Critical function of the necroptosis adaptor RIPK3 in protecting from intestinal tumorigenesis

Abstract

Necroptosis is a programmed form of non-apoptotic cell death that requires the kinase activity of the receptor interacting protein kinase 3 (RIPK3). Although in vitro data suggests that cancer cells lacking expression of RIPK3 are invasive, the physiological role of RIPK3 in a disease-relevant setting remains unknown. Here we provide evidence that RIPK3 has a critical role in suppressing colorectal cancer (CRC). RIPK3-deficient mice were highly susceptible to colitis-associated CRC and exhibited greater production of pro-inflammatory mediators and tumor promoting factors. Tumorigenesis in RIPK3-deficiency resulted from uncontrolled activation of NF-κB, STAT3, AKT and Wnt-β-catenin signaling pathways that enhanced the ability of intestinal epithelial cells (IECs) to aberrantly proliferate in the face of the sustained inflammatory microenvironment and promote CRC. We found that RIPK3 expression is reduced in tumors from patients with inflammatory bowel diseases, and further confirmed that expression of RIPK3 is downregulated in human CRC and correlated with cancer progression. Thus, our results reveal that the necroptosis adaptor RIPK3 has key anti-inflammatory and anti-tumoral functions in the intestine, and define RIPK3 as a novel colon tumor suppressor.

Relevance of necroptosis in cancer

“…Like in AML patients, in primary breast cancer samples RIPK3 loss correlated with methylation of the genomic region near RIPK3 gene's transcription start site, suggesting that a methylation‐mediated mechanism regulates RIPK3 expression during breast cancer development 19 (Table 1). Several reports found that RIPK3 is downregulated in human colon and colorectal cancers compared with adjacent normal tissues 22 , 28 , 29 . Accordingly, loss of Ripk3 increased colon tumourigenesis induced by carcinogens in mice.…”

“…Accordingly, loss of Ripk3 increased colon tumourigenesis induced by carcinogens in mice. The acceleration of tumourigenesis in Ripk3 ‐deficient mice was more likely due to an excessive inflammation 28 . Therefore, the role of RIPK3 in dampening inflammation during colorectal tumourigenesis contrasted with its role in others inflammatory scenarios, where loss of Ripk3 has been described to limit inflammation 30 .…”

“…It is clear now that deregulation of necroptotic regulators occurs in cancer and accumulating evidence has in fact associated level of expression and patient survival. For instance, low RIPK3 levels correlated with poor outcome for colorectal and breast patients 19 , 22 , 28 , 29 (Table 1). This indicates that RIPK3 expression may be negatively selected during the development or progression of breast and colorectal cancers.…”

Different Susceptibilities between Apoe- and Ldlr-Deficient Mice to Inflammation-Associated Colorectal Carcinogenesis

“…Other cytokines ( Tnf-α , IL-1β , Interferon-γ ), inflammatory enzymes ( Cox-2 , Nos2 ), nuclear factor (NF)-κB, and signal transducer and activator of transcription 3 (Stat3) are also involved in inflammation-associated colorectal carcinogenesis [72]. Uncontrolled activation of Nf-κB, Stat3, and Wnt-β-catenin signaling pathways enhances the aberrant proliferation of crypal cells in the sustained inflammatory microenvironment and promotes CRC development [75]. Although we did not assay Stat3 and Nf-κB in the present study, the mRNA expression of Tnf-α , Il-1β , Il-6 , Cox-2 , and Nos2 was assayed in the colorectum of Apoe -deficient, Ldlr -deficient, and their respective WT mice treated with AOM and DSS.…”

The Implications of Several Forms of Programmed Necrosis for Cancer Therapy

“…Necrotic regulators also seem to affect cancer prognosis. For example, low RIP3 levels are correlated with poor outcomes in colorectal and breast cancer patients [30][31][32]. RIP3 expression in the hematopoietic system may limit cancer invasion and metastasis.…”