The literature search was performed using the PubMed, Science Direct, Scopus, and Cochran databases, and all related papers published from 2000 to 2022 were collected using the following keywords: “dietary fat or fatty acid or fat or lipid” and “ALOX or COX or prostaglandin-endoperoxide synthase or PTGS or cyclo-oxygenase or COX or arachidonic lipoxygenase or lipoxygenase” and “colorectal cancer or colon cancer or rectal cancer” and “polymorphism or genetic variation or genotype or SNP.” All the collected papers and their references were reviewed.

All studies that examined the interaction of colorectal cancer with ALOX and COX genes, studies concerning the relationship between the ALOX and COX gene polymorphisms, and studies on the interactions between colorectal cancer, ALOX and COX genes, and dietary fat were included in this study. Unrelated and non-English papers, the review studies, studies on the relationship between ALOX and COX with other cancers, and animal studies were excluded.

In this review study, the quality of the collected studies was assessed by four researchers (MG, HS, SA, and SD). In the case of having opposing ideas, other researchers (MH and HS) would be involved in reaching an agreement. After collecting the papers, all unrelated studies were excluded from the review process according to their titles and abstracts. Then, the full texts of the relevant articles were studied precisely. The standard quality assessment method of the ‘EPOC Risk of Bias Tool’ was applied to assess the quality of the methodologies (20). The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist (21) was used to extract the required data from the included studies. Finally, the data about the participants, intended comparisons, obtained results, and study planning (PICOS) were collected.

The process of including the appropriate studies is presented in Figure 1 . A total of 413 articles were collected in the primary search, of which 354 articles were excluded after the screening of their titles and abstracts. Also, 28 articles were excluded after reading the full texts. Finally, 31 articles qualified to be included in the review process. All articles were published from 2000 to 2022 and were related to the interactions between CRC, ALOX, and COX genes and fat intake. The main characteristics of the studies are presented in Tables 1 , 2 .

The primary function of ALOX is to convert arachidonic acid (AA) into hydroperoxyeicosatetraenoic acid (HPETE) and eventually leukotrienes, a class of paracrine hormones involved in the inflammatory response. For example, ALOX12 converts AA into 12-hydroperoxyeicosatetraenoic acid (12-HPETE), which is involved in the expression of pro-inflammatory cytokine genes such as tumor necrosis factor-α (TNF-α) (36). The role of the ALOX gene in inflammatory diseases and colorectal neoplasia has been frequently reported. For example, the arachidonate-5 lipoxygenase (ALOX5) and 12-lipoxygenase (ALOX12) played pro-carcinogenic roles in colorectal cancer (22). Additionally, overexpression of ALOX5 with its related downstream metabolites has been reported in other cancers such as breast, esophageal, pancreatic, and prostate cancers by stimulation of cell proliferation, tumor angiogenesis, and survival (37). Moreover, it has been reported that ALOX15 is associated with an increased risk of colorectal cancer, particularly in people with higher inflammatory factors (38). In another study, Ruan et al. examined the diagnostic and prognostic values of the ALOX gene family mRNA expression in 438 colon adenocarcinoma tumor samples and 41 adjacent tissue samples of Chinese patients by bioinformatics analysis. They showed that the expression level of ALOXE3, ALOX5, ALOX12, and ALOX12B was upregulated in colorectal tumor samples. Finally, they reported that ALOXE3 and ALOX12 might serve as potential independent prognostic indicators of colon adenocarcinoma (25). Thus, ALOX pathways in the AA metabolism process can be considered crucial pathways in the development of CRC ( Figure 2 ).

Notably, specific polymorphisms of the ALOX gene can affect the susceptibility to CRC. For instance, Goodman et al. assessed the effects of ALOX5 and ALOX12 gene polymorphisms on CRC in African-Americans and Caucasian patients. They found that the rs6413416 and rs4986832 polymorphisms of ALOX5 were associated with a decreased risk of CRC in Caucasians. They hypothesized that these polymorphisms could improve binding to the promoter region, leading to downregulation of ALOX5. In this way, they can lower the cancer risk by reducing enzymatic activity (8). However, the rs4986832 polymorphisms of ALOX5 had no association with the risk of colorectal polyps in Minnesota (24). Kleinstein et al. conducted a study on 2447 cases and 3133 controls regarding the effect of ALOX gene polymorphisms on the risk of CRC. The results showed that the rs2073438 polymorphism of ALOX 12 was related to a lower risk of rectal cancer (OR = 0.66, 95% CI: 0.42–1.04), while the rs4796535 and rs2619112 polymorphisms of ALOX15 were associated with an increased risk of rectal cancer (OR = 1.43, 95% CI: 1.03–1.97 and OR = 1.13, 95% CI: 0.85–1.55, respectively) (22). Moreover, a positive association was found between the ALOX12 rs1126667 polymorphism and a moderately increased risk of CRC (OR = 1.38, 95% CI: 1.09–1.74) (23). However, the association between rs1126667 polymorphism of ALOX12 and the risk of CRC has been reported in African-Americans and Caucasian patients (8). This discrepancy can be due to differences in ethnic or statistical power. A summary of studies on the association between ALOX polymorphisms and CRC is provided in Table 1 .

