Interleukin‐33 predicts poor prognosis and promotes ovarian cancer cell growth and metastasis through regulating ERK and JNK signaling pathways

Abstract

Epithelial ovarian cancer (EOC) is the most lethal gynecological cancer, it remains a huge challenge to understand the cellular and molecular mechanisms of the aggressive behavior of EOC cells. Here we investigated the role of an immunomodulatory cytokine IL-33 and its receptor ST2 in mediating the growth and metastasis of EOC. Our data show that both IL-33 and ST2 were highly up-regulated in EOC tumors compared with normal ovary and ovarian benign tumors, and the expression levels were further increased in tumor tissues at the metastatic site. The expression levels of IL-33 and ST2 were positively correlated with the Ki-67 expression, and negatively correlated with the patient survival time. Using EOC cell lines, we observed that cells knocked down of IL-33 gene by siRNA had reduced migratory and invasive potential, while full length human IL-33 (fl-hIL-33) promoted the invasive, migratory and proliferative capacity of EOC cells and this process could be inhibited by IL-33 decoy receptor sST2. Signaling pathway analysis suggested that IL-33 increased the phosphorylation of ERK and JNK which was blocked by sST2. Fl-hIL-33-induced increases in EOC cell migration, invasive potential and proliferation were specifically abrogated by treatment with the ERK inhibitor U0126 while JNK inhibitor SP600125 only disrupted IL-33-induced enhancement of cell viability. Taken together, our data suggest that IL-33/ST2 axis closely associates with poor prognosis of EOC patients, and it promotes ovarian cancer growth and metastasis through regulating ERK and JNK signaling pathways. Thus IL-33/ST2 might be potential prognosis markers and therapeutic targets for EOC patients.

IL33 Promotes Colon Cancer Cell Stemness via JNK Activation and Macrophage Recruitment

“…In support of this notion, IL33 administration promotes tumorigenesis (10, 16), and soluble ST2 is correlated with tumor burden (14, 39). IL33 predicts poor prognosis, promotes ovarian cancer cell growth and metastasis (40), and activates tumor stroma to promote intestinal polyposis (41). Our bioinformatics and pathologic analyses have demonstrated that the expression of tumor IL33 is associated with poor survival in patients with metastatic colon cancer.…”

Role of Wnt/β-catenin, Wnt/c-Jun N-terminal kinase and Wnt/Ca2+ pathways in cisplatin-induced chemoresistance in ovarian cancer

“…Previous studies have identified that aberrant Wnt/JNK signaling may initiate and stimulate the development of malignant phenotypes through effects on cell proliferation, survival, polarity, invasion and metastasis (Fig. 1C) (29,30). …”

“…Aberrant Wnt/β-catenin, Wnt/JNK and Wnt/Ca 2+ signaling has been associated with increasing ovarian cancer grade and poor survival (21,27,29). However, to the best of our knowledge, the relationship between these signaling pathways and ovarian cancer cisplatin chemoresistance has not yet been investigated (23,29).…”

“…However, to the best of our knowledge, the relationship between these signaling pathways and ovarian cancer cisplatin chemoresistance has not yet been investigated (23,29). …”

Identifying Gene Signature for the Detection of Ovarian Cancer Based on the Achieved Related Genes

“…Another research demonstrated that the adherence and migratory potentials of ovarian cancer cells were significantly reduced when the FAK/STAT1 signaling pathway was inhibited by fludarabine [41] . Through regulating ERK and JNK signaling pathways, IL-33/ST2 axis were closely associated with poor prognosis of epithelial ovarian cancer patients, and further promoted ovarian cancer growth and metastasis [42] . Multicellular organismal process was probably related to human ovarian multicellular spheroid model.…”