Sun TF, Fan KX, Luo YX, Song J, Han ZX, Zhang XL. Relationship between uric acid and colon cancer risk: Dose-response analysis and mechanisms. World J Gastrointest Oncol 2025; 17(9): 107651 [DOI: 10.4251/wjgo.v17.i9.107651]
Corresponding Author of This Article
Xiao-Lan Zhang, Professor, Department of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Hebei Clinical Research Center for Digestive Diseases, No. 80 Huanghe Road, Yuhua District, Shijiazhuang 050000, Hebei Province, China. xiaolanzh@hebmu.edu.cn
Research Domain of This Article
Gastroenterology & Hepatology
Article-Type of This Article
Basic Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Teng-Fei Sun, Yu-Xin Luo, Jia Song, Xiao-Lan Zhang, Department of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Hebei Clinical Research Center for Digestive Diseases, Shijiazhuang 050000, Hebei Province, China
Teng-Fei Sun, Department of Gastroenterology, First Hospital of Qinhuangdao, Qinhuangdao 066000, Hebei Province, China
Ke-Xin Fan, Zhuo-Xiao Han, Department of Pulmonary and Critical Care Medicine, First Hospital of Qinhuangdao, Qinhuangdao 066000, Hebei Province, China
Author contributions: Sun TF was responsible for drafting the manuscript and analyzing the data; Sun TF and Fan KX conducted the majority of the experiments; Fan KX was responsible collecting the data; Fan KX and Han ZX contributed in statistical analysis; Luo YX provided a review and criticism of the statistical analysis; Song J provided interpretation of the data; Han ZX contributed in criticism of the design; Zhang XL was responsible for interpreting the results of the analysis, criticizing the statistical analysis, and revising the manuscript. All authors read and approved the final manuscript.
Institutional review board statement: This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of the First Hospital of Qinhuangdao, No. 2024W006-02.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: The datasets generated analyzed during the current study are available from the corresponding author on reasonable request.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Xiao-Lan Zhang, Professor, Department of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Hebei Clinical Research Center for Digestive Diseases, No. 80 Huanghe Road, Yuhua District, Shijiazhuang 050000, Hebei Province, China. xiaolanzh@hebmu.edu.cn
Received: March 28, 2025 Revised: May 3, 2025 Accepted: June 30, 2025 Published online: September 15, 2025 Processing time: 172 Days and 0.8 Hours
Abstract
BACKGROUND
Uric acid (UA), a key antioxidant metabolite, demonstrates dual roles in cancer. Unfortunately, studies on its role in colon cancer risk are uncommon, and the limited results are inconsistent.
AIM
To elucidate the association between UA and colon cancer risk and its mechanisms.
METHODS
Multivariate logistic regression analysis evaluated the association between UA levels and colon cancer risk. Non-linear relationships were illustrated using restricted cubic splines. The threshold effect was performed to identify cut-off points. Human colon cancer cell lines (HCT-116 and HT29) were exposed to UA for 48 hours. Cell viability was assessed via the cell counting kit-8 assay. The evaluation of cell migration involved wound healing and transwell migration assays. HCT-116 cells were exposed to 4 mg/dL UA for 48 hours. The impact of the subsequent treatment with a phosphoinositide 3-kinases (PI3K) agonist and UA was assessed.
RESULTS
After adjusting for potential confounders, an inverse association was observed between UA and colon cancer risk (odds ratio = 0.65, P < 0.05). A non-linear relationship was identified, with a 4.79 mg/dL cut-off point (P < 0.05). UA inhibited colon cancer cell proliferation and migration. These effects were mediated by the induction of reactive oxygen species and the suppression of the PI3K/protein kinase B/mammalian target of rapamycin pathway.
CONCLUSION
UA acts as a protective agent against colon cancer by inhibiting cell proliferation and migration through increased reactive oxygen species production and modulation of the PI3K/protein kinase B/mammalian target of rapamycin pathway.
Core Tip: This study, encompassing 2020 colon cancer cases and 6060 controls, revealed an inverse association between uric acid levels and the risk of colon cancer. To delve deeper into the underlying mechanisms, we conducted in vitro experiments using colon cancer cells. Our findings demonstrated that uric acid potently inhibits cell proliferation and migration. Mechanistically, these effects were mediated by the induction of reactive oxygen species and the suppression of the phosphoinositide 3-kinases/protein kinase B/mammalian target of rapamycin signaling pathway.
