Hossain Akbor, Tom Lisa N, Melati-Rad Ala, Yamada Miko, Hammerlindl Sabrina, Jagirdar Kasturee, Prow Tarl W, Soyer H Peter, Stark Mitchell S
Frazer Institute The University of Queensland Dermatology Research Centre Brisbane Queensland Australia.
The Melanoma Centre South Brisbane Queensland Australia.
Skin Health Dis. 2024 Mar 16;4(3):e360. doi: 10.1002/ski2.360. eCollection 2024 Jun.
Actinic keratoses (AK) are pre-malignant skin lesions caused by chronic sun exposure. Progression from an AK to intraepidermal carcinoma (IEC) and a cutaneous squamous cell carcinoma (SCC) is well known but the rate of transformation to an invasive SCC is highly variable. Since no definitive biomarkers are available, treatment decisions are made ad hoc.
To fully characterise our AK to SCC progression series, we performed microRNA (miRNA) microarray expression profiling of normal and photodamaged skin, as well as AKs, IEC, and invasive SCCs.
The study recruited 27 patients who donated fresh biopsies of normal skin, photodamaged skin, AK, IEC, and SCC ( = 67 specimens). All miRbase (v.21) miRNAs were profiled to identify miRNAs related to SCC progression. miRNAs were validated using qRT-PCR and in vitro phenotypic assays.
There were 234 robustly expressed miRNAs across the tissue collection, which resulted in 20 miRNA that were differentially expressed ((cor) ≤ 0.05 and ≥ 10 fold) between normal skin and SCC. Hierarchical clustering all samples illustrated that AKs, IEC, and SCCs were largely indistinguishable, which confirms the premalignant status of an AK. A panel of miRNAs showed significant dysregulation between normal and photodamaged skin and AK. Importantly, we found miR-34a-5p and miR-31-5p had significant differential expression between AKs and IEC and IEC and SCC respectively. Phenotypic assays determined that the miR-31 duplex had opposing effects on SCC cell lines which suggests that dysregulation of this duplex may be related to the dynamic control of progression of transformed keratinocytes.
This study confirmed the continuum of AK with IEC and SCC highlighting that miRNA expression plays a role in keratinocyte transformation. Development of our putative miRNA biomarker candidates is warranted to aid in clinical management of patients experiencing high AK load to determine the most appropriate treatment.
光化性角化病（AK）是由长期阳光照射引起的皮肤癌前病变。从AK进展为表皮内癌（IEC）和皮肤鳞状细胞癌（SCC）是众所周知的，但向侵袭性SCC的转化速率差异很大。由于没有明确的生物标志物，治疗决策是临时做出的。
为了全面表征我们的AK到SCC进展系列，我们对正常皮肤、光损伤皮肤以及AK、IEC和侵袭性SCC进行了微小RNA（miRNA）微阵列表达谱分析。
该研究招募了27名捐赠正常皮肤、光损伤皮肤、AK、IEC和SCC新鲜活检组织的患者（共67个标本）。对所有miRbase（v.21）miRNA进行分析，以鉴定与SCC进展相关的miRNA。使用qRT-PCR和体外表型分析对miRNA进行验证。
在整个组织样本中共有234个高表达的miRNA，其中有20个miRNA在正常皮肤和SCC之间差异表达（(cor)≤0.05且≥10倍）。对所有样本进行层次聚类分析表明，AK、IEC和SCC在很大程度上难以区分，这证实了AK的癌前状态。一组miRNA在正常皮肤与光损伤皮肤以及AK之间表现出显著的失调。重要的是，我们发现miR-34a-5p和miR-31-5p分别在AK与IEC以及IEC与SCC之间存在显著差异表达。表型分析确定miR-31双链体对SCC细胞系有相反的作用，这表明该双链体的失调可能与转化角质形成细胞进展的动态控制有关。
本研究证实了AK与IEC和SCC之间的连续性，突出了miRNA表达在角质形成细胞转化中发挥的作用。有必要开发我们假定的miRNA生物标志物候选物，以帮助对AK负荷高的患者进行临床管理，从而确定最合适的治疗方法。
