Srivastava Prateeti, Yadav Vijesh Kumar, Chang Tzu-Hao, Su Emily Chia-Yu, Lawal Bashir, Wu Alexander Th, Huang Hsu-Shan
The Program for Translational Medicine, Graduate Institute of Biomedical Informatics, College of Medical Science and Technology, Taipei Medical University Taipei 110, Taiwan.
Graduate Institute of Biomedical Informatics, College of Medical Science and Technology, Taipei Medical University Taipei 110, Taiwan.
Am J Cancer Res. 2024 Jun 15;14(6):3010-3035. doi: 10.62347/CHXD6134. eCollection 2024.
Pancreatic adenocarcinoma (PAAD), known as one of the deadliest cancers, is characterized by a complex tumor microenvironment, primarily comprised of cancer-associated fibroblasts (CAFs) in the extracellular matrix. These CAFs significantly alter the matrix by interacting with hyaluronic acid (HA) and the enzyme hyaluronidase, which degrades HA - an essential process for cancer progression and spread. Despite the critical role of this interaction, the specific functions of CAFs and hyaluronidase in PAAD development are not fully understood. Our study investigates this interaction and assesses NSC777201, a new anti-cancer compound targeting hyaluronidase. This research utilized computational methods to analyze gene expression data from the Gene Expression Omnibus (GEO) database, specifically GSE172096, comparing gene expression profiles of cancer-associated and normal fibroblasts. We conducted in-house sequencing of pancreatic cancer cells treated with NSC777201 to identify differentially expressed genes (DEGs) and performed functional enrichment and pathway analysis. The identified DEGs were further validated using the TCGA-PAAD and Human Protein Atlas (HPA) databases for their diagnostic, prognostic, and survival implications, accompanied by Ingenuity Pathway Analysis (IPA) and molecular docking of NSC777201, , and preclinical validations. The result revealed 416 DEGs associated with CAFs and 570 DEGs related to NSC777201 treatment, with nine overlapping DEGs. A key finding was the transmembrane protein TMEM2, which strongly correlated with FAP, a CAF marker, and was associated with higher-risk groups in PAAD. NSC777201 treatment showed inhibition of TMEM2, validated by rescue assay, indicating the importance of targeting TMEM2. Further analyses, including IPA, demonstrated that NSC777201 regulates CAF cell senescence, enhancing its therapeutic potential. Both and studies confirmed the inhibitory effect of NSC777201 on TMEM2 expression, reinforcing its role in targeting PAAD. Therefore, TMEM2 has been identified as a theragnostic biomarker in PAAD, influenced by CAF activity and HA accumulation. NSC777201 exhibits significant potential in targeting and potentially reversing critical processes in PAAD progression, demonstrating its efficacy as a promising therapeutic agent.
胰腺腺癌（PAAD）是最致命的癌症之一，其特征是肿瘤微环境复杂，主要由细胞外基质中的癌症相关成纤维细胞（CAF）组成。这些CAF通过与透明质酸（HA）和降解HA的透明质酸酶相互作用，显著改变基质，而这是癌症进展和扩散的一个重要过程。尽管这种相互作用起着关键作用，但CAF和透明质酸酶在PAAD发展中的具体功能尚未完全了解。我们的研究调查了这种相互作用，并评估了一种靶向透明质酸酶的新型抗癌化合物NSC777201。本研究利用计算方法分析了来自基因表达综合数据库（GEO）（具体为GSE172096）的基因表达数据，比较了癌症相关成纤维细胞和正常成纤维细胞的基因表达谱。我们对用NSC777201处理的胰腺癌细胞进行了内部测序，以鉴定差异表达基因（DEG），并进行了功能富集和通路分析。使用TCGA - PAAD和人类蛋白质图谱（HPA）数据库对鉴定出的DEG进行了进一步验证，以评估其诊断、预后和生存意义，并结合了Ingenuity通路分析（IPA）以及NSC777201的分子对接和临床前验证。结果显示，有416个与CAF相关的DEG和570个与NSC777201处理相关的DEG，其中有9个重叠的DEG。一个关键发现是跨膜蛋白TMEM2，它与CAF标志物FAP高度相关，并且与PAAD中的高风险组相关。NSC777201处理显示出对TMEM2的抑制作用，这通过挽救试验得到验证，表明靶向TMEM2的重要性。包括IPA在内的进一步分析表明，NSC777201调节CAF细胞衰老，增强了其治疗潜力。两项研究均证实了NSC777201对TMEM2表达的抑制作用，强化了其在靶向PAAD中的作用。因此，TMEM2已被确定为PAAD中的一种治疗诊断生物标志物，受CAF活性和HA积累的影响。NSC777201在靶向并可能逆转PAAD进展中的关键过程方面具有显著潜力，证明了其作为一种有前景的治疗药物的疗效。