Citation: Sun TF, Fan KX, Luo YX, Song J, Han ZX, Zhang XL. Relationship between uric acid and colon cancer risk: Dose-response analysis and mechanisms. World J Gastrointest Oncol 2025; 17(9): 107651
Colon cancer, a significant global health concern, is the fifth most common malignancy worldwide, with over one million new cases annually[1]. Unfortunately, this disease tragically claims over 600000 lives each year[2]. Given its substantial impact on human health, there is a pressing need to delve deeper into its underlying mechanisms and develop effective prevention and treatment strategies. Although age, gender, and family history are recognized as non-modifiable risk factors, lifestyle choices like smoking, alcohol use, obesity, and red meat consumption can substantially affect the risk of colon cancer[3,4]. Since non-modifiable factors are inherently static, it is crucial to focus on identifying and addressing modifiable risk factors to mitigate the burden of this disease.
Metabolic dysregulation is a modifiable factor with significant implications for cancer prevention and control[5]. Uric acid (UA), a key metabolic intermediate and the body’s primary antioxidant, has been shown to inhibit cancer initiation and progression by modulating oxidative stress and antitumor immunity[6,7]. Numerous studies have also identified an inverse relationship between high UA levels and the risk of cancers such as lung, colorectal, and prostate[8-10]. Conversely, UA can contribute to carcinogenesis by inducing chronic inflammation and oxidative stress[7,11]. However, the role of UA in colon cancer remains unclear, with conflicting findings from previous studies. To address this knowledge gap, we conducted a population-based study. We treated colon cancer cells with UA to investigate its effects on malignant behaviors and explore the underlying mechanisms. Notably, the phosphoinositide 3-kinases (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway is crucial in colon cancer initiation, progression, metastasis, and drug resistance[12]. Therefore, we aimed to determine whether UA could modulate the malignant biology of colon cancer cells through this pathway.
MATERIALS AND METHODS
Study Population
This study selected patients hospitalized with colon cancer at the First Hospital of Qinhuangdao from January 2018 to December 2023. Inclusion criteria for the case group were: (1) 40 years old or above; (2) Postoperative pathological result of colon cancer without distant metastasis; and (3) No antitumor treatment undergone. Exclusion criteria included: (1) Concurrent cancer of other systems; (2) Acute or chronic kidney disease; (3) Use of UA-lowering medications; (4) Incomplete data; and (5) Admission to the intensive care unit for respiratory or circulatory failure. The control group consisted of individuals undergoing health examinations at the same hospital during the same period without colon cancer. Control group inclusion criteria required participants to be 40 years or older and have a colonoscopy confirming the absence of colon cancer. Exclusion criteria included: (1) Concurrent cancer of other systems; (2) Acute or chronic kidney disease; (3) Use of UA-lowering medications; and (4) Incomplete data.
Variables
Demographic characteristics such as age and gender were registered. Body mass index (BMI) was calculated as weight in kilograms divided by the square of height in meters (kg/m2). Past medical history was inquired about, including diabetes, hypertension, and a family history of cancer. Excessive smoking and drinking were also recorded. The participants’ laboratory results were noted; all samples were collected after fasting for 8 hours in the morning (blood samples from cancer patients were taken before any antitumor treatment). Levels of UA, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) were recorded.
Cell culture
Human colon cancer cell lines (HCT-116 and HT29), were obtained from the laboratory’s cell repository. Cells were maintained in RPMI-1640 medium (GibcoTM, Sigma Aldrich, NY, United States) with 10% fetal bovine serum (FBS) and 1% penicillin-streptomycin (Invitrogen, CA, United States) at 37 °C in a 5% CO2 incubator.
UA exposure
UA (Sigma Aldrich, St. Louis, MO, United States) was solubilized in 1 mol/L NaOH. A complete culture medium was prepared using RPMI-1640, 10% FBS, penicillin-streptomycin, and 8 mg/dL UA, and was neutralized to pH 7.2-7.4 with dilute HCl. The solution was passed through a 0.22 μm filter and kept at 4 °C. UA-containing culture media at concentrations of 2 mg/dL and 4 mg/dL were prepared by diluting the stock solution with RPMI-1640 complete medium. Finally, HCT-116 and HT29 colon cancer cells were exposed to UA concentrations of 0 mg/dL (control), 2 mg/dL, 4 mg/dL, and 8 mg/dL for 48 hours.
