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  • br Keywords br Epithelial ovarian cancer br Human

    2020-08-14


    Keywords:
    Epithelial ovarian cancer
    Human chorionic gonadotrophin
    Luteinizing hormone
    Luteinizing hormone (LH)/hCG receptor Overall survival 
    In addition to its critical role during pregnancy, human chorionic gonadotropin (hCG) has been shown to be expressed by various tumor types. Recent studies have similarly documented the presence of the luteinizing hormone (LH)/hCG receptor (LHCGR) in a variety of nongonadal organs; however, its clinicopathological sig-nificance in ovarian cancer remains unclear. The present study used a combination of immunohistochemical, real-time PCR, and western blot analyses to examine hCG and LHCGR GS9620 in normal and cancerous tissues collected from patients with epithelial ovarian cancer (EOC). hCG and LHCGR expression levels were resultantly shown to be significantly increased and decreased in cancerous versus normal (or benign) ovarian tissues, re-spectively (P < 0.05), and both expression pattern changes were associated with more advanced tumor stages and a higher rate of metastasis. Furthermore, patients with tumors with high or low levels of hCG and LHCGR, respectively, experienced a worse overall survival (OS) rate than those with low hCG or high LHCGR expression levels (P < 0.05). In fact, hCG and LHCGR expression levels were independent prognostic factors of patient OS (P < 0.05) for EOC. Collectively, these findings indicate that hCG and LHCGR expression pattern changes are associated with EOC occurrence and progression. Thus, hCG and LHCGR represent promising potential targets to improve the diagnosis, treatment, and prognosis of patients with EOC.
    1. Introduction
    Epithelial ovarian cancer (EOC) is a gynecological malignancy that incurs sufficiently high mortality rates worldwide to be the most lethal gynecological cancer, and the fifth leading cause of cancer-related death in women [1]. For all cancer types, the clinical factors that de-termine patient prognosis include the state (i.e. the histological sub-type, grade, and stage) of the disease at diagnosis, and the extent of residual disease after surgery [2]. EOC induces a high fatality rate largely due to the fact that its onset is often occult, causing it to be detected late. Once diagnosed, the standard treatment for patients with EOC comprises a combination of surgery and chemotherapy [3]. To improve the current prognosis for these patients, more sensitive mar-kers and novel therapeutic targets are urgently needed to facilitate the early detection and effective treatment of ovarian cancer, respectively.
    Human chorionic gonadotropin (hCG) is released by the syncytio-trophoblast of the placenta (which consists of an α and a β subunit), and exists as five independent molecules in the body [4]. In addition,
    hCG (particularly subunit β-hCG) is also expressed by normal non-tro-phoblastic tissues, predominantly including those of the testes, prostate, thymus, skeletal muscles, and pituitary glands [5]. Recent reports have shown that β-hCG is also secreted by a variety GS9620 of malignant tumor types, including ovarian, cervical, vaginal, gastrointestinal, bladder, lung, colorectal, and prostate tumors [5–8]. In fact, hCG has been suggested to promote ovarian cancer progression and metastasis by inducing epithelial-mesenchymal transition (EMT) and inhibiting apoptosis [9,10]. The EMT transforms epithelial cells into cells with migration and invasion, and it is thought to be involved in the metas-tasis process of epithelial tumors [11].
    The heptahelical luteinizing hormone/choriogonadotropin receptor (LHCGR) regulates ovulation by binding both the luteinizing hormone (LH), (which is a product of the anterior pituitary), and hCG. It has also been shown to be expressed by multiple cancer types; for example, LHCGR has been shown to be more highly expressed in human en-dometrial carcinomas than in normal endometrium, and its expression is associated with a poor prognosis in patients with endometrial cancer
    Corresponding authors.
    Fig. 1. hCG and LHCGR gene and protein expression in normal and cancerous fresh ovarian tissues collected from patients with epithelial ovarian cancer
    (EOC). (A) hCG and LHCGR protein expression in normal and cancerous ovarian tissues were compared via a western blot analysis. GAPDH was used as a loading control. (B) Bar chart showing the ratio of hCG to GAPDH protein production. hCG expression was significantly higher in cancerous than normal ovarian tissues. (C) Bar chart showing the ratio of LHCGR to GAPDH protein production. LHCGR expression was significantly lower in cancerous than normal ovarian tissues. (D, E) PCR analyses of (D) hCG, and (E) LHCGR mRNA expression in normal and cancerous ovarian tissues. 18S was used as a loading control for both analyses. All protein and mRNA levels were quantified via a combined analysis of three independent replicate experiments. *P < 0.05. (F) IHC staining for hCG (left) and LHCGR in ovarian cancer tissue. (a) strong staining of hCG in ovarian cancer tissue; (b) low staining of hCG in noncancerous ovarian tissue; (c) negative staining of LHCGR in ovarian cancer tissue; (d) strong staining of LHCGR in noncancerous ovarian tissue.