A rapid increase in colorectal cancer (CRC) incidence has been observed worldwide; CRC rates nearly doubled between 2002 and 2018 due to a shift in lifestyles and diet [1
]. Notably, CRC is the second most prevalent cancer in Asian countries, such as South Korea [5
]. Regarding diet, beverage intake, including tea, increased threefold over a decade in Korea [7
]. Among the variety of teas, green tea may have beneficial effects on CRC due to its polyphenol content [8
]. Moreover, green tea may influence multiple stages of carcinogenesis by reducing antioxidant capacity and preventing inflammation [10
]. Although experimental studies have demonstrated that green tea strongly contributes to a decreased risk of CRC, previous epidemiological studies have reported inconsistent results [12
]. A recent meta-analysis of 12 case-control studies and 17 cohort studies with 1,642,007 participants identified an inverse association between the risk of CRC and green tea consumption [12
]; however, there were no such associations in a Chinese prospective cohort study [13
] and an Australian case-control study [14
]. Furthermore, the evidence linking CRC with tea consumption was classified as limited [15
Both green tea intake and lifestyle factors likely have essential roles in colorectal carcinogenesis. A number of health-related factors, such as body mass index (BMI), alcohol consumption, physical activity, smoking and the dietary inflammatory index (DII), have been associated with CRC risk [16
]. Although some of the investigated factors were found to be related to green tea consumption [19
], no studies have examined the protective effect of green tea intake considering lifestyle factors on CRC risk in South Korea. Furthermore, the variable results of epidemiological studies on the risk of CRC with green tea intake might be the result of numerous lifestyle factors.
Thus, we examined whether green tea consumption was associated with a lower risk of CRC. Additionally, we determined the interactions between CRC and lifestyle factors and how the risk of CRC was altered by the interaction between green tea consumption and lifestyle factors.
In this case-control study, green tea consumption and lifestyle factors contributed to the risk of CRC both independently and mutually. Overall, high green tea consumption, with or without considering lifestyle factors, decreased the risk of CRC. However, regarding moderate green tea intake, different risk patterns were observed depending on healthy and unhealthy lifestyles. In particular, an increased risk of CRC was shown among ever-smokers, ever-drinkers and the high-inflammatory diet group. The protective effect of green tea on the risk of CRC varied according to lifestyle factors and was likely to be stronger in rectal cancer patients than in colon cancer patients.
The effects of green tea consumption on CRC risk remain inconsistent. In the present study, we found that high green tea intake was associated with a decreased risk of overall CRC, as shown in previous studies [12
]. Additionally, in agreement with previous evidence [25
], the protective effects of green tea were likely substantial among those with an unhealthy lifestyle in this study. Recently, a meta-analysis of 29 studies from Asia, Europe, Australia and America with 1,642,007 participants examining the association between the risk of CRC and overall tea intake in stratified analyses revealed an inverse association among green tea consumption (OR 0.87; 95% CI 0.43–0.98), female sex (OR 0.86; 95% CI 0.78–0.94) and rectal cancer (OR 0.91; 95% CI 0.85–0.99) [12
]. Green tea extract can impair key transcription factors in human colon cancer cell lines [26
] and reduce gene expression in rectal cancer cells in vitro [11
]. However, a borderline modest positive association between tea consumption (not herbal) and colon cancer was reported in a pooled analysis of 13 prospective cohort studies conducted in North America and Europe relative risk (RR) for an increase of 250 g/day, 1.04; 95% CI 1.00–1.07) [27
]. No such associations between green tea consumption and CRC risk by anatomical location were observed after adjusting for potential confounders in a Chinese prospective cohort study [13
] or an Australian case-control study [14
]. However, these studies were conducted among participants who mostly did not consume green tea (nearly 85% of the participants were not green tea drinkers) [14
] or those with an already healthy lifestyle, such as women who do not smoke or drink alcohol [13
], suggesting that in addition to high green tea consumption, lifestyle factors could have a substantial principal role in CRC incidence.
