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[Cancer Research 64, 8808-8810, December 15, 2004]
© 2004 American Association for Cancer Research

Advances in Brief

Crucial Role of Phospholipase C{epsilon} in Chemical Carcinogen-Induced Skin Tumor Development

Yunfeng Bai1, Hironori Edamatsu1, Sakan Maeda2, Hiromitsu Saito3, Noboru Suzuki3, Takaya Satoh1 and Tohru Kataoka1

1 Division of Molecular Biology, Department of Molecular and Cellular Biology and 2 Division of Molecular Pathology, Department of Biomedical Informatics, Kobe University Graduate School of Medicine, Kobe, Japan; and 3 Department of Animal Genomics, Functional Genomics Institute, Mie University Life Science Research Center, Mie, Japan


   ABSTRACT
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 ABSTRACT
Introduction
 Materials and Methods
 Results and Discussion
 REFERENCES
 
Mutational activation of the ras proto-oncogenes is frequently found in skin cancers. However, the nature of downstream signaling pathways from Ras involved in skin carcinogenesis remains poorly understood. Recently, we and others identified phospholipase C (PLC) {epsilon} as an effector of Ras. Here we have examined the role of PLC{epsilon} in de novo skin chemical carcinogenesis by using mice whose PLC{epsilon} is genetically inactivated. PLC{epsilon}–/– mice exhibit delayed onset and markedly reduced incidence of skin squamous tumors induced by initiation with 7,12-dimethylbenz(a)anthracene followed by promotion with 12-O-tetradecanoylphorbol-13-acetate (TPA). Furthermore, the papillomas formed in PLC{epsilon}–/– mice fail to undergo malignant progression into carcinomas, in contrast to a malignant conversion rate of approximately 20% observed with papillomas in PLC{epsilon}+/+ mice. In all of the tumors analyzed, the Ha-ras gene is mutationally activated irrespective of the PLC{epsilon} background. The skin of PLC{epsilon}–/– mice fails to exhibit basal layer cell proliferation and epidermal hyperplasia in response to TPA treatment. These results indicate a crucial role of PLC{epsilon} in ras oncogene-induced de novo carcinogenesis and downstream signaling from TPA, introducing PLC{epsilon} as a candidate molecular target for the development of anticancer drugs.


   Introduction
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 ABSTRACT
 Introduction
Materials and Methods
 Results and Discussion
 REFERENCES
 
The ras proto-oncogenes are mutationally activated in about 15% of human neoplasms (1) . Their products, Ras small GTPases, control cell proliferation and differentiation through interaction with multiple effector proteins, among which Raf kinases have been implicated in carcinogenesis from studies on in vitro transformation of fibroblast cell lines (2) and on genomic mutations in malignant melanoma (3) . However, downstream signaling pathways from Ras involved in epithelial cell carcinogenesis remain poorly understood, despite the fact that ras mutations are more frequently found in epithelial cell-derived neoplasms (1) . Likewise, the role of phosphoinositide-specific phospholipase C (PLC) in carcinogenesis remains obscure (4) . PLC produces two vital intracellular second messengers, diacylglycerol and inositol 1,4,5-trisphosphate, which induce activation of protein kinase C and mobilization of Ca2+ from intracellular stores, respectively. Among 12 mammalian PLC isoforms classified into 5 classes (ß, {gamma}, {delta}, {epsilon}, and {zeta}), PLC{epsilon} is characterized by possession of the Ras-associating domains, which are responsible for PLC{epsilon} activation through direct association with the GTP-bound active forms of the small GTPases Ras (5 , 6) , Rap1 (7) , and Rap2 (8) . PLC{epsilon} was also reported to be regulated by {alpha}12, {alpha}13, and ß1{gamma}2 subunits of heterotrimeric G proteins and Rho small GTPase (9) . Identification of PLC{epsilon} as a Ras effector has prompted us to examine the role of PLC{epsilon} in carcinogenesis. Here we show that PLC{epsilon}-deficient mice are resistant to chemical carcinogen-induced skin tumor formation, suggesting a crucial role of PLC{epsilon} in tumor development downstream of Ras signaling.


