Akhtar Javed, Jain Vaishali, Kansal Radhika, Priya Ratna, Sakhuja Puja, Goyal Surbhi, Agarwal Anil Kumar, Ghose Vivek, Polisetty Ravindra Varma, Sirdeshmukh Ravi, Kar Sudeshna, Gautam Poonam
Laboratory of Molecular Oncology, Indian Council of Medical Research (ICMR) - National Institute of Pathology, New Delhi, India.
Jamia Hamdard- Institute of Molecular Medicine, Jamia Hamdard, New Delhi, India.
Front Oncol. 2023 Jan 6;12:1046974. doi: 10.3389/fonc.2022.1046974. eCollection 2022.
Gallbladder cancer (GBC) is an aggressive malignancy of the gastrointestinal tract with a poor prognosis. It is important to understand the molecular processes associated with the pathogenesis of early stage GBC and identify proteins useful for diagnostic and therapeutic strategies. Here, we have carried out an iTRAQ-based quantitative proteomic analysis of tumor tissues from early stage GBC cases (stage I, n=7 and stage II, n=5) and non-tumor controls (n=6) from gallstone disease (GSD). We identified 357 differentially expressed proteins (DEPs) based on ≥ 2 unique peptides and ≥ 2 fold change with p value < 0.05. Pathway analysis using the STRING database showed, 'neutrophil degranulation' to be the major upregulated pathway that includes proteins such as MPO, PRTN3, S100A8, MMP9, DEFA1, AZU, and 'ECM organization' to be the major downregulated pathway that includes proteins such as COL14A1, COL1A2, COL6A1, COL6A2, COL6A3, BGN, DCN. Western blot and/or IHC analysis confirmed the elevated expression of MPO, PRTN3 and S100A8 in early stage of the disease. Based on the above results, we hypothesize that there is an increased neutrophil infiltration in tumor tissue and neutrophil degranulation leading to degradation of extracellular matrix (ECM) proteins promoting cancer cell invasion in the early stage GBC. Some of the proteins (MPO, MMP9, DEFA1) associated with 'neutrophil degranulation' showed the presence of 'signal sequence' suggesting their potential as circulatory markers for early detection of GBC. Overall, the study presents a protein dataset associated with early stage GBC.
胆囊癌（GBC）是一种侵袭性很强的胃肠道恶性肿瘤，预后较差。了解与早期GBC发病机制相关的分子过程，并鉴定对诊断和治疗策略有用的蛋白质非常重要。在此，我们对早期GBC病例（I期，n = 7；II期，n = 5）和来自胆结石疾病（GSD）的非肿瘤对照（n = 6）的肿瘤组织进行了基于iTRAQ的定量蛋白质组分析。我们基于≥2个独特肽段和≥2倍变化且p值<0.05鉴定出357种差异表达蛋白（DEP）。使用STRING数据库进行的通路分析显示，“中性粒细胞脱颗粒”是主要上调的通路，包括MPO、PRTN3、S100A8、MMP9、DEFA1、AZU等蛋白质，而“细胞外基质组织”是主要下调的通路，包括COL14A1、COL1A2、COL6A1、COL6A2、COL6A3、BGN、DCN等蛋白质。蛋白质印迹和/或免疫组化分析证实了疾病早期MPO、PRTN3和S100A8表达升高。基于上述结果，我们推测肿瘤组织中中性粒细胞浸润增加以及中性粒细胞脱颗粒导致细胞外基质（ECM）蛋白降解，从而促进早期GBC中的癌细胞侵袭。一些与“中性粒细胞脱颗粒”相关的蛋白质（MPO、MMP9、DEFA1）显示存在“信号序列”，表明它们作为GBC早期检测循环标志物的潜力。总体而言，该研究呈现了一个与早期GBC相关的蛋白质数据集。
