Background Retinoids are effective in the treatment and preventionof certain human cancers. Most of their actions are thoughtto result from changes in gene expression mediated by nuclearretinoic acid receptors and retinoid X receptors. We conducteda study to determine whether the expression of these receptorswas altered in premalignant oral lesions and, if so, whethertheir expression could be restored by treatment with isotretinoin.
Methods We performed in situ hybridization of retinoic acidreceptors and retinoid X receptors using antisense riboprobesin specimens of oral mucosa from 7 normal subjects and specimensof premalignant oral lesions from 52 patients before treatmentwith isotretinoin and from 39 of the 52 patients after threemonths of treatment.
Results All the normal specimens expressed retinoic acid receptor–messenger RNA (mRNA). In contrast, retinoic acid receptor–mRNA was detected in only 21 of the 52 premalignant oral lesions(P = 0.003). Thirty-five of the 39 specimens available for evaluationafter treatment expressed retinoic acid receptor– mRNA(P<0.001). All normal and premalignant specimens expressedsimilar levels of mRNA for retinoic acid receptor– andretinoic acid receptor– and the three types of retinoidX receptors, , , and . The levels of retinoic acid receptor–mRNA increased in the specimens from 18 of the 22 patients whohad responses to isotretinoin and in 8 of the 17 specimens fromthe patients without responses (P = 0.04).
Conclusions The expression of retinoic acid receptor–mRNA is selectively lost in premalignant oral lesions and canbe restored by treatment with isotretinoin. Restoration of theexpression of retinoic acid receptor– mRNA is associatedwith a clinical response. Retinoic acid receptor– mayhave a role in mediating the response to retinoids and may bea useful intermediate biologic marker in trials of these agentsfor the prevention of oral carcinogenesis.
Retinoids, including vitamin A and its analogues, regulate themorphogenesis, development, and growth and differentiation ofcells.1,2,3 Retinoids can also halt the progression of diseasein premalignant lesions of the oral cavity, cervix, and skinand can prevent the development of second primary tumors associatedwith head and neck and lung cancer.4,5,6,7,8,9,10,11,12,13,14Retinoids exert most of their effects by modulating gene expression.15The effects of retinoids on gene expression depend on two typesof nuclear retinoid receptors, retinoic acid receptors and retinoidX receptors, which act as transcription factors.3,16,17 Bothtypes belong to the superfamily of steroid hormone receptors.16The , , and subtypes of retinoic acid receptors and retinoidX receptors have distinct and conserved amino- and carboxy-terminaldomains.3,16,17 Heterodimers of the retinoic acid receptorsand the retinoid X receptors bind to a specific DNA sequence,the retinoic acid response element. This element is locatedin the promoter region of genes, including the retinoic acidreceptor–2 gene,18 that retinoids regulate. Each receptorsubtype has a specific pattern of expression during embryonaldevelopment and a different distribution in adult tissues. Eachsubtype is therefore thought to regulate the expression of adistinct set of genes.2,3
The association between vitamin A deficiency and the developmentof cancer6 suggests that retinoid-dependent signaling pathwayshave a role in the suppression of carcinogenesis. Changes inthe expression of specific nuclear retinoid receptors may abrogatethese pathways. The patterns of expression of retinoid receptorsin normal, premalignant, and malignant tissue may thereforeprovide clues to the roles of these receptors in the developmentof cancer and in the response of premalignant lesions to retinoidtreatment.
Most reports have described the expression of receptors in culturednormal or malignant cell lines and in embryos.2,3,15,16,17,18,19There are only a few reports on the expression of retinoic acidreceptors in tumor specimens,20,21,22 and no reports on theirexpression in premalignant oral lesions in vivo.
Our group has demonstrated that 13-cis-retinoic acid (isotretinoin)prevents the development of cancer in patients with premalignantoral lesions (e.g., leukoplakia)4,7,11 and inhibits the developmentof second primary tumors in patients with previous head andneck cancer.8,12,13
The current study was undertaken to determine whether the expressionof retinoic acid receptors in normal tissue and in premalignantoral lesions differs and whether isotretinoin, which is activeclinically,4,5,6,7,8,11,12,13 alters the expression of thesereceptors in vivo.
