JAK2/STAT3 pathway as a therapeutic target in ovarian cancers

Abstract

Abstract. The activation of JAK2/STAT3 pathway has been reported to have critical roles in several solid tumors. The present study aimed to evaluate the correlation between JAK2/STAT3 activation and clinicopathological parameters in ovarian cancer types. Tissue microarrays made from the patients treated at the National Defense Medical College Hospital between 1984 and 2008 were evaluated using immunohistochemical (IHC) stainings. Medical charts of these patients including IHC results were retrospectively analyzed, and prognostic factors for progression-free survival and overall survival were evaluated. Among 341 enrolled patients, positive expression of p-STAT3 was observed in 95 cases (28%). Positive p-STAT3 was an independent worse prognostic factor for overall survival in all the cases. Additionally, p-STAT3 expression was related with overall survival in patients with clear-cell histology, but not in serous histology. The effect of an inhibitor of STAT3, niclosamide, was evaluated in ovarian clear-cell cancer cells, and niclosamide treatment decreased expression of p-STAT3, leading to increased apoptosis in a dose-dependent manner in vitro. The activation of JAK2/STAT3 pathway had significant impact on survival of ovarian cancers, especially for the cases with clear-cell histology. Although further analyses are needed, suppression of this pathway could be a candidate for the treatment of ovarian cancers.

Niclosamide inhibits the cell proliferation and enhances the responsiveness of esophageal cancer cells to chemotherapeutic agents

“…In addition, niclosamide treatment did not only markedly suppress the phosphorylation of Y705 of STAT3, but also slightly decreased the total protein levels of STAT3. Similar results were also obtained by Yoshikawa et al in a niclosamide-treated ovarian clear cell line (KK) (49). However, the mechanism resulting in the decrease of STAT3 total protein form by niclosamide treatment is still unclear.…”

Activation of STAT3 and STAT5 Signaling in Epithelial Ovarian Cancer Progression: Mechanism and Therapeutic Opportunity

“…Compared to normal or benign ovarian tumors, pY-STAT3/pY-STAT5 protein expression was significantly higher in the malignant EOC tissues, supporting its role in ovarian carcinogenesis [14,15]. The activation of the STAT3 pathway and the increase in pY-STAT3 (Tyr705) expression directly correlated with higher clinical stage, lower degree of differentiation, presence of lymph node metastasis, and more reduced survival in EOC [15][16][17]. Moreover, elevated pY-STAT3 expression in the omentum was associated with poor survival in patients with high-grade EOC.…”

“…Moreover, elevated pY-STAT3 expression in the omentum was associated with poor survival in patients with high-grade EOC. The activation and translocation of pY-STAT3 to the nucleus was observed in 29-58% of all EOC histotypes [13,16]. Specifically, nuclear pY-STAT3 expression was found to be associated with clear cell and serous carcinoma [17].…”

“…Specifically, nuclear pY-STAT3 expression was found to be associated with clear cell and serous carcinoma [17]. The activation of STAT3 pathway was, in particular, related to overall survival in ovarian clear cell carcinoma patients [16]. In recurrent diseases, levels of STAT3 activation were doubled, indicating that STAT3 activation could be directly associated with disease relapse [18].…”

Small-molecule compounds targeting the STAT3 DNA-binding domain suppress survival of cisplatin-resistant human ovarian cancer cells by inducing apoptosis

“…Numerous clinical studies have shown that up-regulation of phosphorylated STAT3 (pSTAT3) is correlated to poor prognosis in patients with ovarian, colorectal, gastric, pancreatic, renal and cervical cancers [19][20][21][22][23][24][25]. In a study conducted in 341 patients with ovarian cancer, positive expression of p-STAT3 was observed in 28% of patients and was identified as an independent worse prognostic factor for overall survival [26]. Additionally, constitutively activated STAT3 contributes to insensitivity to various therapeutics via aberrant production of cytokines or growth factors in cancer cells [27,28].…”