   Materials and Methods
Top
 ABSTRACT
 Introduction
 Materials and Methods
Results and Discussion
 REFERENCES
 
PLC{epsilon}/– Mice.
Targeted inactivation of the PLC{epsilon} gene was performed by a standard embryonic stem cell-based method.4 The targeted allele (PLC{epsilon}–) expresses a mutant PLC{epsilon} with an in-frame deletion of amino acids 1333 to 1408 corresponding to the NH2-terminal part of the catalytic X domain. This mutant completely lost its PLC catalytic activity. PLC{epsilon}–/– mice were maintained on a mixed 129/Sv x C57BL/6 background.

Reverse Transcription-Polymerase Chain Reaction Analysis.
Reverse transcription-polymerase chain reaction (RT-PCR) was performed as described previously (10) . Primers used for amplification of PLC{epsilon} were 5'-TCAGTGCCTGGAGCAGCAG-3' and 5'-CTTGAAGGGGATCTTGGTTG-3'.

Skin Tumor Formation.
A dorsal area of skin of 8-week–old mice was shaved and treated with a single application of 7,12-dimethylbenz(a)anthracene [DMBA (25 µg in 100 µL of acetone; Sigma, St. Louis, MO] and subsequently treated with 12-O-tetradecanoyl-phorbor-13-acetate [TPA (0.2 mmol/L in 100 µL of acetone; Sigma] twice a week for 20 weeks (11) . Tumors were assessed weekly for up to 30 weeks and defined as raised lesions with a minimum diameter of 1 mm. P values were determined by unpaired Student’s t test using GraphPad InStat software (GraphPad Software, Inc., San Diego, CA).

Histologic Analysis.
Paraffin-embedded sections were prepared and stained with hematoxylin and eosin or with a specific antibody against mouse PLC{epsilon} (10) , keratin 14 (PRB-155P; BAbCO, Berkeley, CA), or keratin 1 (PRB-165P; BAbCO). Detection of immunoreactive signals was performed with HistoMouse Plus kit (Zymed Laboratories, South San Francisco, CA) or with a fluorescein isothiocyanate-conjugated secondary antibody (AP182F; Chemicon, Temecula, CA).

12-O-Tetradecanoylphorbol-13-acetate–Induced Skin Hyperplasia.
A dorsal area of skin of 10-week–old mice was treated with TPA (0.2 mmol/L in 100 µL of acetone). The mouse skin was analyzed by staining with an anti-proliferating cell nuclear antigen (PCNA) antibody (M0879; Dako Cytomation, Copenhagen, Denmark) or hematoxylin and eosin. The thickness of the epidermis was measured at a minimum of five different points on the specimens and averaged.

Analysis of Ha-ras Gene Mutations.
Ha-ras gene mutations at the 61st codon of the tumors were analyzed as described previously (12) .


   Results and Discussion
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results and Discussion
REFERENCES
 
RT-PCR analysis of skin RNA detected two amplified products whose sizes were identical to those predicted from the wild-type and mutant PLC{epsilon} mRNAs (Fig. 1A)Citation . Immunohistochemical analysis showed that PLC{epsilon} is expressed in the epidermis (Fig. 1B)Citation , including keratin 14-positive proliferative keratinocytes and keratin 1-positive differentiating keratinocytes, but not in the dermis, except for hair follicles (Fig. 1C)Citation . To address the role of PLC{epsilon} in de novo skin carcinogenesis, we applied the skin two-stage chemical carcinogenesis protocol (11) on PLC{epsilon}–/– mice. Initiation was carried out with a single application of DMBA, which almost invariably introduced oncogenic mutations on the Ha-ras gene (11 , 12) . Subsequent promotion by repeated treatment with TPA for 20 weeks caused the selective clonal outgrowth of the initiated cells to produce benign squamous tumors (Fig. 2A)Citation . PLC{epsilon}–/– mice showed significant delay in the average time of tumor onset compared with PLC{epsilon}+/+ mice [average ± SE: 12.63 ± 0.42 weeks (PLC{epsilon}–/–; 21 mice analyzed) versus 10.14 ± 0.47 weeks (PLC{epsilon}+/+; 14 mice); P < 0.001; Fig. 2BCitation ]. PLC{epsilon}+/– mice showed an intermediate phenotype (11.79 ± 0.31 weeks; 23 mice; P < 0.01), indicating the existence of an apparent gene-dosage effect. The time to develop the first tumor also showed a significant difference [PLC{epsilon}+/+, 6.06 ± 0.36 weeks; PLC{epsilon}+/–, 7.87 ± 0.30 weeks (P < 0.001); PLC{epsilon}–/–, 9.86 ± 0.43 weeks (P < 0.0001)]. The number of tumors reached a maximum at 15 weeks. At this point, the average number of tumors per mouse was reduced by approximately 70% in PLC{epsilon}–/– mice (4.14 ± 0.40; P < 0.0001) compared with PLC{epsilon}+/+ mice (14.36 ± 1.25). Again, PLC{epsilon}+/– mice showed an intermediate phenotype (10.22 ± 0.65; P < 0.0001; Fig. 2BCitation ). In PLC{epsilon}–/– mice, no tumor greater than 6 mm in diameter was observed at 20 weeks (Fig. 2C)Citation . In the two-stage protocol, a population of papillomas undergo progression into squamous cell carcinoma (SCC) (11) . At 30 weeks after initiation, tumors of at least 2 mm in diameter were isolated and subjected to histologic analysis (Table 1Citation ; Fig. 2DCitation ). In PLC{epsilon}+/+ mice, approximately 20% of the tumors were carcinomas. In contrast, essentially no carcinoma was found in PLC{epsilon}–/– mice. PLC{epsilon}+/– mice showed a partial resistance to malignant progression. Thus, PLC{epsilon} deficiency strongly suppressed malignant progression. All of the tumors tested carried the activating mutations at the 61st codon of the Ha-ras gene, irrespective of the PLC{epsilon} genetic background (data not shown).



