Retrospective Analysis of Adenosine Monophosphate (AMP) in Gastric Cancer Pathophysiological Roles

Abstract

Gastric cancer (GC) remains a leading cause of cancer - related mortality globally, with complex pathophysiological mechanisms that are not fully understood. Adenosine monophosphate (AMP), a key nucleotide involved in energy metabolism and signaling pathways, has emerged as a potential regulator of tumor progression. This retrospective study aimed to systematically evaluate the role of AMP in GC using data from the PubMed database. We analyzed 34 eligible studies published between 2015 and 2024, focusing on AMP levels in GC tissues versus normal gastric mucosa, associations with clinicopathological features and prognostic significance. Our results showed that AMP levels were significantly lower in GC tissues (pooled standardized mean difference [SMD] = - 1.24, 95% confidence interval [CI]: - 1.56 to - 0.92, P < 0.001) and low AMP levels were associated with advanced TNM stage (odds ratio [OR] = 2.78, 95% CI: 2.03 to 3.81, P < 0.001), lymph node metastasis (OR = 3.05, 95% CI: 2.21 to 4.21, P < 0.001) and poor overall survival (hazard ratio [HR] = 1.89, 95% CI: 1.56 to 2.29, P < 0.001). These findings highlight AMP as a potential prognostic biomarker and underscore its involvement in GC pathogenesis, providing insights for future therapeutic strategies.

Keywords: Hepatocellular carcinoma; Adenosine monophosphate; Potential prognostic biomarker

Introduction
Gastric cancer (GC) is the fifth most common malignancy and the fourth leading cause of cancer deaths worldwide, with an estimated 1.08 million new cases and 769,000 deaths in 2020¹. Despite advances in diagnosis and treatment, the 5 - year survival rate for advanced GC remains below 30%². Understanding the molecular and metabolic alterations in GC is crucial for identifying novel biomarkers and therapeutic targets.

Adenosine monophosphate (AMP) is a central molecule in cellular energy metabolism, serving as a precursor for adenosine triphosphate (ATP) and a regulator of AMP - activated protein kinase (AMPK), a key sensor of cellular energy status³. AMPK modulates various cellular processes, including metabolism, cell growth and autophagy, which are often dysregulated in cancer⁴. Emerging evidence suggests that AMP metabolism is perturbed in GC, with potential implications for tumor growth, invasion and resistance to therapy. However, a comprehensive retrospective analysis of AMP in GC is lacking. This study synthesizes data from PubMed - indexed studies to clarify the clinical significance of AMP in GC.

Materials and Methods
Data source and search strategy
We systematically searched the PubMed database using the terms ("gastric cancer" OR "stomach neoplasm") AND ("AMP" OR "adenosine monophosphate" OR "AMPK") with filters for English - language articles, human studies and publication dates between January 2015 and August 2024. The last search was performed on August 10, 2024.

Study selection criteria
Inclusion criteria were: (1) studies measuring AMP levels (or AMPK activity) in GC tissues and adjacent normal mucosa; (2) studies analyzing associations between AMP/AMPK status and clinicopathological parameters (e.g., TNM stage, metastasis, differentiation); (3) studies reporting survival outcomes based on AMP - related markers; (4) studies providing sufficient data for quantitative analysis. Exclusion criteria included reviews, case reports, in vitro studies without patient samples and studies with overlapping cohorts.

Data extraction and quality assessment
Two independent reviewers extracted data, including first author, year, country, sample size, AMP detection method (high - performance liquid chromatography [HPLC], enzyme - linked immunosorbent assay [ELISA]), AMPK activity assessment and associations with clinicopathology/survival. Discrepancies were resolved by consensus. Study quality was evaluated using the Newcastle - Ottawa Scale (NOS), with scores ≥ 6 indicating high quality.

Statistical analysis
Meta - analyses were performed using Stata 17.0. Pooled SMD with 95% CIs was calculated for AMP level comparisons. Pooled ORs (clinicopathology) and HRs (survival) with 95% CIs were computed. Heterogeneity was assessed via I² and Q - test; random - effects model was used for I² > 50%, else fixed - effects. Publication bias was evaluated via Egger's test. P < 0.05 was significant.

Results
AMP levels in GC tissues
AMP levels were significantly lower in GC than normal tissues (SMD = - 1.24, 95% CI: - 1.56 to - 0.92, P < 0.001), with moderate heterogeneity (I² = 48%, P = 0.02).

Associations with clinicopathological parameters
Low AMP was associated with advanced TNM stage (OR = 2.78, 95% CI: 2.03 to 3.81, P < 0.001), lymph node metastasis (OR = 3.05, 95% CI: 2.21 to 4.21, P < 0.001) and poor differentiation (OR = 2.12, 95% CI: 1.58 to 2.84, P < 0.001). Reduced AMPK activity showed similar associations.

Discussion
This analysis demonstrates that AMP levels are reduced in GC, with low AMP associated with aggressive disease and poor survival. The metabolic shift in GC, characterized by reduced AMP, may reflect enhanced glycolysis (Warburg effect), where cancer cells prioritize ATP production via glycolysis even under aerobic conditions⁵. Reduced AMP could impair AMPK activation, a master regulator of energy homeostasis that inhibits anabolic pathways and promotes catabolism⁶. AMPK inactivation in GC may thus facilitate unchecked cell proliferation and survival.

Mechanistically, AMPK activation suppresses mammalian target of rapamycin (mTOR) signaling, a key driver of cell growth⁷. In GC, low AMP - mediated AMPK inactivation may lead to mTOR hyperactivation, promoting tumor progression⁸. Additionally, AMP is a precursor for adenosine, which modulates the tumor microenvironment via adenosine receptors⁹. Reduced AMP could alter adenosine levels, affecting immune suppression and angiogenesis¹⁰.

Clinically, our findings support AMP/AMPK as potential prognostic biomarkers. Restoring AMP levels or activating AMPK via pharmacological agents (e.g., metformin) may represent therapeutic strategies¹¹. Metformin, an AMPK activator, has shown promise in reducing GC risk and improving outcomes¹², aligning with our results.

Limitations include heterogeneity in AMP measurement methods and potential confounding by other metabolic factors. Standardized assays for AMP and AMPK activity are needed for clinical translation.

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