We conducted this study to examine the relation between expression of PPARG (the official symbol for peroxisome proliferator-activated receptor-γ) and patient survival in 470 patients with stage I-IV colorectal cancer. We have shown that PPARG expression is independently associated with good prognosis in colorectal cancer. We have been able to demonstrate that this relation did not appear to be significantly modified by tumor stage or any of the other clinical features and tumoral molecular characteristics. Furthermore, our resource of a large number of colorectal cancers derived from the two independent, prospective cohort studies has enabled us to precisely estimate the frequency of colorectal cancers with PPARG expression, and provided us with robust statistics in survival analysis. Our results suggest that PPARG expression in colorectal cancer is independently associated with low mortality, and marks colorectal cancer with indolent biological behavior.
Examining molecular alterations is important in cancer research.40-46
In particular, determining status of microsatellite instability (MSI), the CpG island methylator phenotype (CIMP) and LINE-1 hypomethylation in colorectal cancer is increasingly important, because these molecular characteristics refect genomic and epigenomic status of cancer cells, and have been related with patient survival in colon cancer.19, 21, 23, 24
In addition to examining status of CIMP, MSI and LINE-1 hypomethylation, we assessed various molecular variables potentially related with PPARG and/or energy balance, including fatty acid synthase (FASN), cyclooxygenase-2 (COX-2), p53, p21, KRAS, BRAF
. Thus, unlike other studies, we were able to evaluate the independent effect of PPARG on patient survival after controlling for those related molecular events.
A role of PPARG in colorectal cancer has been controversial. Animal models generated by different methods show different effects of PPARG. Genetic models with APC mutations suggest that PPARG promote tumorigenesis.10-12
On the contrary, colon tumors induced by carcinogens can be suppressed by thiozolidinedione (TZD) based PPARG agonists, suggesting a tumor-suppressor role of PPARG.4, 13
A large epidemiologic study of a diabetic population suggests that thiozolidinedione usage may reduce the risk of a number of cancers including lung, colon and prostate.47
Various studies have shown the effect of PPARG ligands on normalization of cell cycle progression and cellular differentiation.8, 9, 14
It is proposed that PPARG could be a conditional tumor suppressor or conditional oncogene that modulates the tumor pathogenesis depending on cellular conditions, tissue types, or genetic background of individuals.2
Nonetheless, our current data suggest that PPARG expression may mark an indolent subset of colorectal cancers.
Excess energy balance, obesity and lack of exercise have been linked to increased risks of a variety of human cancers including colorectal cancer.48, 49
PPARG is one of potential molecules that link between energy balance, cellular metabolism and cancer pathogenesis. PPARG has been shown to play an important role in the control of gene expression linked to a variety of cellular processes.1
Activation of PPARG improves insulin sensitivity through a combination of metabolic actions, including partitioning of lipid stores and the regulation of metabolic and inflammatory mediator adipokines.1
Thus, we could hypothesize that there might be an interactive effect of PPARG expression and energy balance (or related tumoral molecular events) on tumor aggressiveness. However, we did not show any significant interaction of PPARG with patient body mass index (BMI), FASN expression or PIK3CA
mutation in terms of patient survival. Nonetheless, it is still possible that energy balance may differentially influence the occurrence of colorectal cancer according to PPARG expression. We await future studies that examine the effect of energy balance on the occurrence of PPARG-positive or negative tumors.
In our dataset, compared to PPARG-negative cases, PPARG-positive cases were more likely to be diagnosed in 1995 or after. This might have been due to poor antigenicity of PPARG in older specimens. However, when we examined the strata of “year of diagnosis” and a potential interaction between PPARG and “year of diagnosis”, “year of diagnosis” did not significantly alter the relation between PPARG and patient survival (p for interaction = 0.80; see ). This suggests that misdiagnosis due to poor antigenicity, if any, did not substantially alter survival analysis results. Moreover, in our multivariate Cox regression analysis, we adjusted hazard ratio (HR) for clinical and tumoral characteristics, including year of diagnosis. Thus, any potential confounding effect of year of diagnosis on patient survival was controlled in our multivariate analysis model.
In our cohorts, data on cancer treatment were limited. Nonetheless, it is unlikely that chemotherapy use differed according to tumoral PPARG status, since such data were not available to patients or treating physicians. In addition, beyond cause of mortality, data on cancer recurrences were not available in these cohorts. Nonetheless, given the median survival for metastatic colon cancer was approximately 10 to 12 months during much of the time period of this study,50
colon cancer-specific survival should be a reasonable surrogate for cancer-specific outcomes.
In summary, our large cohort study suggests that PPARG expression is independently associated with good prognosis in colorectal cancer. Our findings may have considerable clinical implications, given that PPARG has been used as a drug target. Future studies are needed to confirm this association as well as to elucidate exact mechanisms by which PPARG affects tumor behavior.