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  		Fig. 1. Analysis of PLC{epsilon} expression. A, RT-PCR analysis of PLC{epsilon} mRNA in the skin. ß-Actin mRNA was used as an internal control. B and C, immunohistochemical analysis of the expression of PLC{epsilon}, keratin 14 (K14), and keratin 1 (K1) in the PLC{epsilon}+/+ mouse skin. Detection was performed with a fluorescein isothiocyanate-conjugated secondary antibody (B) or the HistoMouse Plus kit (C). Scale bars, 100 µm.

 


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  		Fig. 2. Skin tumor formation. A, representative tumors developed in PLC{epsilon}+/+ (+/+), PLC{epsilon}+/– (+/–), and PLC{epsilon}–/– (–/–) mice at 30 weeks after initiation. B, time course of tumor formation. The average number of tumors per mouse (average ± SE) is shown. C, size distribution of tumors at 20 weeks after initiation. D, photomicrographs of hematoxylin and eosin-stained sections of a representative SCC in a PLC{epsilon}+/+ mouse (+/+) and a papilloma in a PLC{epsilon}–/– mouse (–/–) at 30 weeks. The SCC exhibits tumor invasion (black arrow) and a cancer pearl with parakeratosis (white arrow). Scale bars, 1 mm.

 

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  		Table 1 Histological analysis of tumors

 
We next investigated the effect of PLC{epsilon} deficiency on TPA-induced proliferation of the skin epidermis. Before or after treatment with acetone, there was no apparent difference between PLC{epsilon}+/+ and PLC{epsilon}–/– mice in the skin architecture and the number of proliferating cells positive for PCNA (Fig. 3)Citation . On TPA treatment, PLC{epsilon}+/+ mouse skin showed a marked increase in the number of PCNA-positive cells in the basal layer cells (Fig. 3A)Citation . In striking contrast, PLC{epsilon}–/– mouse skin showed only a moderate increase (Fig. 3A)Citation . TPA-induced epidermal hyperplasia was also suppressed in PLC{epsilon}–/– mice (Fig. 3B)Citation . The average thickness of the epidermis after 48 hours of TPA treatment was 98.4, 66.3, and 31.3 µm in PLC{epsilon}+/+, PLC{epsilon}+/–, and PLC{epsilon}–/– mice, respectively, whereas that after acetone treatment was 27.7, 25.4, and 24.6 µm, respectively.



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  		Fig. 3. Suppression of TPA-induced epidermal cell proliferation in PLC{epsilon}–/– mouse. Mouse skin was treated with acetone alone (Vehicle) or with TPA in acetone (TPA), or left untreated (No treatment). The sections were examined by staining with the anti-PCNA antibody at 24 hours (A) or by staining with hematoxylin and eosin at 48 hours (B). Representative photomicrographs of at least three independent experiments are shown. The frequency of PCNA-positive basal layer cells is shown as percentage in A. Scale bars, 100 µm.

