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Research Letters |

Retinoic Acid Receptor Isoform mRNA Expression Differs Between BCC and SCC of the Skin FREE

Fabian Hartmann, MD; Maria Kosmidis, MD; Beda Mühleisen, MD; Lars E. French, MD; Günther F. L. Hofbauer, MD
[+] Author Affiliations

Author Affiliations: Department of Dermatology, University Hospital Zürich, Zürich, Switzerland.


Arch Dermatol. 2010;146(6):675-676. doi:10.1001/archdermatol.2010.107.
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Treatment with the retinoic acid receptor (RAR) ligands retinol, isotretinoin, and acitretin has a chemopreventive effect on squamous cell carcinoma (SCC) but not on basal cell carcinoma (BCC). This disparity is well documented but incompletely understood. In lung cancer, RARβ1′ was recently found to mediate antiproliferative effects of retinoids.1 We compared RAR isoform messenger RNA (mRNA) expression in BCC with that in SCC.

With institutional review board approval, BCC and SCC tissue samples were acquired. The mean (SD) age of patients with BCC was 69.9 (11.2) years (n = 28); the patients with SCC were aged 73.3 (12.4) years (n = 22).

The real-time polymerase chain reaction primers used were glyceraldehyde-3-phosphate dehydrogenase (GAPDH) (Search-LC GmbH, Heidelberg, Germany), RARα (5′-TGTGGAGTTCGCCAAGCA-3′, 5′-CGTGTACCGCGTGCAGA-3′), RARβ (5′-CTTCCTGCATGCTCCAGGA-3′, 5′-CGCTGACCCCATAGTGGTA-3′), RARβ1′ (5′-ATGAGGAATGAAGCTGAGTAGA-3′, 5′-ATTTGTCCTGGCAGACGAAGCA-3′), RARβ2,4 (5′-GTCTGGGCACCGTCGGGGTAG-3′, 5′-TCTTTTTCCCAGCCCCGAATC-3′), RARγ (5′-CTGCCTCATCTGCGGAGAC-3′, 5′-GCCCTTTCAGCTCCCTTAGTG-3′), and RARβ1 (5′- TGACGTCAGCAGTGACTACTG-3′, 5′- GTGGTTGAACTGCACATTCAGA-3′). Samples were processed in triplicate and verified by sequencing with GAPDH as the internal standard. Expression of mRNA was calculated by the delta threshold cycle. P < .05 (2-tailed, Mann-Whitney test), was considered significant.

Retinoic acid receptor α, RARβ, RARγ, and RARβ2,4 amplified in 28 of 28 BCC samples and 22 of 22 SCC samples; RARβ1, in 27 of 28 BCCs and 22 of 22 SCC; and RARβ1′, in 24 of 28 BCC and 2 of 22 SCC. Quantitatively, RARα was 3.46-fold increased (P < .001); RARγ, 1.63-fold increased (P = .001); and RARβ1′, 23.73-fold increased in BCCs compared with SCCs (P = .03) (Figure 1 and Figure 2), but only 2 SCCs showed amplification for RARβ1′. The findings for RARβ, RARβ1, and RARβ2,4 were indistinct.

Place holder to copy figure label and caption
Figure 1.

Fold expression of complementary DNA retinoic acid receptor (RAR) isoforms in basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). All data are reported as means (SEMs) normalized to glyceraldehyde-3-phosphate dehydrogenase as the internal standard. In all panels, error bars indicate SEMs. A, RARα in BCC (n = 28) (1.97 × 10−3 [2.55 × 10−4]) and SCC (n = 22) (5.70 × 10−4 [4.79 × 10−5]). B, RARβ in BCC (n = 28) (7.91 × 10−5 [1.42 × 10−5]) and SCC (n = 22) (6.26 × 10−5 [1.13 × 10−5]) (P ≥ .05). C, RARγ in BCC (n = 28) (1.25 × 10−2 [1.24 × 10−3]) and SCC (n = 22) (7.65 × 10−3 [7.27 × 10−4]). D, RARβ1 in BCC (n = 27) (9.25 × 10−6 [1.78 × 10−6]) and SCC (n = 22) (8.28 × 10−6 [1.67 × 10−6]) (P ≥ .05). E, RARβ1′ in BCC (n = 24) (6.72 × 10−6 [2.96 × 10−6]) and SCC (n = 2: RARβ1’ could be amplified in only 2 SCC samples) (2.83 × 10−7 [1.71 × 10−8]). F, RARβ2,4 in BCC (n = 28) (7.83 × 10−4 [2.07 × 10−4]) and SCC (n = 22) (4.64 × 10−4 [1.13 × 10−4]) (P ≥ .05).

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Figure 2.

Overall fold expression pattern of complementary DNA retinoic acid receptor (RAR) isoforms in basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), normalized to glyceraldehyde-3-phosphate dehydrogenase. Error bars denote 5th to 95th percentiles. *P < .001. †P = .001. ‡P = .03.

