High expression of hypoxia-inducible factor 1-alpha predicts poor prognosis in pancreatic ductal adenocarcinoma: a meta-analysis and database validation protocol

Abstract

Background: Hypoxia-inducible factor 1-alpha (HIF-1α) is overexpressed in pancreatic ductal adenocarcinomas (PDACs). However, the prognosis of high expression of HIF-1α in PDACs remains controversial because of lacking a solid support. A meta-analysis may help for a better understanding of the role of HIF-1α in the prognosis of PDACs.Methods: By using a systematic approach, we conducted a meta-analysis from current literature. We performed an advanced search in PubMed, Embase, Cochrane Library and Web of Science databases.Recorded studies were published between September 1, 2001, and February 26, 2021, in English and related to the expression of HIF-1α in PDAC. We pooled and combined hazard ratios (HRs) and 95% confidence intervals (CIs) to show the effect of HIF-1α expression on overall survival (OS). We pooled also risk ratios (RRs) and 95% CIs to assess the correlation between HIF-1α expression and clinicopathological characteristics in PDAC. We evaluated publication bias among included studies through the Begg's test and Egger's test. From "Expression Plots" modules in the Gene Expression Profiling Interactive Analysis (GEPIA) database, we showed the difference of mRNA level for HIF1A between 179 pancreatic adenocarcinomas (PAADs) and 171 normal pancreatic tissues.Results: This meta-analysis included 11 studies and 764 patients. High expression of HIF-1α was associated with shorter OS compared to low HIF-1α expression in PDAC (HR =1.74, 95% CI: 1.49-2.04, P<0.001). Patients with high expression of HIF-1α tended to have an increased risk of earlier lymph node metastasis (LNM) (RR =1.63, 95% CI: 1.36-1.95, P<0.001), and more advanced clinical stage (RR =1.64, 95% CI: 1.38-1.97, P<0.001) compared to those with low HIF-1α expression. Expression plots from GEPIA database showed HIF1A overexpressed in PDAC tissues compared to normal tissues (Log 2 FC =2, P<0.01).Conclusions: High HIF-1α expression associated with worse prognosis of PDACs compared to low HIF-1α expression. Since HIF-1α expression is greater in PDAC than normal pancreas, it could serve as a prognostic factor and potential therapeutic target. However, due to the complex role of HIF-1α in physiology and pathology, therapeutic intervention should be considered with caution.

Research on the oncogenic role of the house-keeping gene GAPDH in human tumors

“…Besides, the hyperoxia signaling pathway is involved in aggressive tumor behavior (21), and the GAPDH gene contains a hypoxia response element with a hypoxia inducible factor-1 (HIF-1) transcription factor binding site. By activating HIF-1, the expression of enzymes involved in glycolysis, such as GAPDH, could be enhanced by p-AKT in cancer cells of the colon, kidney and liver (22)(23)(24). Corresponding to this, our analysis of KEGG pathways identified "Glycolysis/ gluconeogenesis" and "HIF-1 signaling pathway" as the enriched hits.…”

O2-Generating Fluorescent Carbon Dot-Decorated MnO2 Nanosheets for “Off/On” MR/Fluorescence Imaging and Enhanced Photodynamic Therapy

“…Since the induction of hypoxia factor 1α (HIF-1α) expression by hypoxia, Western blotting was used to evaluate the effect of HA-MnO 2 –CDs on improving tumor cell hypoxia. Compared with the control group, the HIF-1α protein bands on the surface of cells coincubated with HA-MnO 2 –CDs were narrower and lighter in color (Figure d), indicating a lower HIF-1α protein content on their surface.…”

“…Although the amount of intracellular green fluorescence in the MnO 2 group was less than that in the HA-MnO 2 −CDs group, it was still higher than that in the CDs group, which was related to the Fenton-like reaction of Mn 2+ . 56 These indicated that the intracellular ROS production rate of HA-MnO 2 −CDs was much higher than that of HA-MnO 2 and CDs, providing a Since the induction of hypoxia factor 1α (HIF-1α) expression by hypoxia, 57 Western blotting was used to evaluate the effect of HA-MnO 2 −CDs on improving tumor cell hypoxia. Compared with the control group, the HIF-1α protein bands on the surface of cells coincubated with HA-MnO 2 −CDs were narrower and lighter in color (Figure 6d), indicating a lower HIF-1α protein content on their surface.…”

The contributions of hypoxia to poor outcomes in pancreatic cancer

“…In the study by Zoa et al published in this issue of TCR , the contributions of HIF1α expression to outcome in PDAC are reported ( 11 ). The authors performed a systematic search for publications that report HIF1α expression (by immunohistochemistry) and clinical data, and performed a meta-analysis on the key outcome variables from 11 publications including 764 patients.…”

“…These limitations notwithstanding, the work by Zoa et al ( 11 ) is a solid basis from which to initiate follow-up research. The link between HIF1α and poor outcome has been further consolidated, which will hopefully accelerate the development of clinically applicable inhibitors or biomarkers to guide current treatments, for instance radiation.…”