Proliferation assays
Colon cancer cells (2 × 103) were seeded in triplicate into each well of a 96-well plate and exposed to different UA concentrations. Following incubation, each well-received cell counting kit-8 reagent (BIMAKE, Houston, TX, United States) was further incubated for 2 hours at 37 °C. The absorbance was recorded at a wavelength of 450 nm.
Wound healing assays
Wound healing assays were performed using colon cancer cells seeded in a 24-well plate. A wound was introduced into the cell monolayer using a sterile 100-μL pipette tip after 24 hours. The cells were incubated in RPMI-1640 medium with different concentrations of UA. Wound closure was monitored daily for two days using a microscope (DMI1, Leica, Germany). Image J software (NIH, Bethesda, MD, United States) quantified the wound closure area.
Transwell migration assays
Transwell migration assays utilized 8.0 μm pore polycarbonate membrane inserts (Corning®, CLS3422-48EA, Sigma Aldrich, MO, United States) pre-coated with type I collagen. Colon cancer cells were placed in the upper chamber with serum-free RPMI-1640 medium and different UA concentrations. The lower chamber contained 600 μL of RPMI-1640 medium with 20% FBS as a chemoattractant. Cells that migrated through the membrane after 24 or 48 hours were fixed with methanol, stained with 0.1% crystal violet, and examined microscopically.
Measurement of reactive oxygen species
Cells were incubated with 10 μmol/L 2',7'-dichlorodihydrofluorescein diacetate (Invitrogen-Molecular Probes, CA, United States) for 20 minutes in the dark. After washing with phosphate buffered saline, reactive oxygen species (ROS) fluorescence was measured using confocal microscopy (Nikon C2, Japan). Each experiment was repeated at least three times.
Western blot analysis
Cells were lysed using a lysis buffer supplemented with protease inhibitors (Beyotime Biotechnology, Shanghai, China). Nuclear proteins were isolated using a Beyotime Biotechnology commercial kit (Shanghai, China). Protein concentrations were measured, and equivalent protein quantities were denatured, subjected to sodium-dodecyl sulfate gel electrophoresis, and transferred onto nitrocellulose membranes. Protein bands were identified with an enhanced chemiluminescence kit (Beyotime Biotechnology, Shanghai, China) and quantified against β-tubulin using the Fusion FX5 image acquisition system (Vilber Lourmat, Paris, France). All experiments were conducted in triplicate.
Statistical analysis
Based on data distribution normality, group comparisons were conducted using ANOVA or the Kruskal-Wallis test. The χ2 test was used to compare categorical data. Risk factors were evaluated using logistic regression analysis. We also performed stratified analyses by age, gender, BMI, and other covariates, with interaction analyses across these strata. Moreover, we applied Benjamini-Hochberg correction to compare odds ratio (OR) values in interaction analyses. Nonlinearity was assessed through restricted cubic spline plots. Threshold effect analysis was also used to identify threshold points. Notably, the threshold was identified using a two-piecewise linear regression, iteratively testing all possible cut-points to minimize the residual sum of squares. The threshold was then determined through the likelihood ratio test. Finally, a P value of 0.05 or less was regarded as statistically significant. Statistical analyses were conducted through R software (v4.1.0), EmpowerStats (http://www.empowerstats.com), and GraphPad Prism (v9.0).
RESULTS
Basic characteristics of the population
This study initially included 2199 colon cancer patients in the case group. After excluding 126 individuals with incomplete data, 20 with kidney diseases, 15 with other cancers, and 18 admitted to the intensive care unit, the case group comprised 2020 participants. Initially, 6566 subjects without colon cancer were included in the control group. After excluding 21 with other cancers, 202 with kidney diseases, and 283 with incomplete data, 6060 were included. Subjects were enrolled into four groups according to UA concentration (mg/dL): Q1 group (UA, 0.67-4.40 mg/dL), Q2 group (UA, 4.41-5.41 mg/dL), Q3 group (UA, 5.42-6.29 mg/dL), and Q4 group (UA, 6.30-15.14 mg/dL). Significant differences were observed among the four groups regarding age, gender, smoking and drinking history, family history, BMI, diabetes, hypertension, HDL-C, and LDL-C (P < 0.05) (Table 1).
Table 1 Comparison of general data among different groups, n (%).
