[PMC free content] [PubMed] [CrossRef] [Google Scholar] 42

[PMC free content] [PubMed] [CrossRef] [Google Scholar] 42. that the mice bearing JLP-silenced xenografts Prodigiosin exhibits reduced tumor volume. Analysis of the xenograft tumor tissues indicate a reduction in the levels of JLP, JNK, phosphorylated-JNK, c-Jun and phosphorylated-c-Jun in JLP-silenced xenografts, thereby correlating the attenuated JLP-JNK signaling node with suppressed tumor growth. Thus, our results identify a critical role for JLP-signaling axis in ovarian cancer and provide evidence that targeting this signaling node could provide a new avenue for therapy. gene, which generates three splice variants namely, JLP (3,921 bp; 1307 amino acids), JIP4 (3426 bp; 1142 amino acids), and SPAG9 (2,268 bp; 766 amino acids) [10]. Of these splice variants, JLP is ubiquitously expressed and provide a scaffold function Prodigiosin for both JNK and p38MAPK [6]. Several studies have reported the overexpression of gene product in many cancers [11C15]. However, the use of antibodies that cross-react with all of the splice variants has raised a major concern regarding the true identity of oncogenic splice variant of fusion gene that contains exon-26 of JLP predicts poor outcome in pediatric acute lymphoblastic leukemia patients establishes a prognostic role for JLP [16]. Potential tumor promoting role for JLP is further substantiated by the cBioPortal analysis of TCGA dataset of ovarian cancer tissue, which indicates that the increased expression of correlates with a reduction in the disease free survival of ovarian cancer patients [17C19]. In addition, the observation that the activation of JNK-signaling predicts poor survival of ovarian cancer patients indirectly points to the potential role of JNK-interacting JLP in disease prognosis [20, 21]. In ovarian cancer, lysophosphatidic acid (LPA) has been characterized as a potent lipid growth factor that elicits both mitogenic and motogenic response and thus promotes ovarian cancer progression and intraperitoneal spread of the disease [22C24]. Based on our previous findings that JLP is involved in LPA-stimulated activation of JNK [7, 8], we hypothesized that the aberrant expression of JLP could promote tumorigenesis or tumor progression in ovarian cancer. This was tested in the present study using ovarian cancer cell lines including those representing Prodigiosin high-grade serous ovarian carcinoma (HGSOC) and ovarian cancer xenografts. Our results indicate that JLP is overexpressed in ovarian cancer tissue compared to adjacent normal ovarian tissue. Increased expression of JLP is also observed in a panel of ovarian cancer cells representing high-grade serous ovarian carcinoma. Ectopic overexpression of JLP stimulates the proliferation as well as the invasive migration of ovarian cancer cells. More interestingly, ectopic expression of JLP promotes long-term survival and clonogenicity in normal fallopian tube-derived epithelial cells. We also demonstrate that JLP Prodigiosin physically interacts with JNK and this interaction is stimulated by LPA. Our results also indicate that JLP is critically required for LPA-stimulated activation of JNK as well as LPA-stimulated proliferation and invasive migration of ovarian cancer cells. Using the mouse xenograft ovarian cancer model, we establish that the silencing of JLP attenuates the activation of JNK signaling module in the tumor tissue along with a resultant reduction in tumor growth and intraperitoneal spread of the disease. Thus, our data presented here identifies, for the Rabbit Polyclonal to DRD1 first time, a tumor-promoting role for JLP in ovarian cancer growth and progression. RESULTS Overexpression of JLP in ovarian cancer Our previous studies have indicated that JLP is required for JNK-mediated oncogenic signaling Prodigiosin by the oncogenes and JNK-signaling in ovarian cancer progression, we investigated whether JLP shows increased expression in ovarian cancer tissues. Using antibodies that do not cross-react with JIP4 or SPAG9, we carried out an immunohistochemical analysis to monitor the expression of JLP in ovarian cancer tissue. As shown in Figure ?Figure1A,1A, ovarian cancer tissue showed an increased expression of JLP compared to normal tissue. Increased expression of JLP could also be observed in ovarian cancer cells isolated from the ascites of patients (Figure ?(Figure1B).1B). Next we analyzed the expression of JLP in a panel of ovarian cancer.

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