Prostaglandin H synthase, also known as cyclooxygenase and prostaglandin-endoperoxide synthase (PTGS), catalyzes the first step in the biosynthesis of all prostaglandins and prostacyclins by converting arachidonic acid to prostaglandin H (39). Two forms of human PTGS, PTGS1 and PTGS2 (COX1 and COX2), can be inhibited by non-steroidal anti-inflammatory drugs (NSAIDs). Also, the end products of COX are related to various biological pathways in stimulating tumor growth (26) ( Figure 3 ).

Prostaglandins are upregulated in colorectal cancer, and it was reported that genetic polymorphisms in both COX1 and COX2 are associated with CRC (27, 37). COX2 is involved in cell cycle control, and increased expression of COX-2 in CRC patients compared to normal controls indicates its possible role in the progression of CRC (40). COX2 influences cancer progression by increasing prostaglandin production, preventing tumor cell apoptosis, cell proliferation, and tumor angiogenesis (41). It was reported that aspirin plays a key role in preventing colon cancer by inhibiting COX (37). Ayiomamitis et al. examined the expression of COX1, COX2, prostaglandin-endoperoxide synthase 3 (PTGES3), and telomerase reverse transcriptase (TERT). They used bioinformatics analysis on the Cancer Genome Atlas Colon Adenocarcinoma (TCGA-COAD) and rectal adenocarcinoma (READ) datasets. The results showed an inverse relationship between COX2 expression and telomerase activity in CRC. In the end, they identified differentially methylated patterns within the promoter regions of COX2 and TERT (42). Joanna et al. observed COX2 overexpression in the early stages of colorectal cancer and higher COX2 gene expression in the advanced stages of the disease. The results also indicated that COX2 expression level could affect carcinogenicity by modulating local inflammation (43). In addition, a case–control study on Iraqi patients reported that the expression level of COX2 was upregulated at higher tumor grades (44). This result suggests that considering COX2 as an early marker of progression or initiation of colorectal carcinoma should be investigated by further studies. Moreover, Labda et al. found that COX2 expression was associated with tumor size and degree of differentiation in an observational study including 58 Indonesian CRC patients. However, there was no statistical correlation between COX2 expression and tumor location (45). Jin et al. conducted a case-control study involving 213 Chinese patients with colorectal cancer and 200 controls and reported that the expression level of IGF-IR and COX2 was directly related to the degree of progression and lymphatic metastasis and inversely related to the mean survival rate in CRC patients (46). The results of a Chinese study also indicated that PGE₂ and COX2 expression were significantly associated with tumor invasion, tumor differentiation, lymph node metastasis, and TNM stage and were inversely related to patient survival (47).

Polymorphisms of the COX gene can affect the risk of CRC. In this regard, Lin et al. found that the COX2 rs5273 polymorphism, in about 5% of African Americans, was associated with a lowered risk of CRC (OR = 0.78, 95% CI: 0.49–1.23) (26). The COX2 rs4648298 and rs689469 polymorphisms were reported to be associated with an increased risk of CRC. Analysis of haplotypes confirmed that people with these variants were at an increased risk of colorectal cancer (OR = 2.17, 95% CI: 0.97–4.84, P = 0.06) (27). In contrast with these results, Mosallaei et al. observed a significant relationship between COX2 rs4648298 polymorphism (AA genotype) and a reduced risk of CRC in the Iranian population (OR = 0.14; 95% CI: 0.05–0.34; P <0.001). Interestingly, they found this significant association only in non-smokers (28). This finding suggests that environmental factors may influence the association between the COX gene polymorphism and CRC. Another study showed that the GG genotype of COX2 rs20417 was associated with an increased risk of developing CRC in the Dutch population (OR, 1.45; 95% CI, 1.03–2.04) (30). Interestingly, Xing et al. observed the positive association between the GG genotype of the COX2 rs20417 polymorphism and increased CRC risk in China, especially in smokers and in people with a high Body Mass Index (BMI) (OR: 1.107, 95% CI: 1.107–3.726; P = 0.022) (31). In this line, the Minnesota-based case-control study discovered that COX2 gene expression or COX2 enzyme activity is suppressed and the risk of colorectal polyps is reduced by NSAIDs in individuals with the GG genotype of COX2 rs20417 (OR: 0.66; 95% CI: 0.48–0.92) (29). Ueda et al. investigated the association between the COX2 position 765 G<C, 8473 T>C, and 9850 A>G and CRC risk and reported that among the studied polymorphisms, COX2 8473T>C may reduce the CRC risk in people who consume NSAIDs (OR: 1.57, 95% CI: 1.04–2.38) (32). Another previous study on 104 cases of adenomatous polyps and 115 matched control samples found that COX2 rs689466 polymorphism may have a protective effect on the risk of development of CRC (33). In contrast, Peters et al. identified that overrepresentation of COX2 was associated with a high risk for CRC development in patients with familial adenomatous polyposis (FAP) who had the rs689466 polymorphism GG genotype compared with AA genotype carriers (OR = 2.81; 95% CI = 1.00–7.91, P= 0.042) (34). In addition, Pereira et al. suggested that smoker people with COX2 rs689466 polymorphism had a nearly 6-fold increased CRC risk compared with people without rs689466 risk allele (95% CI: 1.49–22.42, P  =  0.011) (35). Some reasons for these conflicting results on the association between CRC and COX gene can be due to effects of different environmental factors such as lifestyle on this association. Table 2 presents the summary of studies regarding COX polymorphisms and CRC risk.

