kubota, Eiji; Wada, Takeshi; Tanida, Satoshi; Kataoka, Hiromi; Kamiya, Toshio; Higashiyama, Shigeki; Joh, Takashi

doi:10.1038/sj.bjc.6605010

Cited by 38 publications

(44 citation statements)

References 41 publications

(45 reference statements)

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“…In BCL6-positive cells, both the nucleus and the cytoplasm appeared stained and this finding is in accordance with previous data on cellular localization of BCL6 in gastric cancer (21). Moreover, our observations consistently showing that the BCL6 protein is expressed only in the stromal compartment of the normal mucosa support some observations of other authors; BCL6 was considered to be produced at low levels in various tissues, as reported in EST libraries obtained from several epithelial tissues, although Hirata et al (21) reported that BCL6 is expressed in normal gastric epithelial cells and that it is not expressed in normal mucosa of colon and oesophagus. However, in their study, the authors did not examine the stromal compartment of the colon and did not show quantitative data.…”

Section: Discussionsupporting

confidence: 80%

Morphological and quantitative analysis of BCL6 expression in human colorectal carcinogenesis

et al. 2013

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Abstract. The aim of the present study was to determine whether BCL6 is expressed during malignant transformation of the large bowel and to assess whether, and to what extent, immunoreactivity is related to the different stages of neoplastic progression. Samples of normal colorectal mucosa (n=22), microadenomas (n=22) and colorectal cancer (n=22), were analyzed by immunohistochemistry, immunofluorescence coupled with confocal microscopy and western blotting. Our results clearly outlined the marked increase occurring in both intensity and density of BCL6 protein expression in the normal mucosa-microadenoma-carcinoma sequence. Immunohistochemistry and immunofluorescence analyses showed that BCL6 is expressed at low levels in normal mucosa and increases in microadenoma and in cancer with statistical significance. These results were confirmed by western blotting data. The increasing expression of BCL6 in human colorectal cancer development suggests the involvement of BCL6 in tumor progression, from the earliest stages of carcinogenesis with significant increase in cancer. The enhanced understanding of the biological role of BCL6, previously shown to exert a key role in lymphomagenesis, may lead to a re-evaluation of this protein and may highlight the importance of performing further studies in order to identify novel therapeutic targets for colorectal cancer.

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Section: Discussionsupporting

confidence: 80%

Morphological and quantitative analysis of BCL6 expression in human colorectal carcinogenesis

et al. 2013

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“…Therefore, ZEB1 must have increased metastatic potential of gastric diffuse large B-cell lymphomas through another mechanism. Interestingly, loss of BCL6 is associated with disease progression in breast cancer and gastric cancer, 25,26 suggesting that the loss of BCL6 might be responsible for the increased lymph node metastasis in gastric diffuse large B-cell lymphomas too.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of ZEB1 by miR-200 characterizes Helicobacter pylori-positive gastric diffuse large B-cell lymphoma with a less aggressive behavior

et al. 2014

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Primary gastric diffuse large B-cell lymphomas may or may not have a concurrent component of mucosaassociated lymphoid tissue lymphoma. Diffuse large B-cell lymphoma/mucosa-associated lymphoid tissue lymphomas are often associated with Helicobacter pylori (H. pylori) infection, suggesting that the large cells are transformed from mucosa-associated lymphoid tissue lymphomas. In contrast, only limited data are available on the clinical and molecular features of pure gastric diffuse large B-cell lymphomas. In 102 pure gastric diffuse large B-cell lymphomas, we found H. pylori infection in 53% of the cases. H. pylori-positive gastric diffuse large B-cell lymphomas were more likely to present at an earlier stage (73% vs 52% at stage I/II, P ¼ 0.03), to achieve complete remission (75% vs 43%, P ¼ 0.001), and had a better 5-year disease-free survival rate (73% vs 29%, Po0.001) than H. pylori-negative gastric diffuse large B-cell lymphomas. Through genome-wide expression profiles of both miRNAs and mRNAs in nine H. pylori-positive and nine H. pylori-negative gastric diffuse large B-cell lymphomas, we identified inhibition of ZEB1 (zinc-finger E-box-binding homeobox 1) by miR-200 in H. pylori-positive gastric diffuse large B-cell lymphomas. ZEB1, a transcription factor for marginal zone B cells, can suppress BCL6, the master transcription factor for germinal center B cells. In 30 H. pylori-positive and 30 H. pylori-negative gastric diffuse large B-cell lymphomas, we confirmed that H. pylori-positive gastric diffuse large B-cell lymphomas had higher levels of miR-200 by qRT-PCR, and lower levels of ZEB1 and higher levels of BCL6 using immunohistochemistry. As BCL6 is a known predictor of a better prognosis in gastric diffuse large B-cell lymphomas, our data demonstrate that inhibition of ZEB1 by miR-200, with secondary increase in BCL6, is a molecular event that characterizes H. pylori-positive gastric diffuse large B-cell lymphomas with a less aggressive behavior.

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“…Pinto et al (38) demonstrated that, in metastatic lymph nodes, the expression of BCL6 protein was significantly lower compared with that in the corresponding primary breast cancer. Hirata et al (39) revealed that maintenance of BCL6 function was important for the regulation of progression in gastric cancer. In the present study, BCL6 was confirmed to be a target gene of miR-339-5p and was demonstrated to regulate the invasiveness of NSCLC cells in vitro.…”

Section: Discussionmentioning

confidence: 99%

miR-339-5p inhibits metastasis of non-small cell lung cancer by regulating the epithelial-to-mesenchymal transition

Zhang

Yang

et al. 2017

Oncol Lett

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Abstract. Metastasis is a common event in cancer pathology, and represents the primary cause of cancer-associated mortality. Metastasis, which is the process in which cancer cells at the primary tumor site spread to a different location in the body and form a new tumor, is regulated by multiple factors and includes a number of steps and stages. In our previous study, it was demonstrated miR-339-5p inhibits cell migration and invasion in vitro and is associated with the tumor-node-metastasis stage and the lymph node metastasis status of non-small cell lung cancer. In the present study, expression of miR-339-5p was first determined in the tissues and peripheral blood of patients with non-small cell lung cancer (NSCLC) and in NSCLC cell lines. It was then demonstrated that miR-339-5p inhibits A549 and H1299 cell invasion. The underlying molecular events of miR-339-5p action in NSCLC were also explored. By luciferase assay and western blot analysis, B-cell CLL/lymphoma 6 (BCL6) was verified as the direct target gene of miR-339-5p. miR-339-5p may inhibit lung cancer cell invasion and migration by regulating the epithelial-to-mesenchymal transition via BCL6 in vitro. It was also demonstrated that the relative expression of miR-339-5p in the peripheral blood is associated with cancer metastasis in patients with non-small cell lung cancer.

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BCL6 degradation caused by the interaction with the C-terminus of pro-HB-EGF induces cyclin D2 expression in gastric cancers

Cited by 38 publications

References 41 publications

Morphological and quantitative analysis of BCL6 expression in human colorectal carcinogenesis

Morphological and quantitative analysis of BCL6 expression in human colorectal carcinogenesis

Inhibition of ZEB1 by miR-200 characterizes Helicobacter pylori-positive gastric diffuse large B-cell lymphoma with a less aggressive behavior

miR-339-5p inhibits metastasis of non-small cell lung cancer by regulating the epithelial-to-mesenchymal transition

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