Abstract
Stanniocalcin-1 (STC-1) is a glycoprotein hormone involved in diverse biological processes, including regulation of calcium phosphate homeostasis, cell proliferation, apoptosis, inflammation, oxidative stress responses, and cancer development. The role of STC-1 in endometrial cancer (EC) is yet to be elucidated. In this study, we investigated the protein expression pattern of STC-1 in a tissue microarray (TMA) cohort of hysterectomy specimens from 832 patients with EC. We then evaluated the prognostic value of STC-1 expression regarding the clinicopathologic features and patients survival over a period of 140 months. Our results revealed that in EC tissue samples, STC-1 is mainly localized in the endometrial epithelium, although some expression was also observed in the stroma. Decreased STC-1 expression was associated with factors relating to a worse prognosis, such as grade 3 endometrioid tumors (p = 0.030), deep myometrial invasion (p = 0.003), lymphovascular space invasion (p = 0.050), and large tumor size (p = 0.001). Moreover, STC-1 expression was decreased in tumors obtained from obese women (p = 0.014) and in women with diabetes mellitus type 2 (DMT2; p = 0.001). Interestingly, the data also showed an association between DNA mismatch repair (MMR) deficiency and weak STC-1 expression, specifically in the endometrial epithelium (p = 0.048). No association was observed between STC-1 expression and disease-specific survival. As STC-1 expression was particularly low in cases with obesity and DMT2 in the TMA cohort, we also evaluated the correlation between metformin use and STC-1 expression in an additional EC cohort that only included women with DMT2 (n = 111). The analysis showed no difference in STC-1 expression in either the epithelium or the stroma in women undergoing metformin therapy compared to metformin non-users. Overall, our data may suggest a favorable role for STC-1 in EC behavior; however, further studies are required to elucidate the detailed mechanism and possible applications to cancer treatment.
Highlights
Endometrial cancer (EC) is one of the most common gynecological cancers and is the fifth most frequent malignancy among women [1]
As stanniocalcin 1 (STC-1) expression was low in cases with obesity and diabetes mellitus type 2 (DMT2) in the tissue microarray (TMA) cohort, we evaluated the correlation between metformin use and STC-1 expression in an additional EC cohort that only included women with DMT2 (n 111)
44.4% (n 370) of the samples presented with intense STC-1 expression in the epithelium samples compared to 0.3% (n 3) in the stroma samples
Summary
Endometrial cancer (EC) is one of the most common gynecological cancers and is the fifth most frequent malignancy among women [1]. Mammalian stanniocalcin 1 (STC-1) is a 56 kDa homodimeric glycoprotein hormone. It plays a diverse role in many physiological and pathological processes such as calcium and phosphate homeostasis, organogenesis, angiogenesis, cellular metabolism, differentiation, implantation, and lactation [6,7,8]. Zhang et al (2000) were the first group to report about the cytoprotective activity of STC-1 in cerebral neurons against hypoxic/ischemic damage [9]. In line with this, several studies considered STC-1 as a “molecular guard” because it serves as a pro-survival factor protecting against hypoxic, hypercalcaemic, and ischemic damage mainly by modulating inflammatory responses and oxidative stress (1014). Growing evidence indicates that elevated expression of STC-1 is associated with a poor prognosis in various cancers such as human esophageal squamous cell carcinoma, as well as colorectal, glioma, gastric, and breast cancers [19]
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