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Objective: The incidence of endometrial cancer is increasing, and oxidative stress has been suggested to play a vital role in its carcinogenesis. Statins have an impact on the cellular redox-state. The aim of this study was to determine the effects of statin use on redox-state regulating enzymes in endometrial cancer in women with type 2 diabetes. Materials and methods: This retrospective study consisted of 119 women with type 2 diabetes who were diagnosed with endometrial cancer at Oulu University Hospital in Finland between 2007 and 2014. There were 58 statin users and 61 non-users based on medication use at the time of endometrial cancer diagnosis. The expression of redox-state regulating proteins nuclear factor erythroid 2- related factor 2 (Nrf2) and Kelch-like ECH-associated protein 1 (Keap1) in the tumor samples was assessed immunohistochemically, and manganese superoxide dismutase (MnSOD) levels were measured both immunohistochemically and from serum samples. Results: High MnSOD expression predicted better progression-free survival (PFS) in statin non-users in a univariate analysis (p=0.02). There was no statistical difference in overall survival (OS) or PFS between strong and weak expression of Nrf2 and Keap1. After adjusting for stage and statin use, the results were similar. Conclusion: Statin non-users with strong MnSOD expression had better PFS compared to statin users which proves that statins have impact on redox-state regulating enzymes. However, these findings are preliminary and require further research. [ABSTRACT FROM AUTHOR]

Background/aim: Metformin inhibits tumorigenesis in endometrial carcinoma and interferes with the expression of oxidative stress-regulating proteins, such as nuclear factor erythroid 2-related factor 2 (Nrf2) and Kelch-like ECH-associated protein 1 (Keap1). Although manganese superoxide dismutase (MnSOD) is vital for withstanding mitochondrial oxidative stress, it has also been linked with chemoresistance and poorer outcomes in several cancer types. However, data on endometrial cancers are limited. This study aimed to highlight the relationship between mitochondrial redox regulation and endometrial cancer survival in relation to metformin consumption in women with type 2 diabetes mellitus (T2DM)., Patients and Methods: Our retrospective hospital-based cohort study included 121 patients diagnosed with endometrial carcinoma and T2DM between 2007 and 2014. Fifty-eight patients were using metformin at the time of diagnosis. Nrf2 and Keap1 expression levels in the tumor samples were assessed immunohistochemically, and MnSOD levels were measured both immunohistochemically and from the serum samples., Results: High MnSOD tissue expression was associated with better overall survival among metformin users in the univariate analysis (p=0.03). When adjusted for histology and stage, high serum MnSOD was associated with better overall survival (HR=0.22, 95%CI=0.07-0.71, p=0.01). No association was found between MnSOD, Nrf2, or Keap1 and overall survival among metformin non-users., Conclusion: Higher expression of MnSOD in patients with endometrial cancer and T2DM is associated with better overall survival if the patient is consuming metformin., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Khatun, Urpilainen, Ahtikoski, Arffman, Pasanen, Puistola, Tapanainen, Andersson, Butzow, Loukovaara and Piltonen.)