Methods
Characteristics of the Patients
The specimens used in this study were from 7 normal subjectsand 52 patients with histologically confirmed premalignant orallesions. The patients consisted of 27 men and 25 women, manyof whom used tobacco or alcohol or both at the time of the study(Table 1). On biopsy, the lesions of 20 of the patients showedhyperplasia, 24 mild dysplasia, 6 moderate dysplasia, and 2severe dysplasia.
Table 1. Base-Line Characteristics of 52 Patients with Premalignant Oral Lesions.
Tissue Specimens
Punch-biopsy specimens (4 mm in diameter) were obtained fromall 52 patients before they underwent three months of therapywith isotretinoin at a dose of 1.5 mg per kilogram of body weightper day.11 Post-treatment specimens were available from 39 ofthese patients. (The post-treatment specimens from the other13 patients had been totally consumed in previous laboratorystudies.) All biopsies had been performed during an earlier,nonrandomized induction-phase clinical protocol.11 The specimenswere obtained from the premalignant oral lesions before treatment,from the residual lesions after treatment in the patients withpartial or no responses, or from the sites of the original lesions,as identified from pretreatment photographs, in the patientswith complete responses. In each of the two patients with biopsyspecimens from more than one lesion, the specimen selected foranalysis came from the largest lesion, so that only one specimenper patient was analyzed before and after treatment. In addition,punch-biopsy specimens of normal buccal mucosa were obtainedfrom seven volunteers who did not smoke.
The specimens were fixed in 10 percent neutral formalin andembedded in paraffin. The pathology department provided blocksof the tissue specimens, which were cut into 4-µm sectionsand collected on glass slides coated with poly-l-lysine. Thesections were coded, and the receptor analyses were performedin a blinded fashion.
In Situ Hybridization
We used a previously described method ofnonradioactive in situhybridization, without any modifications, to analyze nuclearretinoid receptors in the formalin-fixed, paraffin-embeddedhistologic sections.22,23 The quality and specificity of thedigoxigenin-labeled probes were determined with Northern blotting,and the specificity of the binding of the antisense riboprobeswas verified by using sense probes as controls.23
All sections to be analyzed for the expression of a particularreceptor were stained on the same day with the same reagentsto ensure reliable comparisons. The stained sections were reviewedunder a Nikon microscope by three researchers, including twopathologists, who did not know the treatment status of the patientsfrom whom the specimens had been obtained. The data in Table 2are based on evaluation of the tissue sections for the presenceor absence of staining. The data in Table 3 are based on staining-intensityscores ranging from 0 to 3 (0 indicates no staining, 1 weakstaining, 2 strong staining, and 3 very strong staining).
Table 3. Relation between Increased Expression of Retinoic Acid Receptor–b mRNA and Clinical Response after Treatment with Isotretinoin.
Statistical Analysis
Frequency and summary data are given whenever appropriate. Thechi-square test and Fisher's exact test were used to assessthe association between two binary variables, such as the associationbetween the clinical response and the modulation of nuclearretinoid receptors. McNemar's test was used to compare receptorexpression before and after treatment.24 The two-sample t-testwas used to compare age and receptor expression. Two-sided Pvalues were determined in all analyses.
Results
Serial sections of two specimens of normal buccal mucosa hybridizedwith antisense riboprobes for messenger RNA (mRNA) for retinoicacid receptor–, retinoic acid receptor–, retinoicacid receptor–, and retinoid X receptor– (Figure 1A,Figure 1B, Figure 1C, and Figure 1D). Similar results wereobserved with mRNA for retinoid X receptor– and retinoidX receptor– (data not shown). These receptors were expressedin all the specimens of normal oral mucosa.
