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An antitumorigenic role for murine 8S-lipoxygenase in skin carcinogenesis

Oncogene volume 24, pages 1174–1187 (2005)Cite this article

Abstract

The levels of 8S-lipoxygenase (8S-LOX) expression and of its arachidonic acid metabolite, 8-hydroxyeicosatetraenoic acid (8-HETE), are highly elevated in the early stages of mouse skin carcinogenesis. On the other hand, several reports showing that 8-HETE is also closely associated with keratinocyte differentiation raise a question concerning the role of 8S-LOX/8-HETE in skin carcinogenesis. To address that question, here we conducted a series of gain-of-function studies. Skin targeted loricrin 8S-LOX/C57BL/6J transgenic mice showed a more differentiated epidermal phenotype as well as a 64% reduced papilloma development in a two-stage skin carcinogenesis protocol. Forced expression of 8S-LOX in MT1/2 cells, a murine papilloma cell line, also caused a more differentiated appearance as well as keratin 1 expression. Overexpression of 8S-LOX in CH72 cells, a murine carcinoma cell line, inhibited cell proliferation by 30% in vitro and by 86% in in vivo xenografts. Exogenous addition of 5 μ M 8-HETE to CH72 cells caused cell cycle arrest at the G1 phase. Finally, immunohistochemical analyses showed 8S-LOX protein expression was strictly confined to the differentiated compartment of mouse skin and throughout tumorigenesis. Collectively, these data suggest that 8S-LOX plays a role as a prodifferentiating, antitumorigenic, and tumor suppressing gene in mouse skin carcinogenesis.

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Abbreviations

AA:

arachidonic acid

COX:

cyclooxygenase

PG:

prostaglandin

LOX:

lipoxygenase

HETE:

hydroxyeicosatetraenoic acid

HODE:

hydroxyoctadecadienoic acid

LA:

linoleic acid

TPA:

12-O-tetradecanoylphorbol-13-acetate

PPAR:

peroxisome proliferator-activated receptor

K1:

keratin 1

DMBA:

dimethylbenz[a]anthracene

EMEM:

Eagle's minimal essential medium

FBS:

fetal bovine serum

GAPDH:

glyceraldehyde 3-phosphate dehydrogenase

TTBS:

Tween 20 Tris-buffered saline

BHT:

butylated hydroxytoluene

PBS:

phosphate-buffered saline

LC/MS/MS:

liquid chromatography/tandem mass spectrometry

H&E:

hematoxylin and eosin

TUNEL:

terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling

BrdU:

5-bromo-2′-deoxyuridine

SSR:

simple sequence repeat

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Acknowledgements

We greatly appreciate Drs Philippe Thuillier and Russell D Klein for providing helpful advice and guidance. We also would like to give special appreciation to the Histology and Tissue Processing Facility Core and Cell and Tissue Analysis Facility Core at The University of Texas MD Anderson Cancer Center-Science Park, Research Division. We gratefully acknowledge Dr Howard Thames at the University of Texas MD Anderson Cancer Center for assistance in statistical analysis. The assistance of Amy Pavone for technical advice and Carol Mikulec for cell culture are also deeply appreciated. This work was supported by Grants CA16672, CA83794, and CA100140 from the NCI and ES07784 from the NIEHS.

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Authors and Affiliations

  1. Science Park-Research Division, University of Texas MD Anderson Cancer Center, 1808 Park Road 1C, PO Box 389, Smithville, TX, 78957, USA

    Eunjung Kim, Joyce E Rundhaug, Fernando Benavides & Susan M Fischer

  2. Pharmaceutical Development Center, University of Texas MD Anderson Cancer Center, Houston, TX, 77054, USA

    Peiying Yang & Robert A Newman

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  1. Eunjung Kim
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Correspondence to Susan M Fischer.

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Kim, E., Rundhaug, J., Benavides, F. et al. An antitumorigenic role for murine 8S-lipoxygenase in skin carcinogenesis. Oncogene 24, 1174–1187 (2005). https://doi.org/10.1038/sj.onc.1208269

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