Advanced Research Promotion Center, Health Sciences University of Hokkaido, 1757 Kanazawa, Ishikari-Tobetsu, Hokkaido, 061-0293, Japan.
Centre for Molecular Medicine and Biobanking, University of Malta, Msida, MSD 2080, Malta.
Sci Rep. 2021 May 18;11(1):10563. doi: 10.1038/s41598-021-90077-x.
Pancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic cancer with an abysmal prognosis rate over the last few decades. Early diagnosis and prevention could effectively combat this malignancy. Therefore, it is crucial to discover potential biomarkers to identify asymptomatic premalignant or early malignant tumors of PDAC. Gene expression analysis is a powerful technique to identify candidate biomarkers involved in disease progression. In the present study, five independent gene expression datasets, including 321 PDAC tissues and 208 adjacent non-cancerous tissue samples, were subjected to statistical and bioinformatics analysis. A total of 20 differentially expressed genes (DEGs) were identified in PDAC tissues compared to non-cancerous tissue samples. Gene ontology and pathway enrichment analysis showed that DEGs were mainly enriched in extracellular matrix (ECM), cell adhesion, ECM-receptor interaction, and focal adhesion signaling. The protein-protein interaction network was constructed, and the hub genes were evaluated. Collagen type XII alpha 1 chain (COL12A1), fibronectin 1 (FN1), integrin subunit alpha 2 (ITGA2), laminin subunit beta 3 (LAMB3), laminin subunit gamma 2 (LAMC2), thrombospondin 2 (THBS2), and versican (VCAN) were identified as hub genes. The correlation analysis revealed that identified hub genes were significantly interconnected. Wherein COL12A1, FN1, ITGA2, LAMB3, LAMC2, and THBS2 were significantly associated with PDAC pathological stages. The Kaplan-Meier survival plots revealed that ITGA2, LAMB3, and LAMC2 expression were inversely correlated with a prolonged patient survival period. Furthermore, the Human Protein Atlas database was used to validate the expression and cellular origins of hub genes encoded proteins. The protein expression of hub genes was higher in pancreatic cancer tissue than in normal pancreatic tissue samples, wherein ITGA2, LAMB3, and LAMC2 were exclusively expressed in pancreatic cancer cells. Pancreatic cancer cell-specific expression of these three proteins may play pleiotropic roles in cancer progression. Our results collectively suggest that ITGA2, LAMB3, and LAMC2 could provide deep insights into pancreatic carcinogenesis molecular mechanisms and provide attractive therapeutic targets.
胰腺导管腺癌 (PDAC) 是最常见的胰腺癌形式，在过去几十年中预后率极差。早期诊断和预防可以有效地对抗这种恶性肿瘤。因此，发现潜在的生物标志物来识别无症状的癌前或早期恶性胰腺导管腺癌肿瘤至关重要。基因表达分析是一种识别参与疾病进展的候选生物标志物的强大技术。在本研究中，对包括 321 个 PDAC 组织和 208 个相邻非癌组织样本在内的五个独立基因表达数据集进行了统计和生物信息学分析。与非癌组织样本相比，PDAC 组织中确定了 20 个差异表达基因 (DEG)。基因本体论和途径富集分析表明，DEGs 主要富集在细胞外基质 (ECM)、细胞黏附、ECM-受体相互作用和焦点黏附信号中。构建了蛋白质-蛋白质相互作用网络，并评估了枢纽基因。鉴定出的核心基因包括胶原 XII 型 α1 链 (COL12A1)、纤维连接蛋白 1 (FN1)、整合素亚基 α2 (ITGA2)、层粘连蛋白亚基 β3 (LAMB3)、层粘连蛋白亚基 γ2 (LAMC2)、血小板反应蛋白 2 (THBS2) 和 versican (VCAN)。相关性分析表明，鉴定出的核心基因之间存在显著的相互关联。其中 COL12A1、FN1、ITGA2、LAMB3、LAMC2 和 THBS2 与 PDAC 病理分期显著相关。Kaplan-Meier 生存图表明，ITGA2、LAMB3 和 LAMC2 的表达与患者生存期延长呈负相关。此外，还使用人类蛋白质图谱数据库验证了核心基因编码蛋白的表达和细胞起源。与正常胰腺组织样本相比，核心基因在胰腺癌组织中的蛋白表达更高，其中 ITGA2、LAMB3 和 LAMC2 仅在胰腺癌细胞中表达。这三种蛋白质在胰腺癌细胞中的特异性表达可能在癌症进展中发挥多效作用。我们的研究结果表明，ITGA2、LAMB3 和 LAMC2 可以深入了解胰腺发生的分子机制，并提供有吸引力的治疗靶点。