Figure 1. Expression of mRNA for Retinoic Acid Receptor– (Panel A), Retinoic Acid Receptor– (Panel B), Retinoic Acid Receptor– (Panel C), and Retinoid X Receptor– (Panel D) in Consecutive Sections of Biopsy Specimens from Normal Buccal Mucosa.
The receptors were detected by nonradioactive in situ hybridization and light microscopy. Tissue sections were hybridized with digoxigenin-labeled antisense RNA probes, and the bound probes were detected with an antidigoxigenin antibody–alkaline phosphatase conjugate and a chromogenic substrate.
Loss of Retinoic Acid Receptor– mRNA in Premalignant Oral Lesions
Figure 2A, Figure 2B, Figure 2C, Figure 2D, Figure 2E, Figure 2F,Figure 2G, and Figure 2H shows consecutive sections of aspecimen from a premalignant oral lesion. The expression ofmRNA for retinoic acid receptor–, retinoic acid receptor–,and retinoid X receptor– was similar to that found innormal tissue (Panels A, C, and D). The results were similarfor retinoid X receptor– and retinoid X receptor–mRNA (data not shown). In contrast, retinoic acid receptor–mRNA was not detected in this lesion (Figure 2B).
Figure 2. Expression of mRNA for Retinoic Acid Receptor–, Retinoic Acid Receptor–, Retinoic Acid Receptor–, and Retinoid X Receptor– in Consecutive Sections of Biopsy Specimens from a Patient with a Premalignant Oral lesion.
The expression of mRNA for retinoic acid receptor–, retinoic acid receptor–, retinoic acid receptor–, and retinoid X receptor– is shown at base line (Panels A, B, C, and D, respectively) and after three months of treatment with isotretinoin (Panels E, F, G, and H, respectively).
Retinoic acid receptor– mRNA was detected in 21 of the52 premalignant specimens (40 percent) (Table 2), whereas itwas found in all 7 of the normal specimens (P = 0.003 by Fisher'sexact test). The expression of mRNA for the other retinoid receptorsin the premalignant lesions ranged from 70 percent for retinoidX receptor– to 100 percent for retinoid X receptor–.None of these results differed significantly from those in thenormal tissue (data not shown). There was no association betweenthe expression of retinoic acid receptor– mRNA and age(P = 0.96 by the two-sample t-test), smoking status (P = 0.49by the chi-square test), or use of alcohol (P = 0.39 by thechi-square test).
Because cell strains and cell lines derived from normal andpremalignant tissue from different regions of the oral cavityexpress different levels of retinoic acid receptor– mRNA,25,26we analyzed our data according to the location of the tissuein the oral cavity (Table 2). From 67 to 100 percent of premalignantspecimens from buccal mucosa and other regions of the oral cavityshowed loss of retinoic acid receptor– mRNA expression,as compared with only 25 percent of premalignant specimens fromthe tongue (P = 0.002 by Fisher's exact test).
Increased Retinoic Acid Receptor– mRNA after Treatment with Isotretinoin
To determine whether treatment with retinoids modulates theexpression of retinoid-receptor mRNA in vivo, we analyzed specimensfrom 39 of the 52 patients after three months of treatment withisotretinoin. Figure 2B shows selective loss of retinoic acidreceptor– mRNA in a biopsy specimen obtained before treatment.After treatment, the same premalignant lesion contained abundantmRNA for the receptor (Figure 2F). Ninety percent of the 39specimens from patients who were treated with isotretinoin expressedretinoic acid receptor– mRNA, as compared with 40 percentof the pretreatment specimens (P<0.001 by McNemar's test)(Table 2). The expression of retinoic acid receptor– mRNAincreased in specimens from all regions of the oral cavity (Table 2).Only 3 of the 39 specimens showed decreased levels of retinoicacid receptor– mRNA after treatment.
