Department of Systems Medicine, University of Rome 'Tor Vergata', Via Montpellier 1, 00133, Rome, Italy.
Cutaneous Physiopathology Laboratory and Metabolomic Center, San Gallicano Dermatological Institute, Rome, Italy.
Br J Dermatol. 2017 Dec;177(6):1633-1643. doi: 10.1111/bjd.15703. Epub 2017 Nov 16.
Transforming growth factor (TGF)-β1 exerts inhibitory effects on keratinocyte proliferation.
To examine whether Smad7, a known inhibitor of TGF-β1 signalling, is involved in psoriasis-associated keratinocyte hyperproliferation.
Smad7 was evaluated in skin sections of patients with psoriasis and healthy controls and in mice with Aldara-induced skin pathology by real-time polymerase chain reaction and immunohistochemistry. To assess whether Smad7 positively regulates in vivo keratinocyte growth, mice treated with Aldara received daily cutaneous administration of Smad7 antisense oligonucleotide (AS). Keratin (K)6 and K16, cell-cycle-associated factors, cell-cycle and cell proliferation were evaluated in HaCaT cells either treated with Smad7 AS or transfected with Smad7 plasmid and in mice given Smad7 AS.
Smad7 was highly expressed in keratinocytes of patients with psoriasis and of mice treated with Aldara. In HaCaT cells, Smad7 knockdown inhibited cell growth, reduced K6 and K16 expression and promoted accumulation of cells in the S-phase of the cell cycle. Smad7-deficient keratinocytes exhibited reduced levels of CDC25A protein, a phosphatase that facilitates progression of cells through the S-phase, and hyperphosphorylation of eukaryotic initiation factor 2 (eIF2)α, a negative regulator of CDC25 protein translation. Consistently, Smad7 overexpression in HaCaT cells was followed by induction of K6 and K16 and increased cell proliferation. Topical application of Smad7 AS to Aldara-treated mice reduced epidermal thickness.
Our data show that Smad7 is overexpressed in human and murine psoriasis and suggest a key role of this molecule in the control of keratinocyte proliferation.
转化生长因子 (TGF)-β1 对角质形成细胞增殖具有抑制作用。
研究已知的 TGF-β1 信号通路抑制剂 Smad7 是否参与银屑病相关的角质形成细胞过度增殖。
通过实时聚合酶链反应和免疫组织化学检测，评估 Smad7 在银屑病患者和健康对照者的皮肤切片以及 Aldara 诱导的皮肤病变小鼠中的表达情况。为了评估 Smad7 是否正向调节体内角质形成细胞的生长，接受 Aldara 治疗的小鼠每天接受 Smad7 反义寡核苷酸 (AS) 的皮肤给药。通过用 Smad7 AS 处理 HaCaT 细胞或转染 Smad7 质粒，以及用 Smad7 AS 处理小鼠，评估细胞周期相关因子 K6 和 K16、细胞周期和细胞增殖。
Smad7 在银屑病患者和 Aldara 处理的小鼠的角质形成细胞中高表达。在 HaCaT 细胞中，Smad7 敲低抑制细胞生长，降低 K6 和 K16 的表达，并促进细胞在细胞周期的 S 期积累。Smad7 缺陷型角质形成细胞表现出 CDC25A 蛋白水平降低，CDC25A 是一种促进细胞通过 S 期的磷酸酶，以及真核起始因子 2 (eIF2)α 的过度磷酸化，eIF2α 是 CDC25 蛋白翻译的负调节剂。一致地，Smad7 在 HaCaT 细胞中的过表达导致 K6 和 K16 的诱导和细胞增殖的增加。Smad7 AS 局部应用于 Aldara 处理的小鼠可减少表皮厚度。
我们的数据表明，Smad7 在人类和小鼠银屑病中过度表达，并表明该分子在控制角质形成细胞增殖中起关键作用。
