Wang Jihan, Ni Zhaohui, Duan Zipeng, Wang Guoqing, Li Fan
Department of Pathogenobiology, Jilin Key Laboratory of Biomedical Materials, College of Basic Medical Science, Jilin University, Changchun, China.
Department of Pathogenobiology, Jilin Key Laboratory of Biomedical Materials, College of Basic Medical Science, Jilin University, Changchun, China; The Key Laboratory for Bionics Engineering, Ministry of Education, China, Jilin University, Changchun, China.
PLoS One. 2014 Jun 13;9(6):e99835. doi: 10.1371/journal.pone.0099835. eCollection 2014.
Tissue hypoxia induces reprogramming of cell metabolism and may result in normal cell transformation and cancer progression. Hypoxia-inducible factor 1-alpha (HIF-1α), the key transcription factor, plays an important role in gastric cancer development and progression. This study aimed to investigate the underlying regulatory signaling pathway in gastric cancer using gastric cancer tissue specimens. The integration of gene expression profile and transcriptional regulatory element database (TRED) was pursued to identify HIF-1α ↔ NFκB1 → BRCA1 → STAT3 ← STAT1 gene pathways and their regulated genes. The data showed that there were 82 differentially expressed genes that could be regulated by these five transcription factors in gastric cancer tissues and these genes formed 95 regulation modes, among which seven genes (MMP1, TIMP1, TLR2, FCGR3A, IRF1, FAS, and TFF3) were hub molecules that are regulated at least by two of these five transcription factors simultaneously and were associated with hypoxia, inflammation, and immune disorder. Real-Time PCR and western blot showed increasing of HIF-1α in mRNA and protein levels as well as TIMP1, TFF3 in mRNA levels in gastric cancer tissues. The data are the first study to demonstrate HIF-1α-regulated transcription factors and their corresponding network genes in gastric cancer. Further study with a larger sample size and more functional experiments is needed to confirm these data and then translate into clinical biomarker discovery and treatment strategy for gastric cancer.
组织缺氧会诱导细胞代谢重编程，并可能导致正常细胞转化和癌症进展。缺氧诱导因子1α（HIF-1α）作为关键转录因子，在胃癌发生和发展中起重要作用。本研究旨在利用胃癌组织标本探究胃癌潜在的调控信号通路。通过整合基因表达谱和转录调控元件数据库（TRED）来鉴定HIF-1α↔NFκB1→BRCA1→STAT3←STAT1基因通路及其调控的基因。数据显示，在胃癌组织中有82个差异表达基因可受这五个转录因子调控，这些基因形成了95种调控模式，其中七个基因（MMP1、TIMP1、TLR2、FCGR3A、IRF1、FAS和TFF3）是枢纽分子，它们至少同时受这五个转录因子中的两个调控，并且与缺氧、炎症和免疫紊乱相关。实时定量PCR和蛋白质印迹法显示，胃癌组织中HIF-1α的mRNA和蛋白质水平以及TIMP1、TFF3的mRNA水平均升高。这些数据是首次在胃癌中证明HIF-1α调控的转录因子及其相应的网络基因。需要进行更大样本量的进一步研究和更多功能实验来证实这些数据，并进而转化为胃癌的临床生物标志物发现和治疗策略。
