Inflammatory bowel disease-related colorectal cancer: Past, present and future perspectives

Figure 3 The inflammatory pathways leading to the development of IBD-related colorectal cancer. A: The role of the JAK/STAT3 pathway in the development of IBD-related colorectal cancer. Various in vivo and in vitro models have shown that the JAK/STAT3 pathway plays a vital role in oncogenesis. The signal transduction of IL-6 involves the activation of JAK, activating transcription factors of the signal transducers and activators of STAT3. This is followed by its phosphorylation, dimerization and nuclear translocation of STAT3, initiating transcription of STAT3 target genes (including cyclin D1, Bcl-xL, c-myc, Mcl1, surviving and VEGF) leading to carcinogenesis. PI3K mediated activation of Forkhead box O3 (FOXO) leads to inhibition of gene transcription, whereas PI3K mediated activation of mTOT leads to oncogene transcription-mediated development of oncogenesis; B: The canonical Wnt-pathway in the development of IBD-related colorectal cancer. The canonical Wnt-pathway (β-catenin mediated Wnt-signaling) regulates proliferation and differentiation of the colonic stem cell in the normal colon. However, the loss of the adenomatous polyposis coli (APC) gene results in the shift of β-catenin from the membrane to the nucleus leading to increased transcription of cyclin D1 and c-myc genes thereby triggering carcinogenesis. IBD: Inflammatory bowel disease; CRC: Colorectal cancer; JAK: Juan kinase; P: Phosphorylation; STAT3: Signal transducer and activator of transcription proteins 3; PI3K: Phosphoinositide-3-kinases; Akt: RAC-alpha serine/threonine-protein kinase; FOXO: Forkhead box; mTOT: Mechanistic target of rapamycin; Ras: Small GTPase; Raf: Rapidly accelerated fibrosarcoma; MEK: Mitogen-activated extracellular signal-regulated kinase; ERK: Extracellular-signal-regulated kinase; Wnt: Wingless and int-1; Dsh: Dishevelled; AXIN: Axin-related protein 1; LKB1: Liver kinase B1; APC: Anaphase-promoting complex; GSK: Glycogensynthase kinase; MYC: C-myc; COX-2: Cyclooxygenase-2.