Data-independent acquisition and quantification of extracellular matrix from human lung in chronic inflammation-associated carcinomas.
Data-independent acquisition and quantification of extracellular matrix from human lung in chronic inflammation-associated carcinomas.
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作者：
与慢性炎症和癌症相关的早期事件涉及细胞外基质(ECM)的显著重塑，这极大地影响其组成和功能特性。使用肺鳞状细胞癌(LSCC)，一种慢性炎症相关癌症(CIAC)，我们优化了一个强大的蛋白质组流水线，以发现潜在的生物标记物特征和特别是间质中的蛋白质变化。我们结合了新鲜人体组织的ECM浓缩、数据独立获取(DIA)策略和严格的统计处理来分析“肿瘤”和匹配来自LSCC患者的邻近组织学正常(“匹配正常”)组织。总体而言，至少有两个独特的多肽对1802个蛋白质组进行了量化，其中56%的蛋白质被注释为“胞外”。与“匹配的正常”组织相比，“肿瘤”组织中的529个蛋白质显著改变，证实了CIAC进展过程中细胞外基质的戏剧性重塑。典型的特征是基底膜蛋白和富含亮氨酸的小蛋白的协调丢失。使用我们的ECM蛋白质组流水线发现的SERPINH1/热休克蛋白47的间质水平显著增加，并通过从喉癌患者的独立队列中获得的“肿瘤”和“匹配的正常”组织的免疫组织化学(IHC)来验证。这一整合的工作流程为CIAC进展过程中的ECM重塑提供了新的见解，并确定了潜在的生物标记物特征和未来的治疗目标。
Early events associated with chronic inflammation and cancer involve significant remodeling of the extracellular matrix (ECM), which greatly affects its composition and functional properties. Using lung squamous cell carcinoma (LSCC), a chronic inflammation-associated cancer (CIAC), we optimized a robust proteomic pipeline to discover potential biomarker signatures and protein changes specifically in the stroma. We combined ECM enrichment from fresh human tissues, data-independent acquisition (DIA) strategies, and stringent statistical processing to analyze “Tumor” and matched adjacent histologically normal (“Matched Normal”) tissues from patients with LSCC. Overall, 1802 protein groups were quantified with at least two unique peptides, and 56% of those proteins were annotated as “extracellular.” Confirming dramatic ECM remodeling during CIAC progression, 529 proteins were significantly altered in the “Tumor” compared to “Matched Normal” tissues. The signature was typified by a coordinated loss of basement membrane proteins and small leucine-rich proteins. The dramatic increase in the stromal levels of SERPINH1/heat shock protein 47, that was discovered using our ECM proteomic pipeline, was validated by immunohistochemistry (IHC) of “Tumor” and “Matched Normal” tissues, obtained from an independent cohort of LSCC patients. This integrated workflow provided novel insights into ECM remodeling during CIAC progression, and identified potential biomarker signatures and future therapeutic targets.
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