TrkB/BDNF signaling pathway is a potential therapeutic target for pulmonary large cell neuroendocrine carcinoma

IF 5.4 3区材料科学 Q2 CHEMISTRY, PHYSICAL

ACS Applied Energy Materials Pub Date : 2013-03-01 DOI:10.1016/j.lungcan.2012.12.004

Seiichi Odate , Katsuya Nakamura , Hideya Onishi , Masayuki Kojima , Akihiko Uchiyama , Kenji Nakano , Masato Kato , Masao Tanaka , Mitsuo Katano

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引用次数: 51

Abstract

Tropomyosin-related kinase B (TrkB) plays an important role in tumor progression in various kinds of cancers; however, little is known about biological significance of TrkB in human lung cancer, especially large cell neuroendocrine carcinoma (LCNEC). We hereby investigated the expressions of TrkB and its ligand brain-derived neurotrophic factor (BDNF) in clinical specimens and their influences on phenotypes of invasiveness and tumorigenicity for LCNEC. The expressions of TrkB and BDNF analyzed by immunohistochemistry for patients samples with lung cancer (n = 104) were significantly higher in neuroendocrine tumor (NET) compared with non-NET. In particular, LCNEC, a subtype of NET, exhibited significantly higher TrkB and BDNF expressions than another NET type: small cell lung cancer (SCLC), and a significant correlation between TrkB and BDNF expressions was noted in LCNEC but not in SCLC. In vitro assay, exogenous BDNF addition enhanced the invasion into matrigels of LCNEC cells, whereas inhibition of TrkB or BDNF suppressed matrix metalloproteinase-2 and -9 activities and the invasiveness. Exogenous BDNF also increased anchor-independent colony formation on soft agar gels for LCNEC, while inhibition of TrkB or BDNF suppressed the anchorage-independency. In vivo experiments, implanted LCNEC cells pretreated with TrkB-siRNA developed no subcutaneous tumor in all six nude mice, although those with control-siRNA formed tumors in four of six nude mice. In conclusion, BDNF/TrkB signal is involved in malignant progression of invasiveness and tumorigenicity for LCNEC, and may be a potential target for LCNEC without standard therapy.

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TrkB/BDNF信号通路是肺大细胞神经内分泌癌的潜在治疗靶点

原肌球蛋白相关激酶B (TrkB)在各种癌症的肿瘤进展中起重要作用;然而，TrkB在人肺癌，特别是大细胞神经内分泌癌(LCNEC)中的生物学意义尚不清楚。我们在此研究了TrkB及其配体脑源性神经营养因子(BDNF)在LCNEC临床标本中的表达及其对侵袭性和致瘤性表型的影响。免疫组化分析肺癌(n = 104)患者样本中TrkB和BDNF的表达在神经内分泌肿瘤(NET)中明显高于非NET。特别是，作为NET亚型的LCNEC, TrkB和BDNF的表达明显高于另一种NET类型:小细胞肺癌(SCLC)，并且TrkB和BDNF的表达在LCNEC中有显著相关性，而在SCLC中没有。体外实验表明，外源BDNF的加入增强了LCNEC细胞对基质的侵袭，而TrkB或BDNF的抑制抑制了基质金属蛋白酶-2和-9的活性和侵袭性。外源BDNF也增加了LCNEC在软琼脂凝胶上锚定非依赖性菌落的形成，而抑制TrkB或BDNF则抑制了锚定非依赖性。在体内实验中，经TrkB-siRNA预处理的LCNEC细胞在6只裸鼠中均未形成皮下肿瘤，而经对照sirna处理的LCNEC细胞在4只裸鼠中形成肿瘤。综上所述，BDNF/TrkB信号参与了LCNEC的侵袭性和致瘤性的恶性进展，可能是LCNEC在没有标准治疗的情况下的潜在靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

ACS Applied Energy Materials Materials Science-Materials Chemistry

CiteScore

10.30

自引率

6.20%

发文量

1368

期刊介绍： ACS Applied Energy Materials is an interdisciplinary journal publishing original research covering all aspects of materials, engineering, chemistry, physics and biology relevant to energy conversion and storage. The journal is devoted to reports of new and original experimental and theoretical research of an applied nature that integrate knowledge in the areas of materials, engineering, physics, bioscience, and chemistry into important energy applications.