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在过表达前体蛋白转化酶PACE4（PCSK6）的转基因小鼠中，苯并芘诱导的鳞状细胞癌侵袭性增强。

Enhanced aggressiveness of benzopyrene-induced squamous carcinomas in transgenic mice overexpressing the proprotein convertase PACE4 (PCSK6).

作者信息

Bassi Daniel E, Cenna Jonathan, Zhang Jirong, Cukierman Edna, Klein-Szanto Andres J

机构信息

Department of Pathology, Fox Chase Cancer Center, Philadelphia, Pennsylvania.

Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.

出版信息

Mol Carcinog. 2015 Oct;54(10):1122-31. doi: 10.1002/mc.22183. Epub 2014 May 21.

DOI:10.1002/mc.22183
PMID:24845697
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4240754/
Abstract

PACE4 (PCSK6) is a proprotein convertase (PC) capable of processing numerous substrates involved in tumor growth, invasion, and metastasis. Because of the human relevancy of the tobacco-associated carcinogen benzo[a]pyrene (B(a)P) we investigated whether transgenic mice in which this PC is targeted to the epidermis (K5-PACE4) may be more susceptible to B(a)P complete carcinogenesis than wild type (WT) mice. In an in vitro experiment, using cell lines derived from skin tumors obtained after B(a)P treatment, we observed that PACE4 overexpression and activity accounts for an increased proliferation rate, exaggerated sensitivity to the PC inhibitor CMK, and interference with IGF-1R autophosphorylation. Squamous cell carcinomas, obtained from K5-PACE4 mice subjected to complete chemical carcinogenesis, were characterized by a 50% increase in cell proliferation, when compared with similar tumors from WT mice. In addition, tumors from K5-PACE4 mice showed deeper invasion into the underlying dermis. Thus, mice overexpressing PACE4 exhibited tumors of increased growth rate and invasive potential when exposed to the human carcinogen B(a)P, further supporting the significance of PCs in tumor growth and progression.

摘要

PACE4（PCSK6）是一种前蛋白转化酶（PC），能够加工多种参与肿瘤生长、侵袭和转移的底物。鉴于烟草相关致癌物苯并[a]芘（B(a)P）与人类的相关性，我们研究了将这种PC靶向表皮的转基因小鼠（K5-PACE4）是否比野生型（WT）小鼠更易受B(a)P完全致癌作用的影响。在一项体外实验中，我们使用经B(a)P处理后获得的皮肤肿瘤衍生的细胞系，观察到PACE4的过表达和活性导致增殖速率增加、对PC抑制剂CMK的敏感性增强以及对IGF-1R自磷酸化的干扰。与WT小鼠的相似肿瘤相比，经完全化学致癌作用处理的K5-PACE4小鼠产生的鳞状细胞癌的细胞增殖增加了50%。此外，K5-PACE4小鼠的肿瘤对下方真皮的侵袭更深。因此，过表达PACE4的小鼠在接触人类致癌物B(a)P时表现出肿瘤生长速率增加和侵袭潜力增强，进一步支持了PC在肿瘤生长和进展中的重要性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fcf3/4240754/91f08836e450/nihms-598625-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fcf3/4240754/04c4dc23b4c6/nihms-598625-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fcf3/4240754/9932e3c74afc/nihms-598625-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fcf3/4240754/403700a50ef4/nihms-598625-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fcf3/4240754/1e2fb0e1d314/nihms-598625-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fcf3/4240754/91f08836e450/nihms-598625-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fcf3/4240754/04c4dc23b4c6/nihms-598625-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fcf3/4240754/9932e3c74afc/nihms-598625-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fcf3/4240754/403700a50ef4/nihms-598625-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fcf3/4240754/1e2fb0e1d314/nihms-598625-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fcf3/4240754/91f08836e450/nihms-598625-f0005.jpg

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Polycyclic aromatic hydrocarbons as skin carcinogens: comparison of benzo[a]pyrene, dibenzo[def,p]chrysene and three environmental mixtures in the FVB/N mouse.
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Expression of paired basic amino acid-cleaving enzyme 4 (PACE4) correlated with prognosis in non-small cell lung cancer (NSCLC) patients.成对碱性氨基酸裂解酶4（PACE4）的表达与非小细胞肺癌（NSCLC）患者的预后相关。
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