Activation of the mTORC1 and STAT3 pathways promotes the malignant transformation of colitis in mice

Abstract

Chronic inflammation is an underlying risk factor for colorectal cancer. No direct evidence has proven that inflammation in the colon promotes carcinogenesis. STAT3 plays an important role in the development of colitis-associated colorectal cancer (CAC). There is crosstalk between the mammalian target of rapamycin complex 1 (mTORC1) and the STAT3 pathways. The aim of the present study was to confirm that colitis promotes CAC and if so, to explore the function of the STAT3 and mTORC1 pathways in CAC. C57BL/6 mice were treated with axozymethane (AOM) and dextran sulfate sodium (DSS) to induce CAC. By varying the concentration of DSS (0, 1 and 2% respectively), we mimicked the CAC model with different degrees of inflammation and determined the risk of carcinogenesis. Expression of the STAT3 and mTORC1 pathways was detected. Finally, rapamycin, an mTORC1 inhibitor, was used to treat the CAC model. Tumor load, protein and gene expression of chemokines were determined. The multiplicity and tumor load of the high inflammation group were higher than those of the low inflammation group. Immunohistochemical staining and western blot analysis revealed that activation of the STAT3 and mTORC1 pathways increased gradually in the inflammation tissues and tumors. When we treated the mice with rapamycin, the tumor incidence, multiplicity and tumor load decreased. In addition, rapamycin widely suppressed the expression of pro‑inflammatory and anti-inflammatory chemokines in the tissues, including tumor necrosis factor-α, interferon-γ, IL-6, IL-10 and IL-12α. In conclusion, inflammation promotes the development of CAC via the STAT3 and mTORC1 pathways, which may be a viable treatment strategy for the chemoprevention of CAC.

Inflammatory and redox reactions in colorectal carcinogenesis

“…Genetic variations in the JAK/STAT signaling pathway appear to influence CRC carcinogenesis . Interestingly, cross‐talk between STAT3 and the mammalian target of rapamycin complex 1, which controls anabolic cell growth and proliferation, can promote CRC in colitic mice …”

Luteolin decreases invasiveness, deactivates STAT3 signaling, and reverses interleukin-6 induced epithelial–mesenchymal transition and matrix metalloproteinase secretion of pancreatic cancer cells

“… 26 , 27 After being activated, STAT3 mediates the expression of a variety of genes, among which many are associated with cellular proliferation, apoptosis, and malignant transformation. 28 , 29 Furthermore, it has been confirmed that STAT3 plays a critical role in K-ras-dependent pancreatic carcinogenesis. 20 , 30 , 31 Therefore, STAT3 and its associated pathways are thought to be increasingly important in cancer research and as potential factors in clinical cancer treatment.…”

Reg3g Promotes Pancreatic Carcinogenesis in a Murine Model of Chronic Pancreatitis

“…The process has been studied quite widely in murine models [36][37][38]. Evidence that p65 is closely allied to the viral oncoprotein v-Rel firstly establishes a link between NFjB and cancer [39].…”