Using the presence of colon cancer as the dependent variable, UA was included as an independent variable in logistic regression model 1. UA was revealed to be a protective factor for colon cancer [OR = 0.69, 95% confidence interval (CI): 0.66-0.72]. In logistic regression model 2, which included UA, age, and gender, UA was protective (OR = 0.65, 95%CI: 0.62-0.68). After adjusting for confounding factors such as age, gender, BMI, smoking and drinking history, family history, diabetes, hypertension, LDL-C, and HDL-C in model 3, UA remained protective (OR = 0.65, 95%CI: 0.61-0.69) (Table 2).
Table 2 Uric acid and colon cancer risk in different models.
Interaction analysis was conducted between UA and variables such as age, gender, BMI, diabetes, and hypertension. The findings revealed notable interactions between UA, age, and hypertension (P < 0.05). In the population under 60, the OR for UA was 0.54 (95%CI: 0.49-0.60), while in the population aged 60 and above, the OR was 0.71 (95%CI: 0.67-0.76). Among individuals with hypertension, the OR for UA was 0.61 (95%CI: 0.57-0.65). In those without hypertension, the OR was 0.81 (95%CI: 0.73-0.90). In all these different subpopulations, UA remained a protective factor for colon cancer (P < 0.05) (Figure 1A).
Figure 1 Association between uric acid and colon cancer risk.
A: Forest plot of interaction analysis; B: Nonlinear relationship between uric acid and colon cancer risk. BMI: Body mass index; OR: Odds ratio; CI: Confidence interval; RCS: Restricted cubic spline; UA: Uric acid.
Nonlinearity detection and threshold effect analysis results
Restricted cubic spline analysis revealed a significant non-linear association between UA and colon cancer risk (P < 0.05). In these groups, the risk of colon cancer declined with increasing UA levels, with this trend being more pronounced at initial levels (Figure 1B). Threshold effect analysis revealed that in the overall population, the decreasing trend of colon cancer risk with increasing UA levels was more pronounced when UA < 4.79 mg/dL; in males, this trend was more evident when UA < 4.69 mg/dL, and in females when UA < 4.83 mg/dL (Table 3).
Table 3 Threshold effect analysis in different gender groups.
UA treatment significantly decreased the viability of HCT-116 and HT29 colon cancer cells in a dose-dependent manner after 48 hours. Figure 2 illustrates the cell morphology of colon cells following intervention with different concentrations of UA. Subsequently, 10 mg/dL UA induced the shrinkage and deformation of colon cancer cells. Figure 3 shows that 10 mg/dL UA significantly reduced the viability of colon cancer cells. It could also be seen that 10 mg/dL UA had cytotoxicity to colon cancer cells. Therefore, we chose 2 mg/dL UA, 4 mg/dL UA, and 8mg/dL UA for subsequent experiments. Figure 3 illustrates a significant decline in cell viability with rising UA concentrations (0 mg/dL > 2 mg/dL > 4 mg/dL) (P < 0.05). There was no significant difference in cell viability between the UA treatment groups of 4 mg/dL and 8 mg/dL (P > 0.05).
Figure 2 Cell morphology of colon cells after intervention with different concentrations of uric acid.
A: Cell morphology of HCT-116 cells after intervention with different concentrations of uric acid; B: Cell morphology of HT29 cells after intervention with different concentrations of uric acid.
Figure 3 Effect of uric acid on the proliferation and migration of HCT-116 and HT29 cells.
A: Effect of uric acid (UA) on the proliferation of HCT-116 cells; B and C: Effect of UA on the migration of HCT-116 cells detected by wound assay; D: Effect of UA on the migration of HCT-116 cells detected by transwell assay; E: Effect of UA on the proliferation of HT29 cells; F and G: Effect of UA on the migration of HT29 cells detected by wound assay; H: Effect of UA on the migration of HT29 cells detected by transwell assay. aP < 0.05; NS: Not statistically significant. UA: Uric acid.
UA inhibited colon cancer cell migration
HCT-116 and HT29 human colon cancer cells were exposed to varying UA concentrations for 48 hours. Transwell migration assays demonstrated that UA markedly reduced cell migration dose-dependently. The migration distance significantly decreased as UA concentrations increased (0 mg/L > 2 mg/L > 4 mg/L, P < 0.05). Although a slight decrease in migration was observed at 8 mg/L compared to 4 mg/L, this difference was not statistically significant (P > 0.05). Thus, UA inhibits the metastasis of colon cancer cells by suppressing cell migration (Figure 3).
