IL22RA1/STAT3 Signaling Promotes Stemness and Tumorigenicity in Pancreatic Cancer

Abstract

Chronic inflammation is a feature of pancreatic cancer, but little is known about how immune cells or immune cell-related signals affect pancreatic cancer stemness and development. Our previous work showed that IL22/IL22RA1 plays a vital role in acute and chronic pancreatitis progression by mediating cross-talk between immune cells and acinar cells or stellate cells, respectively. Here, we find IL22RA1 is highly but heterogeneously expressed in pancreatic cancer cells, with high expression associated with poor prognosis of patients with pancreatic cancer. The IL22RA1 population from pancreatic cancer harbored higher stemness potential and tumorigenicity. Notably, IL22 promoted pancreatic cancer stemness via IL22RA1/STAT3 signaling, establishing the mechanism of regulation of cancer stemness by microenvironmental factors. Moreover, STAT3 was indispensable for the maintenance of IL22RA1 cells. Overall, these findings provide a therapeutic strategy for patients with PDAC with high expression of IL22RA1. IL22RA1/STAT3 signaling enhances stemness and tumorigenicity in pancreatic cancer. .

OLFM4 Enhances STAT3 Activation and Promotes Tumor Progression by Inhibiting GRIM19 Expression in Human Hepatocellular Carcinoma

“…Activation of STAT3 induces tumor cell proliferation by promoting cell‐cycle progression, enhances tumor cell survival by inhibiting apoptosis, and accelerates tumor invasion and migration by promoting epithelial‐mesenchymal transition (EMT) . In addition, STAT3 is reported to mediate cancer stem cell–like property by enhancing anoikis resistance, which is related to chemoresistance and poor prognosis . However, in HCC, little is known about the clinical significance of STAT3 function, and the precise mechanisms of its activation are still unclear.…”

“…(6,7) In addition, STAT3 is reported to mediate cancer stem cell-like property by enhancing anoikis resistance, which is related to chemoresistance and poor prognosis. (8,9) However, in HCC, little is known about the clinical significance of STAT3 function, and the precise mechanisms of its activation are still unclear. Moreover, because STAT3 is essential for cell survival in normal organs, therapies targeting STAT3 are not common.…”

Pancreatic Cancer Thrives on Hijacking a Homeostatic Tissue Repair Pathway

“…[12][13][14][15][16] Activation of Stat3 downstream of IL-22 seems to serve as an important canonical signal responsible for potentiating protumorigenic role of IL-22 in colon and pancreatic cancer, and, in particular, in enhancing stem cell-like properties of cancer cells. 17,18 Lanfranca et al use a model of induced pancreatitis or genetically engineered mouse models of PDAC to show that levels of IL-22 increase in the context of the diseased pancreas. They further demonstrate that IL-22-producing T cells accumulate at the tumor site.…”

“…20 Although this and other studies on the role of IL-22 in PDAC formation provide an important insight into ability of tissue repair pathways to synergize with oncogenic stimulation, many questions remain outstanding. 5,18 It is not clear how Th22 cells are recruited to regions of pancreatic inflammation and/or tumor formation and how IL-22 signaling cooperates with Kras and/or p53-driven cues to potentiate transformation. It is also not well-understood how distinct stimuli, such as IL-22 working through Stat3, and IL-17, working through at least in part mitogenactivated protein kinase pathway, may feed into mechanisms of potentiating acinoductal metaplasia, stem cell enrichment, and, as a result, tumorigenesis: Do they affect similar cell types and subtypes and at what stages in cancer development?…”

KLF3 is a crucial regulator of metastasis by controlling STAT3 expression in lung cancer

“…For example, the overexpression of IL-22RA1 promotes stemness and tumorigenicity in pancreatic cancer by regulating the STAT3 signaling pathway. 21 In addition, it has recently been shown that the activation of the STAT3 signaling pathway promotes colon cancer metastasis by regulating epithelialmesenchymal transition (EMT). 22,23 The STAT3 signaling pathway seems to be necessary for cancer metastasis.…”