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

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 (Log2FC =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.


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Results of syntheses 20a For each synthesis, briefly summarise the characteristics and risk of bias among contributing studies. 20b Present results of all statistical syntheses conducted. If meta-analysis was done, present for each the summary estimate and its precision (e.g. confidence/credible interval) and measures of statistical heterogeneity. If comparing groups, describe the direction of the effect. 20c Present results of all investigations of possible causes of heterogeneity among study results. 20d Present results of all sensitivity analyses conducted to assess the robustness of the synthesized results.

Reporting biases 21
Present assessments of risk of bias due to missing results (arising from reporting biases) for each synthesis assessed.
Certainty of evidence 22 Present assessments of certainty (or confidence) in the body of evidence for each outcome assessed.

Discussion 23a
Provide a general interpretation of the results in the context of other evidence. 23b Discuss any limitations of the evidence included in the review. 23c Discuss any limitations of the review processes used. 23d Discuss implications of the results for practice, policy, and future research.

OTHER INFORMATION
Registration and protocol 24a Provide registration information for the review, including register name and registration number, or state that the review was not registered.

24b
Indicate where the review protocol can be accessed, or state that a protocol was not prepared. 24c Describe and explain any amendments to information provided at registration or in the protocol.

Support 25
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Competing interests 26 Declare any competing interests of review authors.
Availability of data, code and other materials 27 Report which of the following are publicly available and where they can be found: template data collection forms; data extracted from included studies; data used for all analyses; analytic code; any other materials used in the review. Identify the report as a systematic review.

Objectives 2
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Eligibility criteria 3
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Information sources 4 Specify the information sources (e.g. databases, registers) used to identify studies and the date when each was last searched.
Risk of bias 5 Specify the methods used to assess risk of bias in the included studies.
Synthesis of results 6 Specify the methods used to present and synthesize results.

Included studies 7
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Synthesis of results 8 Present results for main outcomes, preferably indicating the number of included studies and participants for each.
If meta-analysis was done, report the summary estimate and confidence/credible interval. If comparing groups, indicate the direction of the effect (i.e. which group is favoured).

DISCUSSION
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Interpretation 10 Provide a general interpretation of the results and important implications.

Funding 11
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