| Background: Nuclear hormone receptor superfamily is one of the biggesttranscription factor families. More and more members of this family have been determinedthrough the recent decade, which makes the structure and the function of these receptorsbecome one of the molecular scientific focuses. Nuclear hormone receptor superfamilycomes from the same ancestor, and has the same structural character. Thses receptors arevery critical for the development and keeping the inner homeostasis in many physiologicalprocesses, by combining with specific response elements and regulating the transcription oftheir taget genes.There are so many members from this family, which beyond the original expecations.So far, the number is over150, which make this family be the biggest transcription familyin eukaryotes, including glucocorticoid receptor, mineralcorticoid hormone receptor, PR,AR, ER, TR, VDR, RXR, RAR, also lots of orphan receptors whose ligands haven’t beendetermined.Nuclear hormone receptors are also of critical importance for skin homeostasis, wherethey modulate cellular metabolism, proliferation, differentiation, cell apoptosis andinflammation. The cutaneous effects of GR, AR and ER on skin were explored initially.With the decelopment of following researches, sequence homology comparisons haveuncovered the complete superfamily of related receptors, many of which are also implicatedin cutaneous homeostasis. Among those receptors, one subgroup acts in concert with theretinoid X receptor by heterodimerizaiton and has been successfully targeted fordermatological therapy, such as RAR and VDR. Ongoing research is aimed at delineatingthe cutaneous effects of additional members of this subgroup including peroxisomeproliferator-activated receptors and the live X receptors. The various receptors exertdifferential effects on skin and can be rationally chosen as targets for the treatment of cutaneous pathologies.In the case of NHRS, the ligand occupancy of the recptor is typically paralleled by themagnitude of the hormone response, whereas for other receptors; i.e., membrane receptors,occupancy of a small percentage of the receptors suffices to elite a maximal response.So, how many NHRs are there in the skin and how is the expression level? How theirligands influence the skin biology? Is there any difference between the expression of theNHRs in the normal skin cells and squamous cell carcinoma cells? Whether thosedifferences are critical in the carcinogenesis of the cutaneous cancer or can provide specifictargets for clinical treatment? These questions remain uncovered. Therefore, weinvestigated the expression of NHRs in the cutaneous component cells and squamous cellcarcinoma cells using the nuclear hormone receptors PCR array plate. We also derminedeffect of the thyroid hormone analogue in epidermal cells and lots of related ligands insquamous cell carcinoma cell, which helps find a new target for clinical therapy for therelated skin diseases.Methods and Results:1. The expression levels of the nuclear hormone receptors in the skin component cellswere detected by the qPCR array, which indicated that the subgroup of the RXRheterodimer receptors composed the most aboundant receptors, and mainly expressed inkeratinocyte.2. The immunohistochemistry results demonstrated that TR ligand TRIAC induced cellproliferation, thickened the epiderimis but inhibited the cell differentiation inTRIAC-treated C57/BL mice.3. TRIAC prompted keratinocyte proliferation but inhibited cell differentiation in vitro,which were detected by MTS, PCR, and Western Blotting, respectively. FACSdemonstrated that TRIAC prompted cell cycle from G1phrase to S phrase.4. qPCR array also showed that the expression levels of those receptors were higher insquamous cell carcinoma cell than that in the normal keratinocyte, suggesting that thosechanges might get involved in the carcinogenesis of the tumor.5. A431cell proliferation was detected by MTS after several different receptor ligandstreatments, which indicated that only LXR ligands inhibited A431proliferation, whereasother ligands had no significant effect. 6. FACS results showed that LXR ligands induced the percentage of the G0/G1phase cells increasing dramatically, but the S phase decreasing significantly.7. PCR and Western blotting showed that the expression level of PCNA decreaseddramatically after the LXR ligands treatment, while KLF4and cell cycle inhibitor p21exprssion increased.8. Silencing of the LXRβ in A431cells reduced the effects of the LXR ligands asmentioned above.Conclusion:The majortity of the most abundant nuclear hormone receptors in human cutaneouscomponent cells belong to the subgroup of RXR heterdimer receptors. Epidermis is themain target region of those receptors. One of thyroid hormone receptor ligands, TRIACpromotes epidermal cell proliferation but inhibits cell differentiation both in vitro and invivo. The expression levels of those receptors mentioned are higher in A431cell than thatin normal human kerationcyte. LXR ligands inhibit A431cell proliferation, induce cellcycle arrest in vitro in an LXRβ-dependent manner，through regulating the expression oftranscription factor-KLF4and cell cycle inhibitor p21. |
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