HABP2 is a Novel Regulator of Hyaluronan-Mediated Human Lung Cancer Progression.
HABP2 is a Novel Regulator of Hyaluronan-Mediated Human Lung Cancer Progression.
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DOI：
10.3389/fonc.2015.00164
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发表时间：
2015
影响因子：
4.7
通讯作者：
Singleton PA
中科院分区：
文献类型：
--
作者：
Mirzapoiazova T;Mambetsariev N;Lennon FE;Mambetsariev B;Berlind JE;Salgia R;Singleton PA
肺癌是一种毁灭性的疾病，治疗选择有限。许多肺癌的微环境发生了变化，包括细胞外基质糖胺聚糖（HA）的上调，我们先前已经证明HA可以调节细胞外丝氨酸蛋白酶（HA结合蛋白2（HABP 2））的活性。本研究检测了HABP 2对HA介导的人肺癌动力学的功能作用。使用抗HABP 2抗体对肺癌患者样品进行免疫组织化学分析。使用免疫印迹分析、迁移、外渗和尿激酶纤溶酶原激活物（uPA）激活测定（有或没有高分子量HA或低分子量HA（LMW-HA））来评价稳定对照、shRNA和HABP 2过表达的人肺腺癌细胞。在人肺癌异种移植模型中，使用裸鼠肺中的连续肿瘤体积测量和巢蛋白免疫反应性分析原发肿瘤生长速率和肺转移。我们提供的证据表明HABP 2是肺癌进展的重要调节因子。HABP 2表达在几种亚型的非小细胞肺癌患者样本中增加。此外，HABP 2过表达增加LMW-HA诱导的人肺腺癌细胞中uPA活化、迁移和外渗。在体内，与载体对照细胞相比，人肺腺癌细胞中HABP 2的过表达使裸鼠中的原发性肿瘤生长率增加约2倍，肺转移增加约10倍（n = 5/条件）。我们的数据表明HABP 2对uPA活化和肺癌进展可能有直接影响。我们的观察表明，HABP 2在非小细胞肺癌中的探索值得进一步研究，作为诊断和治疗的选择。
Lung cancer is a devastating disease with limited treatment options. Many lung cancers have changes in their microenvironment including upregulation of the extracellular matrix glycosaminoglycan, hyaluronan (HA), which we have previously demonstrated can regulate the activity of the extracellular serine protease, hyaluronan binding protein 2 (HABP2). This study examined the functional role of HABP2 on HA-mediated human lung cancer dynamics. Immunohistochemical analysis was performed on lung cancer patient samples using anti-HABP2 antibody. Stable control, shRNA, and HABP2 overexpressing human lung adenocarcinoma cells were evaluated using immunoblot analysis, migration, extravasation, and urokinase plasminogen activator (uPA) activation assays with or without high-molecular weight HA or low-molecular weight HA (LMW-HA). In human lung cancer xenograft models, primary tumor growth rates and lung metastasis were analyzed using consecutive tumor volume measurements and nestin immunoreactivity in nude mouse lungs. We provide evidence that HABP2 is an important regulator of lung cancer progression. HABP2 expression was increased in several subtypes of patient non-small cell lung cancer samples. Further, HABP2 overexpression increased LMW-HA-induced uPA activation, migration, and extravasation in human lung adenocarcinoma cells. In vivo, overexpression of HABP2 in human lung adenocarcinoma cells increased primary tumor growth rates in nude mice by ~2-fold and lung metastasis by ~10-fold compared to vector control cells (n = 5/condition). Our data suggest a possible direct effect of HABP2 on uPA activation and lung cancer progression. Our observations suggest that exploration of HABP2 in non-small cell lung carcinoma merits further study both as a diagnostic and therapeutic option.