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首页> 外文期刊>The Laryngoscope: A Medical Journal for Clinical and Research Contributions in Otolaryngology, Head and Neck Medicine and Surgery, Facial Plastic and Reconstructive Surgery .. >Dominant negative p63 isoform expression in head and neck squamous cell carcinoma.
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Dominant negative p63 isoform expression in head and neck squamous cell carcinoma.

机译：头颈部鳞状细胞癌中主要的p63亚型阴性表达。

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OBJECTIVES/HYPOTHESIS: p63, a member of the p53 family of genes, is vital for normal epithelial development and may play a critical role in epithelial tumor formation. Although p63 has been identified in various head and neck malignancies, a detailed analysis of which of the six isoforms of the p63 gene is present in normal mucosa and head and neck malignancies has not yet been performed. The study analyzed p63 isoform expression on the RNA and protein level in normal, diseased, and malignant mucosa of the head and neck to examine the differential expression of p63 isoforms in head and neck tumors versus adjacent nonmalignant tissue and to identify the predominant p63 isoform expressed in head and neck squamous cell carcinoma (HNSCC). STUDY DESIGN: Three experiments were performed. In experiment 1, p63 expression was analyzed by immunohistochemical analysis in 36 HNSCC specimens and matched normal tissue control specimens harvested from the same patient. Western blot analysis was also performed on matched specimens to confirm the identity of the p63 isoforms that were found. In experiment 2, reverse transcriptase polymerase chain reaction (RT-PCR) analysis was performed on matched normal and tumor specimens to analyze and quantitatively compare p63 isoform expression at the RNA level. In experiment 3, p63 expression was evaluated by immunohistochemical analysis in oral lichen planus, a benign mucosal lesion marked by hyperdifferentiation and apoptosis. METHODS: Immunohistochemical analysis, RT-PCR, and Western blot analysis of p63 were performed on HNSCC specimens and matched normal tissue control specimens. p63 expression in oral lichen planus specimens was also examined by immunohistochemical analysis. RESULTS: In experiment 1, analysis of 36 HNSCC specimens from various head and neck subsites showed p63 expression in all tumors and matched normal tissue specimens (36 of 36). Western blot analyses indicated that dominant negative (DeltaN) isoform p63alpha (DeltaNp63alpha) is the major isoform expressed at the protein level in tumors and adjacent normal tissue. In experiment 2, RT-PCR analyses of 10 matched specimens confirmed that, although all three DeltaNp63 isoforms (DeltaNp63alpha, DeltaNp63beta, and DeltaNp63gamma) are expressed in normal and malignant mucosa of the head and neck, DeltaNp63alpha is the predominant transcript expressed. In experiment 3, immunohistochemical analysis of p63 in the pro-apoptotic condition of lichen planus indicated that p63 is underexpressed as compared with normal mucosal specimens. CONCLUSION: Although all three DeltaNp63 isoforms are present in HNSCC, DeltaNp63alpha protein is the predominant isoform expressed in these malignancies. DeltaNp63alpha is also overexpressed in tumors compared with matched normal tissue specimens and is underexpressed in the pro-apoptotic condition of lichen planus. These findings suggest that DeltaNp63alpha plays an anti-differentiation and anti-apoptotic role in the mucosal epithelium of the head and neck, possibly playing a pivotal role in the formation of HNSCC. Currently, DeltaNp63alpha is an attractive target for mechanistic study aimed at therapeutic intervention.
机译：目的/假设：p63是p53基因家族的成员，对正常的上皮发育至关重要，并可能在上皮肿瘤的形成中起关键作用。尽管已经在各种头颈部恶性肿瘤中鉴定出p63，但是尚未进行对p63基因的六个同工型中哪些存在于正常粘膜和头颈部恶性肿瘤中的详细分析。该研究分析了正常，患病和恶性的头颈部粘膜中p63亚型的RNA和蛋白质水平，以检查p63亚型在头颈部肿瘤与邻近的非恶性组织中的差异表达，并确定主要的p63亚型表达在头颈部鳞状细胞癌（HNSCC）中。研究设计：进行了三个实验。在实验1中，通过免疫组织化学分析了从同一患者收集的36份HNSCC标本和匹配的正常组织对照标本中的p63表达。还对匹配的标本进行了蛋白质印迹分析，以确认发现的p63亚型的身份。在实验2中，对匹配的正常和肿瘤标本进行了逆转录酶聚合酶链反应（RT-PCR）分析，以分析和定量比较RNA水平上的p63亚型。在实验3中，通过免疫组织化学分析评估了口腔扁平苔藓中的p63表达，扁平苔藓是一种以高分化和凋亡为标志的良性粘膜病变。方法：对HNSCC标本和匹配的正常组织对照标本进行p63的免疫组织化学分析，RT-PCR和Western blot分析。还通过免疫组织化学分析检查了口腔扁平苔藓标本中的p63表达。结果：在实验1中，对来自不同头颈部亚部位的36例HNSCC标本的分析显示，p63在所有肿瘤和匹配的正常组织标本中均表达（36中的36）。 Western印迹分析表明，显性阴性（DeltaN）同工型p63alpha（DeltaNp63alpha）是在肿瘤和邻近正常组织中以蛋白水平表达的主要同工型。在实验2中，对10个匹配标本进行RT-PCR分析证实，尽管所有三种DeltaNp63亚型（DeltaNp63alpha，DeltaNp63beta和DeltaNp63gamma）均在正常和恶性的头颈部粘膜中表达，但DeltaNp63alpha是主要的转录本。在实验3中，在扁平苔藓促凋亡状态下对p63的免疫组织化学分析表明，与正常黏膜标本相比，p63的表达不足。结论：尽管HNSCC中存在所有三种DeltaNp63亚型，但DeltaNp63alpha蛋白是在这些恶性肿瘤中表达的主要亚型。与匹配的正常组织标本相比，DeltaNp63alpha在肿瘤中也过表达，而在扁平苔藓的促细胞凋亡条件下表达不足。这些发现表明，DeltaNp63alpha在头和颈部的粘膜上皮细胞中具有抗分化和抗凋亡的作用，可能在HNSCC的形成中起关键作用。目前，DeltaNp63alpha是针对治疗干预的机制研究的有吸引力的靶标。

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