Relation between Retinoic Acid Receptor– mRNA and Clinical Response to Treatment
Of the 39 patients with premalignant oral lesions who were studiedafter treatment with isotretinoin, 22 (56 percent) had clinicalresponses to treatment (Table 3). There were 4 complete responsesand 18 partial responses. The specimens from all 18 patientswith partial responses (obtained from residual lesions) revealedhistologic abnormalities. The specimens from the four patientswith complete responses (obtained from the sites of the originallesions) showed dysplasia in two and hyperplasia in two. Eighteenof the 22 patients with clinical responses (82 percent) hadincreased levels of retinoic acid receptor– mRNA, as comparedwith 8 of the 17 patients without responses (47 percent). Eighteenof the 26 patients (69 percent) with up-regulated expressionof retinoic acid receptor– mRNA after treatment had clinicalresponses, as compared with only 4 of the 13 patients (31 percent)without retinoic acid receptor– up-regulation (P = 0.04by Fisher's two-sided exact test).
There was no association between the pretreatment expressionof retinoic acid receptor– mRNA and the clinical responseto isotretinoin. Fifty-eight percent of the patients with noretinoic acid receptor– mRNA at base line (14 of 24) hadclinical responses, as compared with 53 percent of the patientswith retinoic acid receptor– mRNA at base line (8 of 15)(P = 0.76 by the chi-square test). Furthermore, all 14 patientswithout retinoic acid receptor– mRNA at base line whohad complete or partial responses had an up-regulation of retinoicacid receptor– mRNA. All four patients with complete responsesalso had an up-regulation of retinoic acid receptor– mRNA.
Discussion
Encouraging results with retinoids in clinical prevention andtherapy trials4,5,6,7,8,9,10,11,12,13,14 have stimulated effortsto understand how these agents act at the cellular and molecularlevels. In this study, we analyzed the expression of mRNA forthe six known retinoid-receptor subtypes in normal and premalignantoral tissue before and after treatment with isotretinoin. Becausethere are no useful antibodies for the detection of nuclearretinoid receptors in histologic specimens, our analysis waslimited to the detection of retinoid-receptor mRNA by in situhybridization.
We found a selective loss of retinoic acid receptor– mRNAin premalignant oral lesions. Because we were able to analyzeonly mRNA, we cannot exclude the possibility that in some specimensin which retinoic acid receptor– mRNA was detected, thelevel of protein was suppressed at the post-transcriptionalstage. Retinoic acid receptor– mRNA was detected in allthe samples of normal tissue but in only 40 percent of the samplesof premalignant tissue. This finding is consistent with in vitrodata25,26 and with our findings in specimens from patients withhead and neck cancer.22 These studies suggest that loss of retinoicacid receptor– mRNA is an early event in oral carcinogenesis.
The mechanisms underlying the loss of retinoic acid receptor–mRNA in premalignant oral lesions are not understood. We canspeculate that no changes have occurred in the retinoic acidreceptor– gene. No gene deletions or rearrangements werefound in cell lines from patients with head and neck cancerthat failed to express retinoic acid receptor– mRNA,26and in the present study its expression was up-regulated bytreatment with isotretinoin.
The expression of retinoic acid receptor– mRNA may dependon the intracellular level of retinoids. Studies in rats havedemonstrated that the expression of retinoic acid receptor–mRNA is selectively reduced in several organs during vitaminA deficiency and is enhanced by retinoic acid.27,28 It is unlikelythat our patients had vitamin A deficiency, but we cannot excludethe possibility that the premalignant tissue was deficient invitamin A because of a reduced uptake of vitamin A from plasmaor an abnormally elevated rate of catabolism of intracellularretinoic acid.