UA modulates ROS levels and the PI3K/Akt/mTOR signaling pathway
Impact of UA on ROS levels in HCT-116 cells: ROS generation is a hallmark of cancer cell transformation. Figure 3 demonstrates that a 48-hour treatment with 4 mg/dL UA significantly elevated ROS fluorescence intensity relative to the control group (P < 0.05) (Figure 4).
Figure 4 Effect of uric acid on reactive oxygen species in HCT-116 cells.
A: Reactive oxygen species (ROS) expression in HCT-116 cells before uric acid intervention; B: ROS expression in HCT-116 cells after uric acid intervention for 48 hours; C: Comparison of different groups of ROS expression. aP < 0.05 vs 0 mg/dL group or between groups; NS: Not statistically significant, compared with the 0 mg/dL group. ROS: Reactive oxygen species; DAPI: 4'-6-diamidino-2-phenylindole.
Effects of PI3K activation on HCT-116 cells proliferation and migration: HCT-116 cells underwent a 48-hour treatment with 4 mg/dL UA. Three groups were established: A control group (0 mg/dL UA), a group treated with 4 mg/dL UA, and a group treated with 4 mg/dL UA plus the PI3K activator 740Y-P. Figure 5 demonstrates that the PI3K activator had no impact on the cell morphology of HCT-116 cells. Furthermore, Figure 6 also revealed that the PI3K activator mitigated the inhibitory effects of UA on HCT-116 cell proliferation and migration.
Figure 6 Effects of 740Y-P on the proliferation and migration of HCT-116 cells and the phosphoinositide 3-kinases/protein kinase B/mammalian target of rapamycin signaling pathway.
A: Effect of phosphoinositide 3-kinases activator 740Y-P on the proliferation of HCT-116 cells; B and C: Effect of 740Y-P on HCT-116 cell migration; D-F: Effect of 740Y-P on phosphoinositide 3-kinases/protein kinase B/mammalian target of rapamycin signaling pathway. aP < 0.05 vs 0 mg/dL group or between groups; NS: Not statistically significant vs 0 mg/dL group. PI3K: Phosphoinositide 3-kinases; p-PI3K: Phosphorylation-phosphoinositide 3-kinases; AKT: Protein kinase B; p-AKT: Phosphorylation-protein kinase B; mTOR: Mammalian target of rapamycin; p-mTOR: Phosphorylation-mammalian target of rapamycin.
Impact of PI3K agonists on the PI3K/Akt/mTOR signaling pathway: Our results demonstrate that adding 740Y-P to the 4 mg/dL UA group significantly increased the phosphorylation of PI3K, Akt, and mTOR (P < 0.05). Simultaneously, the total protein levels of these kinases remained unchanged (P > 0.05) (Figure 6). Importantly, these results indicate that UA inhibits colon cancer HCT-116 cells’ viability and metastasis by inducing ROS production and suppressing the PI3K/Akt/mTOR signaling pathway.
DISCUSSION
UA, the end product of purine metabolism, is derived from dietary intake and endogenous production. Maintaining normal UA levels prevents various health conditions, including diabetes, dyslipidemia, and cardiovascular diseases[13-15]. As the most abundant antioxidant in the human body, UA possesses potent free radical scavenging activity (up to 60%) in human blood, suggesting its potential role in mitigating aging and cancer. Notably, these are often associated with oxidative stress and free radical damage[16,17]. Consequently, the role of UA in cancer has garnered increasing interest. Given that UA can be transported from the bloodstream to the intestine, there is a potential link between UA excretion and gastrointestinal health. Around two-thirds of UA is eliminated via urine, with the rest eliminated through the digestive system. However, the specific role of UA in colon cancer remains understudied.
