OCT4 accelerates tumorigenesis through activating JAK/STAT signaling in ovarian cancer side population cells

Abstract

BackgroundAlthough surgery, chemotherapy, and radiotherapy eliminate clinically apparent ovarian tumor, the 5-year survival rate is no more than 45%. Cancer stem cells (CSCs) have been identified for precaution of tumor metastasis and recurrence in many kinds of cancers including ovarian cancer.AimThis study aims to explore the function of OCT4, a CSC marker, in ovarian cancer progression and to investigate its underlying mechanism.Materials and methodsBy Hoechst side population (SP) technique, CSC-like SP cells from human ovarian cancer SKOV3 and A2780 cells were isolated and used for this study. shRNA and lentivirus targeting human OCT4 gene were used to knock down OCT4 in SP cells and upregulate OCT4 in non-SP (NSP) cells stably. Peficitinib was used to inhibit JAK/STAT signaling. Cell counting kit-8, flow cytometry, and in vivo xenograft model were used to evaluate the effects of OCT4/JAK/STAT on the viability, drug resistance, apoptosis, cycle, and tumorigenesis of the SP cells. Immunofluorescence staining was used to detect the location of STAT6.ResultsResults showed that OCT4 was upregulated in the SP of SKOV3 and A2780 cells when compared with the NSP cells. Downregulation of OCT4 inhibited SP cell viability, tumorigenesis, and reduced cell drug resistance and induced a G2/M phase arrest, while upregulation of OCT4 conferred NSP cell malignant features. Besides, OCT4 upregulation in NSP cells increased the phosphorylated levels of proteins in JAK and STAT families, especially in JAK1 and STAT6. Furthermore, the roles of apoptosis inhibition and viability, invasion, and tumorigenesis promotions induced by OCT4 in NSP cells were all abolished when adding peficitinib.ConclusionOur study demonstrated that OCT4 accelerated ovarian cancer progression through activating JAK/STAT signaling pathway.

SPTBN1 suppresses the progression of epithelial ovarian cancer via SOCS3-mediated blockade of the JAK/STAT3 signaling pathway

“…Excessive activation of STATs can lead to an increase in SOCS gene expression due to a negative feedback mechanism. The JAK/STAT signaling pathway can regulate the expression of genes related to immunity, proliferation, differentiation, apoptosis and tumorigenesis [26,[32][33][34][35][36][37].…”

“…The SOCS (suppressors of cytokine signaling) family includes cytokine signal suppressors, which can negatively regulate the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway [20,21]. Deletion of the suppressor of cytokine signaling 3 (SOCS3) gene and activation of the JAK-STAT signaling pathway are closely related to hepatocarcinogenesis [22], gastric cancer [23], malignant fibrous histiocytoma [24], as well as the occurrence, development and metastasis of EOC [25][26][27]. Since cytokines such as interferon-γ (IFNγ) play an important role in antitumor immunity, the SOCS-JAK interaction has also been demonstrated as a potentially druggable target for cancer immunotherapy [28].…”

Co‐cultured bone marrow mesenchymal stem cells repair thioacetamide‐induced hepatocyte damage

“…Immunofluorescence staining was used to detect HepG2 STAT3 protein phosphorylation. The staining method was performed according to the process described in a previous study (Ruan, Yang, & Cheng, 2019) with minor modifications. The TAA‐treated HepG2 and HepG2 co‐cultured with mBMSCs were washed with PBS, fixed by a 4% paraformaldehyde solution, and treated with permeabilization solution at 4°C.…”

Targeting cancer stem cell pathways for cancer therapy

“…330 Oct4 also activates the JAK1/STAT6 pathway in ovarian CSCs. 331 In CD44 + CD24 − breast and colorectal CSCs, erythropoietin, and IL-6 activate the JAK2/STAT3 pathway. [332][333][334] Retinol-binding protein 4 activates JAK2/STAT3 signaling by its STRA6 receptor in colon CSCs.…”