br Association of hCG and
3.3. Association of hCG and LHCGR L-α-Hydroxyglutaric Acid patterns with patient clinicopathological parameters
Statistical analyses revealed that hCG expression was significantly higher in advanced (III/IV) than in early (I/II) stage EOC, and high hCG expression levels were significantly associated with exhibited patient FIGO tumor stages (P < 0.001), and rates of metastasis (P < 0.001). In contrast, hCG expression levels did not vary significantly with patient age at diagnosis (P = 0.259), tumor grade (P = 2.921), tumor histolo-gical classification (P = 0.529), ascites accumulation (P = 0.479), nor serum CA-125 levels (P = 0.765) (Table 3). Conversely, LHCGR ex-pression was significantly decreased in advanced (III/IV) compared with early (I/II) stage EOC, and thus, low LHCGR expression levels were significantly associated with more advanced patient FIGO stages (P < 0.001), and higher rates of metastasis (P < 0.001). LHCGR ex-pression levels did not vary significantly with patient age (P > 0.999), tumor grade (P = 0.137), histological classification (P = 0.710), ascites accumulation (P = 0.843), nor serum CA-125 levels (P = 0.493) (Table 4). Thus, these results indicate that high hCG and low LHCGR expression levels are both associated with EOC progression.
Generated expression data were also analyzed to evaluate a poten-tial correlation between hCG and LHCGR expression levels in ovarian cancer tissues; the results showed an obvious negative correlation be-tween the hCG and LHCGR (R= –0.249, P = 0.003) (Fig. 4).
3.4. High hCG and low LHCGR expression levels show poor EOC prognosis
unfavorable prognostic factors for patient OS, independent of other clinicopathological factors (Table 5). Similarly, the multivariate COX regression model was used to demonstrate that LHCGR expression (HR 0.320; P = 0.001) was a favorable prognostic factor for patient OS, independent of other clinicopathological factors (Table 6). Finally, patients who exhibited tumors with high or low levels of hCG and LHCGR expression, respectively, experienced a worse OS rate than those who exhibited tumors with low hCG, or high LHCGR expression levels (Fig. 5).
Over the last three decades, the 5-year OS rate for ovarian cancer has remained at 38–46% . The majority of patients with ovarian cancer are still diagnosed at advanced stages of the disease, due to its often occult onset; thus, it is essential to develop novel indicators to facilitate its early detection and diagnosis, and eﬀective prognosis.
In recent studies, β-hCG was found to be associated with a poor prognosis, and increased rate of metastasis in various malignant tu-mors, such as bladder, osteoblastoma, endometrial, colon, lung, and testicular tumors, and furthermore, has been suggested to regulate ovarian cancer metastasis by controlling EMT and apoptosis [9,10,23,24]. Its receptor, LHCGR, is well established to critically reg-ulate ovulation, and to be essential for follicular maturation, ovulation, and corpus luteum function . The LHCGR has also been shown to be expressed in a range of normal nongonadal tissues (including bovine, porcine, rat, mouse, rabbit, and human uterine, adrenal, bone, fallopian tube, brain, retinal, skin, placental, seminal vesicle, prostate, female breast, and thyroid tissues), and its expression has been found to be upregulated in granulosa cells (GC) in women with polycystic ovary syndrome (PCOS) [16,26–28]. Furthermore, the LHCGR is also ex-pressed by several tumor types, including endometrial and breast tu-mors [8,12,13]. Some previous reports suggested that the interaction between hCG and LHCGR in endometrial cancer tissues may stimulate cell growth and promote neovascularization ; however, others have proposed that the eﬀect of hCG on ovarian cancer cells is likely LHCGR-independent .
In fact, the eﬀect of LHCGR in tumors, to date, remains con-troversial. For example, it was previously demonstrated that human endometrial cancers exhibit increased LHCGR expression compared to normal tissues , and LH-mediated LHCGR activation has been suggested to contribute to the etiology and/or progression of ovarian cancer [16,17,30]. In addition, LHCGR mRNA expression levels have been shown to be both significantly enhanced, and negatively corre-lated with LH serum levels in patients with ovarian cancer, (although the latter finding was determined via a study that analyzed a small cohort of patients over several decades) . In contrast, various other studies have suggested that LHCGR is likely associated with anti-on-cogenic activities; for example, its expression has been found to be higher in normal breast than in breast-cancer tissues .