Our findings indicate that UA protects against colon cancer (OR = 0.65, 95%CI: 0.61-0.69). Previous research on the link between UA and colon cancer has produced mixed outcomes, with some studies indicating a protective effect of UA. For example, Taghizadeh et al[18] found that UA levels were a protective factor linked to a reduced mortality risk for colon cancer. Additionally, a Mendelian randomization study by Lee and Nam[9] demonstrated a negative association between UA and colorectal cancer. Other studies examining the link between UA and cancer have reported similar findings. For instance, a meta-analysis by Xue et al[19] found that high UA levels may lower breast cancer risk in women, indicating a protective effect. Low serum UA levels also act as a risk factor for prostate cancer[8]. Additionally, Hsueh et al[20] found that low UA levels in male laryngeal squamous cell carcinoma patients are linked to poor prognosis. In contrast, high UA levels correlate with improved 5-year overall survival, disease-free survival, and cancer-specific survival. These results support previous research emphasizing UA’s significant role in cancer inhibition. However, some studies have reported conflicting results. Li et al[21] found a positive correlation between UA levels and colon cancer incidence. Similarly, Liu et al[22] indicated that elevated UA levels and gout are linked to a higher risk of colon cancer. Moreover, a cohort study using the UK Biobank database by Mi et al[23] elucidated a U-shaped association between UA levels and colon cancer incidence. In contrast, the Kühn et al[24] study found no link between UA levels and the risk of colon cancer. Regarding discrepancies with previous studies, we have identified several key methodological differences that may account for these variations, including: (1) Distinct study populations; (2) Different analytical approaches; and (3) Variations in adjusted confounding factors. More importantly, our study featured several methodological strengths that enhance the reliability of our conclusions: A substantially larger sample size of colorectal cancer patients (n = 2020) compared to previous investigations, comprehensive stratified analyses across relevant subpopulations, and rigorous threshold effect analyses.
Previous studies have yielded inconclusive results regarding the impact of UA on colon cancer. Thus, our study explores the cellular effects of UA on human colon cancer HCT-116 and HT29 cells across different concentrations. This data lays a foundation for further clinical research. Notably, our investigation is the first to explore how UA influences the malignant behavior of colon cancer cells on a cellular level. We provide compelling evidence that UA inhibits both the proliferation and migration of these cancer cells. Our findings showed that UA significantly reduced the proliferation and migration of both cell lines in a dose-dependent manner (P < 0.05). Although higher UA concentrations (4 mg/dL to 8 mg/dL) showed more pronounced inhibitory effects, the difference was not statistically significant (P > 0.05). These in vitro findings align with our clinical observations. As shown in Figure 1B, the inhibitory effect of UA on colon cancer risk plateaued beyond 4.79 mg/dL. Notably, no significant difference between 4 mg/dL and 8 mg/dL UA was observed in suppressing colon cancer cell growth, suggesting a potential saturation effect.
Several studies have established a non-linear relationship between UA levels and cancer. Consistent with our research findings, Yan et al[25] demonstrated a negative correlation between UA and prostate cancer. Furthermore, among participants without hypertension, the association between UA levels and prostate cancer exhibited a U-shaped curve. Huang et al[26] also revealed a U-shaped relationship between UA levels and the risk of liver cancer in males. These findings collectively suggest that UA can exert unique effects depending on its concentration. Although the patterns of non-linear relationships observed in previous studies may not entirely align with those in our current research, they all corroborate the notion that varying UA concentrations yield differential effects.
Since UA concentrations are often linked to an increased risk of cardiovascular and cerebrovascular diseases, it follows that, despite the negative correlation between UA levels and the risk of colon cancer, an excessively high UA concentration is not desirable. Consequently, we conducted a threshold effect analysis to elucidate the threshold further. Figure 1B illustrates a non-linear relationship between UA levels and colon cancer risk, where increasing UA concentrations up to 4.79 mg/dL correspond to an apparent decreased trend, transitioning to a stabilized trend. Jiang et al[27] identified a non-linear J-shaped association between UA levels and stroke risk. Specifically, the lowest risk of stroke was observed at a UA level of 4.2 mg/dL, near the threshold of 4.7 mg/dL identified in our current study. Furthermore, a cohort study targeting the Chinese population revealed that among women with baseline UA levels below 4.30 mg/dL, an elevated risk of cardiovascular disease-related mortality was observed. Conversely, women with baseline UA levels ranging from 4.30 to 4.72 mg/dL exhibited a relatively lower risk of cardiovascular disease-related death. Notably, this finding is analogous to our study’s 4.67 mg/dL threshold[28].
