Banerjee Abhijit G, Bhattacharyya Indraneel, Lydiatt William M, Vishwanatha Jamboor K
Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, 984525 Nebraska Medical Center, Omaha, NE 68198-4525, USA.
Cancer Res. 2003 Nov 15;63(22):7769-76.
The small leucine-rich proteoglycan decorin has been associated with negative regulation of cell growth. It has a prominent role in transforming growth factor (TGF)-beta and epidermal growth factor receptor activation pathways that contributes to its role in cellular proliferation, angiogenesis, and immunomodulation. Our studies are directed toward analysis of decorin gene expression, identified through DNA microarray studies, in oral premalignant and malignant tissues as well as representative cell lines of an oral cancer progression model. We have used long oligonucleotide microarray analysis, immunohistochemistry, confocal microscopy, reverse transcription-PCR, sequencing, and Western immunoblot techniques to characterize decorin expression in oral premalignant archival tissues and an oral cancer progression cellular model. We have further analyzed the deduced amino acid sequence derived from full-length cDNA that do not show any deletion or mutations of the decorin expressed in oral premalignant and malignant cell lines. In our studies, we show aberrant expression of decorin in dysplastic oral epithelial cells. Both promoters P1 and P2 drive the aberrant expression resulting in exon 1a as well as exon 1b carrying transcripts. Intracellular accumulation and nuclear localization of aberrantly expressed decorin were observed in dysplastic oral tissues and in the respective cell lines. Decorin expressed in oral cancer may have lost its ability to inhibit TGF-beta signaling and activate epidermal growth factor receptor signaling pathways because of such aberrant nuclear localization, resulting in a major dysfunction of otherwise a natural extracellular antagonist of TGF-beta and a putative tumor suppressor protein. The aberrant nuclear localization of a leucine-rich repeat protein might result in additional protein-protein interactions and resulting changes in gene expression. Further studies to characterize such interacting proteins and localization-dependent effects of aberrant decorin expressed in oral cancer progression are warranted.
富含亮氨酸的小分子蛋白聚糖核心蛋白聚糖与细胞生长的负调控有关。它在转化生长因子（TGF）-β和表皮生长因子受体激活途径中发挥着重要作用，这有助于其在细胞增殖、血管生成和免疫调节中的作用。我们的研究旨在分析通过DNA微阵列研究确定的核心蛋白聚糖基因在口腔癌前组织和恶性组织以及口腔癌进展模型的代表性细胞系中的表达情况。我们使用了长寡核苷酸微阵列分析、免疫组织化学、共聚焦显微镜、逆转录PCR、测序和Western免疫印迹技术来表征口腔癌前存档组织和口腔癌进展细胞模型中核心蛋白聚糖的表达。我们进一步分析了从全长cDNA推导的氨基酸序列，该序列在口腔癌前和恶性细胞系中表达的核心蛋白聚糖未显示任何缺失或突变。在我们的研究中，我们显示了发育异常的口腔上皮细胞中核心蛋白聚糖的异常表达。启动子P1和P2均驱动异常表达，导致外显子1a以及携带转录本的外显子1b。在发育异常的口腔组织和相应的细胞系中观察到异常表达的核心蛋白聚糖的细胞内积累和核定位。由于这种异常的核定位，口腔癌中表达的核心蛋白聚糖可能已经失去了抑制TGF-β信号传导和激活表皮生长因子受体信号传导途径的能力，导致原本是TGF-β天然细胞外拮抗剂和假定肿瘤抑制蛋白的主要功能障碍。富含亮氨酸重复蛋白的异常核定位可能导致额外的蛋白质-蛋白质相互作用，并导致基因表达的变化。有必要进一步研究表征在口腔癌进展中异常表达的核心蛋白聚糖的此类相互作用蛋白和定位依赖性效应。
