Abstract
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.
Highlights
Gastric cancer is the fourth most common cancer and the second leading cause of cancer-related death in the world, which affects approximately 800,000 people and 65,000 cancer-related deaths annually [1]
Reprogramming of energy metabolism has been included as an emerging hallmark of cancer [4] and abnormal energy metabolism is detectable in different human cancer, i.e., cancer cells will reprogram their metabolism by increase in glycolysis instead of the mitochondrial oxidative phosphorylation to generate cell energy [5]
Hypoxia-inducible factor 1-alpha (HIF-1a) was significantly highly expressed in gastric cancer tissues compared to the adjacent normal tissues (P,0.01)
Summary
Gastric cancer is the fourth most common cancer and the second leading cause of cancer-related death in the world, which affects approximately 800,000 people and 65,000 cancer-related deaths annually [1]. HIF-1 is composed of a constitutively expressed b-subunit and a hypoxia-inducible a-subunit. The latter (HIF-1a) is only stabilized under hypoxic conditions and regulates HIF-1 transcriptional activity [9]. Previous studies showed up-regulation of HIF-1a expression in gastric cancer tissues and cells [12,13], whereas the precisely underlying regulatory mechanisms remain to be defined. In this study, we utilized the Affymatrix Exon Arrays to identify the differential gene expression profile in gastric cancer tissues, and performed real time PCR and western blot analyses to validate the data. This study could identify a systematic exposition of the associated transcriptional regulation modes related with hypoxia and provide insightful information for future biomarker discovery and novel treatment strategy for gastric cancer
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