Graphic Jump Location

Based on the different retinoid sensitivity of BCC and SCC, we expected RAR isoform differences. Interestingly, only 2 of 22 SCCs expressed RARβ1′ at a much lower level than BCCs (9%). In contrast to lung cancer, RARβ1′ does not seem to be pivotal for retinoid chemoprevention in SCC. Levels of RARα and RARγ were higher in BCC than in SCC, which fits with reported RAR and retinoid X receptor (RXR) isoform expression.2

Other factors may mediate chemoprevention. Acitretin binds with low affinity to RARs but with high affinity to cellular retinoic acid binding proteins (CRABPs). Acitretin shifts the distribution of endogenous tretinoin from CRABPs to RAR-RXR heterocomplexes, potentiating its effect. Tazarotene specifically activates RARβ and RARγ and only weakly activates RARα with chemopreventive effect on BCC in Ptch1± mice.3 In human lung cancer, RARβ4 seems carcinogenic.4 Differential activation of RAR isotypes may therefore have carcinogenic or anticarcinogenic effects as shown by the relative superiority of tazarotene in BCC over other retinoid-related compounds with simultaneous RARα and RARβ isoform activation.3

In summary, RAR isoform mRNA expression differs between BCC and SCC. Unlike in lung cancer, the mRNA levels of the recently reported isoform RARβ1′ do not explain SCC retinoid sensitivity. Rather, we assume, the relative sensitivity to retinoid treatment of SCC vs BCC is mediated by differential RAR activation or indirect effects such as shifting endogenous retinoids from CRABPs to RAR-RXR heterocomplexes.

Correspondence: Dr Hofbauer, Department of Dermatology, University Hospital Zürich, Gloriastrasse 31, 8091 Zürich (hofbauer@usz.ch).

Accepted for Publication: December 12, 2009.

Author Contributions: Dr Hofbauer had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Hofbauer. Acquisition of data: Hartmann and Kosmidis. Analysis and interpretation of data: Mühleisen, French, and Hofbauer. Drafting of the manuscript: Hartmann and Hofbauer. Critical revision of the manuscript for important intellectual content: Kosmidis, Mühleisen, and French. Statistical analysis: Hofbauer. Obtained funding: Hofbauer. Administrative, technical, and material support: Kosmidis, Mühleisen, and Hofbauer. Study supervision: French and Hofbauer.

Financial Disclosure: None reported.

Funding/Support: This study was supported by the Department of Dermatology, University Hospital Zürich.

Additional Contributions: William Jeffrey Petty, MD, and Jason T. Graves, BSc, provided the RARβ1′ plasmid.

Petty  WJLi  NBiddle  A  et al.  A novel retinoic acid receptor beta isoform and retinoid resistance in lung carcinogenesis. J Natl Cancer Inst 2005;97 (22) 1645- 1651
PubMed
Xu  XCWong  WYGoldberg  L  et al.  Progressive decreases in nuclear retinoid receptors during skin squamous carcinogenesis. Cancer Res 2001;61 (11) 4306- 4310
PubMed
So  PLFujimoto  MAEpstein  EH  Jr Pharmacologic retinoid signaling and physiologic retinoic acid receptor signaling inhibit basal cell carcinoma tumorigenesis. Mol Cancer Ther 2008;7 (5) 1275- 1284
PubMed
Xu  XC Tumor-suppressive activity of retinoic acid receptor-beta in cancer. Cancer Lett 2007;253 (1) 14- 24
PubMed

Figures

Place holder to copy figure label and caption
Figure 1.

Fold expression of complementary DNA retinoic acid receptor (RAR) isoforms in basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). All data are reported as means (SEMs) normalized to glyceraldehyde-3-phosphate dehydrogenase as the internal standard. In all panels, error bars indicate SEMs. A, RARα in BCC (n = 28) (1.97 × 10−3 [2.55 × 10−4]) and SCC (n = 22) (5.70 × 10−4 [4.79 × 10−5]). B, RARβ in BCC (n = 28) (7.91 × 10−5 [1.42 × 10−5]) and SCC (n = 22) (6.26 × 10−5 [1.13 × 10−5]) (P ≥ .05). C, RARγ in BCC (n = 28) (1.25 × 10−2 [1.24 × 10−3]) and SCC (n = 22) (7.65 × 10−3 [7.27 × 10−4]). D, RARβ1 in BCC (n = 27) (9.25 × 10−6 [1.78 × 10−6]) and SCC (n = 22) (8.28 × 10−6 [1.67 × 10−6]) (P ≥ .05). E, RARβ1′ in BCC (n = 24) (6.72 × 10−6 [2.96 × 10−6]) and SCC (n = 2: RARβ1’ could be amplified in only 2 SCC samples) (2.83 × 10−7 [1.71 × 10−8]). F, RARβ2,4 in BCC (n = 28) (7.83 × 10−4 [2.07 × 10−4]) and SCC (n = 22) (4.64 × 10−4 [1.13 × 10−4]) (P ≥ .05).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Overall fold expression pattern of complementary DNA retinoic acid receptor (RAR) isoforms in basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), normalized to glyceraldehyde-3-phosphate dehydrogenase. Error bars denote 5th to 95th percentiles. *P < .001. †P = .001. ‡P = .03.

Graphic Jump Location

Tables

References

Petty  WJLi  NBiddle  A  et al.  A novel retinoic acid receptor beta isoform and retinoid resistance in lung carcinogenesis. J Natl Cancer Inst 2005;97 (22) 1645- 1651
PubMed
Xu  XCWong  WYGoldberg  L  et al.  Progressive decreases in nuclear retinoid receptors during skin squamous carcinogenesis. Cancer Res 2001;61 (11) 4306- 4310
PubMed
So  PLFujimoto  MAEpstein  EH  Jr Pharmacologic retinoid signaling and physiologic retinoic acid receptor signaling inhibit basal cell carcinoma tumorigenesis. Mol Cancer Ther 2008;7 (5) 1275- 1284
PubMed
Xu  XC Tumor-suppressive activity of retinoic acid receptor-beta in cancer. Cancer Lett 2007;253 (1) 14- 24
PubMed

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