Page 103 - JCTR-11-5

Journal of Clinical and
Translational Research Uric acid, CTGF genotype, and prostate cancer

1. Introduction cytokine with contextdependent tumorsuppressive and
tumorpromoting roles, is implicated in prostate cancer
Prostate cancer ranks as the second most frequently initiation and progression. 17,18 CTGF has been shown to
diagnosed cancer and the fifth leading cause of cancer- modulate TGFβ signaling, thereby influencing prostate
related deaths among men worldwide, with an estimated cancer pathogenesis. Notably, TGFβ levels are elevated in
19
1.46 million new cases and 396,000 deaths reported in hyperuricemic individuals and correlate positively with uric
2022. Despite its high prevalence and substantial impact on acid concentration. Taken together, these observations
1
20
health and quality of life, the underlying causes of prostate suggest that CTGF may modulate the relationship between
cancer remain largely unclear. Established risk factors uric acid and prostate cancer development.
include advancing age, family history, race or genetic
2
predisposition, a Western diet, and alcohol consumption. The aim of the present study was to determine whether
Identifying new, and particularly modifiable, risk factors the relationship between serum uric acid and prostate
and biomarkers is crucial for improving strategies for cancer incidence differs by CTGF genotype.
prevention, early detection, and treatment. 2. Methods
Uric acid, a by-product of purine metabolism, is a
known biomarker of inflammation and can be modified 2.1. Study cohort
by lifestyle changes. It has been studied for its potential The Kuakini Japan-Hawaii Cancer Study (Kuakini-
3-5
role in prostate cancer development. 6-15 However, its JHCS) is based on the Kuakini Honolulu Heart Program
association with prostate cancer risk remains inconclusive. (Kuakini-HHP) cohort. The Kuakini-HHP Examination 1
Some research suggests that elevated uric acid promotes was conducted between 1965 and 1968, recruiting 8,006
chronic inflammation and oxidative damage, thereby American men of Japanese ancestry aged 45–68 years, all of
facilitating tumorigenesis, and finds a positive association whom were residents of the Hawaiian island of Oahu. The
with prostate cancer risk. Gout, a condition associated Kuakini-JHCS was initiated during the third examination
6,7
with hyperuricemia, has been reported to elevate the risk of the Kuakini-HHP cohort, conducted between 1971 and
of prostate cancer. Other studies propose that uric acid 1974 (n = 6,860; age range 51–75 years), when the cancer
8
functions as an antioxidant, reducing oxidative stress and surveillance program was established. 21,22
inflammation, both of which contribute to carcinogenesis,
and report an inverse relationship between uric acid levels 2.2. Definition of risk factors and potential
and prostate cancer incidence. 9-11 Yet other investigations confounders
found no significant correlation between uric acid levels All variables in the present study were measured during the
and prostate cancer risk, implying that uric acid may not Kuakini-HHP Examination 1. The assay for serum uric acid
23
play a critical role in the pathogenesis of prostate cancer. 12-15 (non-fasting) was performed using an automatic colorimetric
One reason these studies have observed conflicting method (Technicon AutoAnalyzer Methodology N-13b)
associations between uric acid and prostate cancer is their with a phosphotungstic acid reagent. Further details can be
reliance on conventional epidemiological frameworks, found in our earlier publication. Hyperuricemia was defined
24
which typically treat exposures and outcomes as having as a serum uric acid level ≥7.0 mg/dL (≥0.416 mmol/L) at
simple, linear, and independent relationships. Such baseline, while levels below this threshold were classified
frameworks typically overlook nonlinear dynamics, as normouricemia. To assess the association of uric acid
especially the interactive effects that contribute to the concentrations with prostate cancer risk, we also categorized
characterization of biological systems. To address this participants into quartiles (Q1-Q4) based on their serum
limitation, we propose employing an integrative modeling uric acid concentrations. Gout, a condition associated with
approach that simultaneously incorporates genetic hyperuricemia, was self-reported at baseline.
susceptibility, uric acid levels, and their gene–environment Body mass index (BMI) was computed as weight
interactions. This approach would capture more of the in kilograms divided by height in meters squared.
underlying complexity and potentially reveal subtler Physical activity index (PAI) was quantified as metabolic
associations between uric acid and prostate cancer risk. output during a typical 24-h period by multiplying a
Connective tissue growth factor (CTGF), also known weighting factor by the reported number of hours spent
as cellular communication network factor 2 (CCN2), in five activity levels (no activity = 1.0, sedentary = 1.1,
is a secreted protein associated with the extracellular slight = 1.5, moderate = 2.4, and heavy = 5.0). Smoking was
25
matrix (ECM). CTGF interacts with multiple cell categorized as either a never smoker or a smoker (including
surface receptors, ECM components, and cytokines. past or current cigarette smoking). Pack-years of cigarette
16
Transforming growth factorβ (TGFβ), a pleiotropic smoking were computed for past and current smokers.

Volume 11 Issue 5 (2025) 97 doi: 10.36922/JCTR025260029