We selected a concentration of 4 mg/dL UA for our intervention based on the observation that colon cancer risk decreased with increasing UA levels. As such, this trend plateaued at concentrations exceeding 4.79 mg/dL. Importantly, we do not advocate clinically elevating UA levels to higher concentrations. High UA levels have been associated with increased mortality risk, which could negatively impact patient outcomes. A study by Hu et al[29] on United States adults elucidated a U-shaped association between UA levels and all-cause and cancer-specific mortality, with inflection points at 6 mg/dL for males and 4 mg/dL for females. Furthermore, a study involving 127771 elderly individuals in Taipei found that serum UA levels below 4 mg/dL and above or equal to 8 mg/dL were independently linked to higher risks of cardiovascular and all-cause mortality compared to UA levels of 4-5 mg/dL[30].
UA is closely associated with ROS. Physiological levels of ROS are crucial for cellular signaling; however, excessive ROS can be harmful, leading to diseases such as cardiovascular and neurological disorders, diabetes, and cancer[31-34]. Elevated ROS levels can also induce oxidative DNA damage, leading to mutations and cellular transformation. Research has consistently shown that ROS influences gene expression, stimulates cell proliferation, and contributes to tumorigenesis and progression. However, excessive ROS levels can cause oxidative damage to cellular macromolecules, including proteins, nucleic acids, and lipids, which may inhibit cancer development and progression. Numerous anticancer drugs exert their therapeutic effects by increasing ROS production to eliminate cancer cells and overcome drug resistance[35-38]. As shown in Figure 4, our findings indicate that UA promotes ROS generation. The reversal of UA’s inhibitory effects on colon cancer cell proliferation and migration by ROS scavengers indicates that UA influences these cells by modulating ROS levels.
To directly investigate the relationship between the PI3K/Akt/mTOR signaling pathway and UA’s effects on colon cancer, HCT-116 cells were pretreated with the PI3K agonist 740Y-P and co-treated with UA. Western blot analysis demonstrated that pretreatment with 740Y-P counteracted UA’s suppression of HCT-116 colon cancer cell proliferation and migration and reversed UA-induced alterations in phosphorylated-PI3K, phosphorylated-Akt, and phosphorylated-mTOR expression (Figure 6). These findings indicate that UA impedes colon cancer cell proliferation and migration by promoting intracellular ROS accumulation and suppressing the PI3K/Akt/mTOR pathway. PI3K, an intracellular lipid kinase, regulates cell proliferation, differentiation, and survival. The PI3K/Akt/mTOR signaling pathway is often overexpressed in cancers, including colon cancer, significantly contributing to cancer development by influencing proliferation, apoptosis, and migration[39,40]. Notably, several anticancer medications have demonstrated the ability to suppress growth and proliferation and trigger autophagy-mediated cell death in cancer cells, such as colon cancer, by elevating ROS levels and suppressing the PI3K/Akt/mTOR signaling pathway[41-44]. These findings align with the roles of ROS and the PI3K/Akt/mTOR signaling pathway identified in our experiment.
CONCLUSION
This study is the first to demonstrate that UA suppresses HCT-116 colon cancer cell proliferation and migration by enhancing ROS production and inhibiting the PI3K/Akt/mTOR pathway. Thus, it is essential to sustain optimal UA levels. While low UA levels can benefit specific contexts, excessively low levels may have adverse effects. Due to the strong link between elevated UA levels and increased risk of cardiovascular and all-cause mortality, it is crucial to prevent excessive UA elevation. Therefore, a balanced approach is essential to keep UA levels healthy. Our experiments show that UA inhibits malignant behaviors in colon cancer cells, and clinical studies have established a threshold level. However, our study has recognized limitations, such as the inability of in vitro studies to fully reflect in vivo conditions. Therefore, further research is required to explore the connection between UA levels and colon cancer prognosis to determine the optimal UA level for reducing colon cancer risk and improving prognosis.
ACKNOWLEDGEMENTS
The authors thank research group on the correlation and mechanism of purine metabolism with colorectal cancer.
Footnotes
Provenance and peer review: Unsolicited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Oncology
Country of origin: China
Peer-review report’s classification
Scientific Quality: Grade B, Grade C, Grade C, Grade C
Novelty: Grade C, Grade C, Grade C, Grade C
Creativity or Innovation: Grade B, Grade C, Grade C, Grade C
Scientific Significance: Grade B, Grade C, Grade C, Grade D
P-Reviewer: Dabla PK; Jeong KY; Li XB S-Editor: Wu S L-Editor: A P-Editor: Guo X
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