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首页> 外文期刊>Journal of dermatological science >L-3-Phosphoserine phosphatase (PSPH) regulates cutaneous squamous cell carcinoma proliferation independent of L-serine biosynthesis.
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L-3-Phosphoserine phosphatase (PSPH) regulates cutaneous squamous cell carcinoma proliferation independent of L-serine biosynthesis.

机译：L-3-磷酸丝氨酸磷酸酶（PSPH）调节皮肤鳞状细胞癌的增殖，而与L-丝氨酸的生物合成无关。

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BACKGROUND: L-3-Phosphoserine phosphatase (PSPH) is a highly conserved and widely expressed member of the haloacid dehalogenase superfamily and the rate-limiting enzyme in l-serine biosynthesis. We previously found Psph expression to be uniquely upregulated in a alpha6beta4 integrin transgenic mouse model that is predisposed to epidermal hyperproliferation and squamous cell carcinoma (SCC) formation implicating a role for Psph in epidermal homeostasis. OBJECTIVE: We examined the status of PSPH in normal skin epidermis and skin tumors along with its sub-cellular localization in epidermal keratinocytes and its requirement for squamous cell carcinoma (SCC) proliferation. METHODS: First, an immunohistochemical study was performed for PSPH in normal skin and skin cancer specimens and in cultured keratinocytes. Next, biochemical analyses were performed to confirm localization of PSPH and to identify candidate binding proteins. Finally, proliferation and apoptosis studies were performed in human SCC and normal keratinocytes, respectively, transduced with vectors encoding small hairpin RNAs targeting PSPH or overexpressing a phosphatase-deficient PSPH mutant. RESULTS: PSPH is expressed throughout the proliferative layer of the epidermis and hair follicles in rodent and human skin and is highly induced in SCC. In keratinocytes, PSPH is a cytoplasmic protein that primarily localizes to endosomes and is present primarily as a homodimer. Knock down of PSPH dramatically diminished SCC cell proliferation and cyclin D1 levels in the presence of exogenous of l-serine production suggesting a non-canonical role for PSPH in epithelial carcinogenesis. CONCLUSIONS: Psph is highly induced in proliferative normal keratinocytes and in skin tumors. PSPH appears to be critical for the proliferation of SCC cells; however, this phenomenon may not involve the phosphoserine metabolic pathway.
机译：背景：L-3-磷酸丝氨酸磷酸酶（PSPH）是卤代酸脱卤酶超家族和1-丝氨酸生物合成中的限速酶的高度保守和广泛表达的成员。我们先前发现Psph表达在alpha6beta4整联蛋白转基因小鼠模型中独特上调，该模型易发生表皮过度增殖和鳞状细胞癌（SCC）形成，暗示Psph在表皮稳态中的作用。目的：我们检查了正常皮肤表皮和皮肤肿瘤中PSPH的状态，以及其在表皮角质形成细胞中的亚细胞定位及其对鳞状细胞癌（SCC）增殖的需求。方法：首先，对正常皮肤和皮肤癌标本以及培养的角质形成细胞中的PSPH进行了免疫组织化学研究。接下来，进行生化分析以确认PSPH的定位并鉴定候选结合蛋白。最后，分别在人类SCC和正常角质形成细胞中进行增殖和凋亡研究，这些细胞是用编码靶向PSPH或过表达磷酸酶缺陷型PSPH突变体的小发夹RNA的载体转导的。结果：PSPH在啮齿动物和人皮肤的表皮和毛囊的整个增生层中表达，并在SCC中被高度诱导。在角质形成细胞中，PSPH是一种细胞质蛋白，主要定位于内体，主要以同型二聚体的形式存在。在存在外源性的L-丝氨酸产生的情况下，抑制PSPH会显着降低SCC细胞增殖和细胞周期蛋白D1的水平，这表明PSPH在上皮癌变中的非典型作用。结论：Psph在增殖性正常角质形成细胞和皮肤肿瘤中被高度诱导。 PSPH对于SCC细胞的增殖似乎至关重要。但是，这种现象可能不涉及磷酸丝氨酸代谢途径。

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