Haider Asifa S, Peters Sara B, Kaporis Helen, Cardinale Irma, Fei Ji, Ott Jurg, Blumenberg Miki, Bowcock Ann M, Krueger James G, Carucci John A
Laboratory of Investigative Dermatology, Rockefeller University, New York, New York, USA.
J Invest Dermatol. 2006 Apr;126(4):869-81. doi: 10.1038/sj.jid.5700157.
Using high-density oligonucleotide arrays, we measured expression of >12,000 genes in surgical excisions of invasive human squamous cell carcinomas (SCCs) versus site-matched control skin. This analysis defined >1,900 genes with altered expression in SCCs that were statistically different from controls. As SCCs are composed of epithelial cells, which are both hyperplastic and invasive, we sought to define gene sets associated with these biologic processes by comparing gene expression to psoriasis vulgaris, which is a condition of benign keratinocyte hyperplasia without invasiveness or pre-malignant potential. Through this analysis, we found genes that were commonly upregulated in both conditions and unique genes with increased expression in SCCs. Differential gene regulation in these two conditions was confirmed by real-time reverse transcription-PCR and immunohistochemistry. We found that benign hyperplasia is associated with upregulation of genes including DEFB4 (defensin B4), SERPINB3 (serine proteinase inhibitor, member 3), STAT1 (signal transducer and activator of transcription 1), K16 (keratin 16), CEACAMs (carcinoembryonic antigen-related cell adhesion molecules), and WNT 5A (wingless-type MMTV integration site family, member 5A). WNT receptor frizzled homolog 6 (FZD6) and prostaglandin-metabolizing enzyme hydroxyprostaglandin dehydrogenase were increased in SCC alone. Growth factor pleiotrophin (PTN) was expressed at higher levels in non-tumor-bearing skin adjacent to excised SCC. SCC was further characterized by upregulation of matrix metalloproteinases 1, 10, and 13, cathepsin L2, cystatin E/M as well as STAT3 and microseminoprotein, beta (MSMB), and downregulation of inducible nitric oxide synthase, granzyme B, CD8, and CD83. The current study defines a unique gene expression signature for cutaneous SCC in humans and suggests potential roles for WNT, FZD, and PTN in the pathogenesis of SCC.
我们使用高密度寡核苷酸阵列，测量了侵袭性人类鳞状细胞癌（SCC）手术切除标本与部位匹配的对照皮肤中12000多个基因的表达。该分析确定了SCC中1900多个表达改变且与对照有统计学差异的基因。由于SCC由增生性和侵袭性的上皮细胞组成，我们试图通过将基因表达与寻常型银屑病进行比较来确定与这些生物学过程相关的基因集，寻常型银屑病是一种良性角质形成细胞增生性疾病，无侵袭性或癌前潜能。通过该分析，我们发现了在两种情况下均上调的基因以及在SCC中表达增加的独特基因。通过实时逆转录PCR和免疫组织化学证实了这两种情况下的差异基因调控。我们发现良性增生与包括DEFB4（防御素B4）、SERPINB3（丝氨酸蛋白酶抑制剂3）、STAT1（信号转导和转录激活因子1）、K16（角蛋白16）、CEACAMs（癌胚抗原相关细胞粘附分子）和WNT 5A（无翅型MMTV整合位点家族成员5A）等基因的上调有关。WNT受体卷曲同源物6（FZD6）和前列腺素代谢酶羟基前列腺素脱氢酶仅在SCC中增加。生长因子多效蛋白（PTN）在切除的SCC旁的非肿瘤皮肤中表达水平更高。SCC的进一步特征是基质金属蛋白酶1、10和13、组织蛋白酶L2、胱抑素E/M以及STAT3和微精蛋白β（MSMB）上调，诱导型一氧化氮合酶、颗粒酶B、CD8和CD83下调。本研究确定了人类皮肤SCC独特的基因表达特征，并提示WNT、FZD和PTN在SCC发病机制中的潜在作用。
