Abstract
Ovarian cancer is a leading cause of cancer mortality in women world-wide. Considerable progress has been made to characterize the different subtypes of ovarian cancer, but specific therapies remain limited and prognosis poor. Cytokine signaling via the interleukin-6 receptor (IL-6R) family and related receptors has been implicated in a number of cancers, including those with an ovarian origin. The leptin receptor (LEPR) is structurally related to these receptors and utilizes similar downstream pathways. LEPR has diverse roles in metabolism, appetite and bone formation with obesity linked to both elevated levels of leptin and increased cancer incidence. This study investigated a potential role for LEPR signaling in ovarian cancer. Leptin stimulation led to increased proliferation, survival and migration of LEPR-expressing ovarian cancer cell lines, with the effects shown to be mediated by the downstream Janus kinase 2/Signal transducer and activator of transcription 3 (JAK2/STAT3) pathway. A significant correlation was identified between high co-expression of leptin and LEPR and decreased patient survival. This study collectively suggests that leptin/LEPR signaling via JAK2/STAT3 has the potential to significantly impact on pathogenesis in a subset of ovarian cancer patients who may benefit from strategies that dampen this pathway.
Highlights
Ovarian cancer remains the most lethal gynecological cancer, and represents one of the major causes of cancer morbidity and mortality in women worldwide [1]
This study collectively suggests that leptin/leptin receptor (LEPR) signaling via JAK2/STAT3 has the potential to significantly impact on pathogenesis in a subset of ovarian cancer patients who may benefit from strategies that dampen this pathway
Leptin signaling via LEPR has a wide variety of roles in regulating energy metabolism, appetite regulation, bone formation and angiogenesis [3, 22, 23]
Summary
Ovarian cancer remains the most lethal gynecological cancer, and represents one of the major causes of cancer morbidity and mortality in women worldwide [1]. This is partly as a result of the largely asymptomatic nature of early disease, with women usually presenting with advanced disease when the tumor has already spread into the peritoneum and sometimes to distant metastatic sites [2]. Leptin has been shown to have an important role in cell proliferation, invasion, metastasis and/or survival in several cancer types, such as breast, liver, colon, esophageal and endometrial cancers [6,7,8,9,10], including a role in ovarian cancer proliferation [11]. In www.impactjournals.com/oncotarget breast cancer, the effects of leptin have been shown to be mediated through the activation of specific genes by STAT3, including cyclin D1 and c-Myc for proliferation [12] and VEGF and its receptor for angiogenesis [13]
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