 
We have shown here that PLC{epsilon} plays a crucial role in skin papilloma formation and malignant progression, which are induced by ras activation followed by TPA treatment. Furthermore, PLC{epsilon} is shown to function downstream of TPA to induce hyperproliferation of the basal layer cells and skin hyperplasia. Thus, it is likely that PLC{epsilon} functions in TPA-induced tumor promotion of the initiated cells carrying the activated ras genes. There are two possible mechanisms linking TPA to PLC{epsilon} activation. TPA may activate PLC{epsilon} through Ras activation, which is mediated by RasGRP1, a TPA-regulated Ras-specific guanine nucleotide exchange factor (GEF) expressed in keratinocytes (13) . Rap1, whose activation is mediated by TPA-responsive Rap GEFs including CalDAG-GEFI (14) and RasGRP2 (15) , may also be responsible for PLC{epsilon} activation. Alternatively, TPA may activate PLC{epsilon} through secretion of tumor necrosis factor (TNF)-{alpha} from keratinocytes (16) and subsequent TNF-{alpha}–induced Ras activation (17) . TNF-{alpha} has been implicated in both two-stage skin carcinogenesis and TPA-induced skin hyperplasia (16) .

Because targeted inactivation of protein kinase C (PKC) {eta} resulted in enhancement of both papilloma formation and TPA-induced skin hyperplasia, TPA-induced down-regulation of PKC{eta} is thought to play a crucial role in induction of these phenomena (18) . In the present study, TPA treatment failed to compensate for the deficiency in papilloma formation and skin hyperplasia of PLC{epsilon}–/– mice, although TPA is known to mimic diacylglycerol, a product of PLC{epsilon}, in regulating PKC{eta}. The result indicates that the PLC{epsilon} pathway has an intrinsic role in skin hyperplasia and carcinogenesis, which is independent of the PKC{eta} pathway. This intrinsic function may be mediated by another of its products, inositol 1,4,5-trisphosphate. On the other hand, activation of PLC{epsilon} in DMBA-initiated cells, which must be induced by constitutively active Ras and produce diacylglycerol, could not substitute for TPA treatment in promoting papilloma formation. This suggests that TPA possesses another target that is also required for tumor promotion. In addition, papillomas developed in PLC{epsilon}–/– mice failed to undergo malignant conversion. It was reported that prostaglandins are involved in skin tumor progression in addition to promotion (19) and play a key role in intestinal polyposis (20) . Considering that arachidonic acid, a precursor of prostaglandins, can be produced from diacylglycerol, it is possible that the role of PLC{epsilon} may be mediated through prostaglandin signaling.

Our present results have shown that PLC{epsilon} plays a crucial role in ras oncogene-induced de novo carcinogenesis of skin epithelial cells. They also provide the first concrete evidence for the importance of the PLC signaling in carcinogenesis. This leads to the idea that specific inhibitors of PLC{epsilon} may be useful for treatment and prevention of certain types of cancer.


   ACKNOWLEDGMENTS
 
We thank Dr. Atsu Aiba, Dr. Ushio Kikkawa, Dr. Makoto Tadano, Shuzo Ikuta, and Tadashi Murase for helpful discussion and Shuichi Matsuda for excellent technical assistance.


   FOOTNOTES
 
Grant support: Grant-in-Aid for Priority Areas 12215098 (T. Kataoka); Grants-in-Aid for Scientific Research 15390093 (T. Kataoka), 16790187 (H. Edamatsu), and 15570117 (T. Satoh); and 21st Century COE Programs (T. Kataoka and T. Satoh) from the Ministry of Education, Science, Sports and Culture of Japan.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: Y. Bai and H. Edamatsu contributed equally to this work.

Requests for reprints: Tohru Kataoka, Division of Molecular Biology, Department of Molecular and Cellular Biology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan. E-mail: kataoka{at}kobe-u.ac.jp

4 M. Tadano, H. Edamatsu, S. Minamisawa, U. Yokoyama, Y. Ishikawa, N. Suzuki, H. Saito, D. Wu, M. Masago-Toda, Y. Yamawaki-Kataoka, T. Setsu, T. Terashima, S. Maeda, T. Satoh, and T. Kataoka. Congenital semilunar valvulogenesis defect in mice deficient in phospholipase C{epsilon}, submitted for publication. Back

Received 8/30/04. Revised 10/12/04. Accepted 10/21/04.


   REFERENCES
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 ABSTRACT
 Introduction
 Materials and Methods
 Results and Discussion
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