COX enzymes (COX1, COX2) are important factors in the biosynthetic pathway of PGs from AA. ALOX enzymes (ALOX5, ALOX12, and ALOX15) convert PUFA to fatty acid hydroperoxides, which results in the production of LTs. Recent studies reported an association between the CRC risk with the amount of fatty acids intake and COX and ALOX polymorphisms ( Figure 4 ). Habermann et al. identified an association between COX1 rs10306110 polymorphism and low intake of docosahexaenoic acid (DHA), a fatty acid with anti-inflammatory properties, with an increased risk of colon cancer (OR = 1.6, 95% CI: 1.1–2.3, adjusted P = 0.06) (38). Notably, supplementation with some fatty acids such as ω-3 fatty acids plays a protective role in colon cancer by attenuating the pro-inflammatory state and decreasing the production of PGE₂ (48). These results conform to studies that indicated that omega-3 long-chain polyunsaturated fatty acids (n−3 LC-PUFA) may lower cancer risk by suppressing oxidative stress, tumor apoptosis, and inflammatory pathways by modulation of COX activity and inhibition of arachidonic acid-derived eicosanoids (49–51). However, a case–control study on 310 patients with colorectal cancer and 1,177 controls provided epidemiological evidence for the possible link between PGs production from n−6 PUFAs through the enzymatic activity of COX2 and increased risk of colon cancer. They reported an association between COX2 rs20417 polymorphism and an increased risk of colon cancer in individuals with high n−6 PUFA intake (OR = 2.38, 95% CI = 1.23–4.59, P = 0.07). However, there was no association between this polymorphism and the risk of rectal cancer regardless of the dietary n−6 PUFA intake levels (52). These results emphasize the importance of lifestyle modification in the carriers of the high-risk allele of the COX gene. Moreover, Siezen et al. demonstrated that colorectal adenoma risk could be modified by the interaction between polymorphisms in AA pathway genes and fish consumption. They showed that the COX2 rs5277 polymorphism in people with high fish consumption played a protective role against CRC compared with people with low fish intake (53). In another work, Siezen et al. confirmed the inverse association between high fish consumption and CRC risk. However, they could not find any significant interaction between CRC and SNPs in the genes involved in the AA pathway (54). Interestingly, another study indicated that the effects of n−3 PUFA intake and NSAIDs on CRC may differ in people with COX1 polymorphisms. Among the wild-type homozygous individuals (PP genotype) with COX1 rs3842787 polymorphism, high fish consumption and regular use of NSAIDs were associated with a decreased risk of CRC. In comparison, an inverse association was observed in individuals with at least one risk allele (PL, LL genotypes) in the COX-1 rs3842787 polymorphism (55). Furthermore, dietary supplementation with n−3 PUFA, particularly DHA and EPA, was reported to have antineoplastic effects on CRC by modifying the epigenetic modification like DNA methylation (56). Table 3 summarizes studies regarding the association between ALOX, COX polymorphism, dietary fatty acid, and CRC risk.

Regarding the interactions between ALOX and COX gene polymorphisms, Siezen et al. reported that these SNPs are associated with colorectal adenoma risk and that these associations are modified by fish consumption. No association was found between SNP rs5277 in the COX2 gene and rs743646 in the ALOX15 gene (53).