High BMI and physical inactivity were independent risk factors for CRC in this study; physical activity was the strongest among the investigated health-related factors associated with CRC by anatomical site. Several previous studies have found that a variety of health-related factors, such as elevated fasting glucose, high total cholesterol, no use of postmenopausal hormones, no use of aspirin, no cancer screening, and being tall were associated with an increased risk of CRC [19
]. In the Physician’s Health Study, age, smoking and daily alcohol use were risk factors for colon and rectal cancer [29
]. In the Shanghai Women’s Health Study, age, BMI, waist-to-hip ratio, physical activity, red meat intake and vegetable and fruit intake were identified as risk factors for overall CRC [19
]. Interestingly, Yang et al. [19
] reported that interactions between green tea consumption and lifestyle factors were observed but were not significant; the risk of CRC among regular green tea drinkers was substantially reduced compared with that among non-drinkers, but only in participants who had an unhealthy lifestyle (i.e., stratified by physical activity as yes, RR 0.64; 95% CI 0.38–1.07, or no, RR 0.52; 95% CI 0.31–0.88; p
for interaction = 0.57). In the present study, we observed significant interactions of green tea consumption with tobacco smoking, alcohol consumption and a high DII (data not shown). Moreover, high green tea intake was associated with a decreased risk of CRC, but an inconsistent risk depending on lifestyle factors was found in the group of moderate green tea intake, similar to previous findings [25
Although a dose response association between green tea intake and the risk of CRC was examined in previous epidemiological studies [12
], we found different risk patterns for CRC and the amount of green tea consumption depending on smoking and drinking status and a high-inflammatory diet. High green tea consumption decreased the risk of CRC, but moderate green tea consumption increased the risk of CRC in ever-smokers, ever-drinkers and the high-DII group. In never-smokers, never-drinkers and the low-DII group, high green tea consumption also had a protective effect, but moderate consumption had no effect. Similarly, a Chinese hospital-based case-control study [34
] reported inconsistent results; tea consumption roughly decreased oral cancer risk. However, in the analysis of the joint effects of smoking, alcohol consumption and tea consumption considering five categories (zero and quartile one to four), the highest cancer risk was shown in the middle category compared to the other categories. There is no evidence of the protective effect of green tea intake interacting with tobacco smoking and alcohol intake on CRC. At most, three likely explanations for this finding could be as follows. First, each lifestyle factor (smoking, alcohol consumption and a high-inflammatory diet) might attenuate the protective effect of green tea on CRC. It is clear that the examined factors are known to be associated with predispositions to various diseases, including cancer [22
]. Furthermore, the synergistic effect between alcohol and tobacco in cancer has been reported [34
]. In this study, nearly 70% of the ever-drinkers were ever-smokers (data not shown), suggesting that the synergistic effect possibly already modified the true association between health-related factors and CRC. Second, the temperature of tea, age at tea-drinking initiation, concentration of tea consumed and duration of tea consumption, which are known as modifiable factors on cancer risk [34
], were not considered in this study. Third, the amount of green tea consumption in the second tertile (maximum, 21.28 g/day; median, 5.08 g/day) might be insufficient to identify an association with the risk of CRC. Based on the evidence regarding the concentration of catechins in green tea [37
], it could be speculated that nearly 4.26 mg to 8.51 mg of catechins were consumed by the patients in the second tertile of green tea consumption. However, Bettuzzi et al. [38
] showed that the efficacy of green tea on reducing premalignant prostate cancer lesions was due to catechins at 600 mg/day. Future studies are needed to clarify the dose response association between green tea consumption and CRC.
The underlying mechanism of the protective effect of green tea considering lifestyle factors on CRC requires further investigation, but green tea consumption and lifestyle factors may contribute to the risk of CRC both independently and mutually. Green tea might modify the colorectal carcinogenic process through several intracellular and extracellular processes, such as antioxidant activity, inflammation reduction, gut microbiota alterations, enzymatic inhibition in lipid or glucose metabolism and epigenetic changes [10
]. Recent animal studies have demonstrated that green tea extract can inhibit the occurrence and formation of precancerous lesions in the colon [8
]. In particular, the protective effect of green tea was found to be more effective in a group of mice fed a Western diet, which was high in fat and simple sugars, than in a group of mice fed a control diet [40
]. Furthermore, experimental studies have shown that a green tea polyphenol, epigallocatechin-3-gallate (EGCG), suppresses the activity of colorectal cancer stem cells [9
], thereby leading to the regulation of cellular proliferation, differentiation and apoptosis, especially through the Wnt signaling pathway [9
]. Additionally, EGCG modulates a number of mRNAs and proteins in colorectal carcinogenesis [26
]. However, the protective effect of green tea on CRC risk could be modified by environmental factors. Cigarettes contain more than 60 carcinogenic chemicals, and the risk of CRC may differ based on an individual’s genetic susceptibility to cigarette smoke [43
]. With respect to alcohol consumption and an unhealthy diet [41
], the interaction of environmental factors with gene polymorphisms could affect the association with the risk of CRC. Moreover, the anatomical site may affect the protective effect of green tea considering lifestyle factors. In the present study, a similar pattern of the protective effect of green tea and lifestyle factors on CRC was found for rectal cancer but not colon cancer. Because the colon and rectum differ in their physiologically multifunctional processes, such as bile acid metabolism, enzyme activity and microbiota composition, environmental factors and green tea intake may have different effects on colorectal carcinogenesis due to the anatomical site [42
]. In particular, a lower level of Bifidobacterium, which is known to protect the gut microbial environment, was found in patients with rectal neoplasms [47
]. Moreover, a case-control study [24
] and a meta-analysis [12
] also reported inverse associations of green tea and total tea intake, respectively, with CRC risk that were confined to rectal cancer. However, the evidence is limited, warranting further studies on any related mechanisms.
The protective effect of high green tea consumption on the incidence of CRC might be helpful for individuals with unhealthy lifestyle habits, such as alcohol or tobacco use. Additionally, public health interventions to promote both an increased intake of green tea and adherence to a healthy lifestyle to reduce the risk of CRC should be considered. Nevertheless, this study had several limitations that should be noted. First, on the basis of the case-control condition, this study might have potential information and selection bias; the controls may have been more health-conscious than the cases. This factor may result in an overestimated association between green tea consumption and CRC. Second, residual confounding should be mentioned; it likely exists to distort the true association between green tea intake and the risk of CRC. Third, the information on green tea might not be sufficient to evaluate the actual amount of green tea intake because our database did not have any green tea extract information, and the levels of bioactive compounds in green tea vary by season, climate and tea processing conditions [37
]. Fourth, because this study included only the Korean population, this result cannot be generalized; thus, it should be interpreted with caution.