Roles of Necroptosis, Apoptosis, and Inflammation in Colorectal Carcinogenesis: A Longitudinal Human Study

Abstract Necroptosis triggers an inflammatory cascade associated with antimicrobial defense. No prospective human study has yet explored the role of necroptosis in colorectal cancer (CRC) development. We conducted quantitative analysis of biomarkers for necroptosis (transient receptor potential melastatin 7 (TRPM7) and phosphorylated mixed lineage kinase-like protein (pMLKL)), inflammation (cyclooxygenase-2, COX-2), apoptosis (BAX and TUNEL), and cell proliferation (Ki67). This was done using tissue microarray biospecimens from the Cooperative Human Tissue Network and rectal biopsies from a longitudinal study within the Personalized Prevention of Colorectal Cancer Trial. In the human colorectal adenoma-carcinoma sequence, we observed an inverse expression trend between BAX and TRPM7; TRPM7 decreased from normal mucosa to small and large adenomas but significantly increased in early CRC stages (Ptrend=0.004). It maintained high levels through all cancer stages. An increased COX-2 intensity in the epithelium was noted during tumorigenesis (Ptrend=0.02) and was significantly associated with an elevated risk of metachronous polyps (odds ratio =3.04, 95% confidence interval:1.07-8.61, Ptrend=0.02). The combined composite index scores of TRPM7 and COX-2 were strongly linked to 6- to 47-fold increased risks for metachronous adenoma/serrated polyps while combined scores of pMLKL or TRPM7 with BAX were associated with an 11.5- or 13.3-fold elevated risk for metachronous serrated polyps. In conclusion, our findings suggest that COX-2 expression within normal-looking colorectal mucosa is significantly associated with an increased risk of metachronous colorectal polyp. Furthermore, our results propose the hypothesis that synergistic interactions among necroptosis, inflammation, and apoptosis could play a pivotal role in human colorectal tumorigenesis.