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Enhanced aggressiveness of benzopyrene‐induced squamous carcinomas in transgenic mice overexpressing the proprotein convertase PACE4 (PCSK6)
Author(s) -
Bassi Daniel E.,
Cenna Jonathan,
Zhang Jirong,
Cukierman Edna,
KleinSzanto Andres J.
Publication year - 2015
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/mc.22183
Subject(s) - biology , proprotein convertases , proprotein convertase , carcinogenesis , cancer research , carcinogen , genetically modified mouse , transgene , cell growth , cell , cancer , endocrinology , biochemistry , gene , genetics , lipoprotein , ldl receptor , cholesterol
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. © 2014 Wiley Periodicals, Inc.