Other possible causes of a reduction in the expression of retinoicacid receptor– mRNA include overexpression of retinoicacid receptor–1 mRNA, which could antagonize the transactivationof the retinoic acid response element for the retinoic acidreceptor– gene,17,29 and decreased levels of coactivators(e.g., cellular E1A-like proteins30 and estrogen receptor–associatedproteins31) essential for transactivation through the retinoicacid response element. The loss of expression of retinoic acidreceptor– mRNA by HeLa cells was not caused by mutationsin the retinoic acid response element or other proximal regulatoryelements of the retinoic acid receptor– promoter.32
Regardless of the mechanism, aberrations in the level and functionof retinoic acid receptor– mRNA may promote carcinogenesis.This hypothesis is supported by the finding that a number oflung-cancer cell lines fail to express retinoic acid receptor–mRNA.20,21,33,34 Most of the neoplastic cells and tissues thatexpress little or no retinoic acid receptor– mRNA stillexpress mRNA for retinoic acid receptor–, retinoic acidreceptor–, and at least one of the retinoid X receptors,which may mediate the transactivation of retinoid-responsivegenes. This observation raises the possibility that retinoicacid receptor– regulates specific genes that are importantfor the suppression of carcinogenesis. It is relevant that transfectionof the retinoic acid receptor– gene decreases the tumorigenicityof human lung-cancer cells.35 Moreover, transient transfectionwith this gene results in retinoic acid–dependent suppressionof cell proliferation.36 The in vivo data presented here suggestthat loss of the expression of retinoic acid receptor–mRNA may have an important role in the expansion of premalignantclones.
We also found that a significant proportion of the patientshad increased expression of retinoic acid receptor– mRNAin oral premalignant tissue after treatment with isotretinoin.This finding is important, even though our study was not randomized;the incidence of an increase in retinoic acid receptor–mRNA had a random-chance probability of <0.001 (Table 2).
The ability of retinoic acid to induce the expression of retinoicacid receptor– mRNA in cultured cell lines has been welldocumented,18,37 and in vivo induction has been reported invitamin A–deficient rats38,39 and fetal mice.40 Of thesix subtypes of retinoid receptors, retinoic acid receptor–appears to be the most closely regulated by retinoids. Retinoicacid can induce the expression of retinoic acid receptor–mRNA in certain normal human cells (e.g., oral keratinocytes,25tracheobronchial epithelial cells,34 and senescent mammary epithelialcells41) and in nontumorigenic HeLa-cell hybrids, but not inthe malignant counterparts of these cells.32 These differencessuggest that transformed cells have an aberrant response toretinoic acid.
Another important finding of this study is the significant associationbetween the increased expression of retinoic acid receptor–mRNA and clinical responses of premalignant oral lesions toisotretinoin. The importance of this association can be seenboth in the high percentage of patients with clinical responsesand increased expression of retinoic acid receptor– mRNA(82 percent) and in the percentages of patients with increasedand unchanged expression of retinoic acid receptor– mRNAamong those with clinical responses (69 and 31 percent, respectively;P = 0.04). It is possible that retinoic acid receptor–contributes to the suppression of the premalignant phenotypeand is thus causally linked to the clinical outcome in chemopreventiontrials of retinoids.
Our results suggest that retinoic acid receptor– may bea useful intermediate marker in trials of retinoids for theprevention of oral carcinogenesis. However, we must be cautiousin this recommendation, because 47 percent of the patients withoutclinical responses had increased expression of retinoic acidreceptor– mRNA. Our trial was brief (three months), andthese patients might have had clinical responses in a longertrial. As with any potential intermediate marker (includingthe response of premalignant lesions), the use of retinoic acidreceptor– mRNA as a marker will have to be validated bycomparison with the incidence of cancer (currently the onlydefinitive end point for cancer prevention) in long-term clinicaltrials.42
Supported in part by grants from the National Cancer Institute(CA46303 and PO1 CA 52051) and the Rippel Foundation.
We are indebted to Drs. Pierre Chambon and Ronald Evans forthe complementary-DNA probes, to Susan Cweren for the preparationof tissue sections, and to Melinda Garza for assistance in thepreparation of the manuscript.
Source Information
From the Departments of Tumor Biology (R.L., X.-C.X.), Thoracic and Head and Neck Medical Oncology (S.M.L., J.S.L., W.K.H.), Pathology (J.Y.R.), and Biomathematics (J.J.L.), University of texas M.D. Anderson Cancer Center, Houston.
Address reprint requests to Dr. Lotan at the Department of Tumor Biology-108, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030.
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