|Year : 2023 | Volume
| Issue : 2 | Page : 111-117
Stanniocalcin 2 is induced by estrogen and promotes growth in endometrial cancer via AMPK pathway
Qianqian Wang, Qiqi Wang, Yiqi Zhao
Center for Reproductive Medicine, Department of Obstetrics, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang Province, China
|Date of Submission||05-Sep-2022|
|Date of Decision||22-Nov-2022|
|Date of Acceptance||01-Dec-2022|
|Date of Web Publication||20-Apr-2023|
Dr. Qiqi Wang
Center for Reproductive Medicine, Department of Obstetrics, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, No. 158, Shangtang Road, Hangzhou City, Zhejiang Province
Source of Support: None, Conflict of Interest: None
Stanniocalcin 2 (STC2) is identified as a glycosylated peptide hormone and estrogen-responsive gene in cancer cells. STC2 participates in angiogenesis, cell development, cytoprotection, and calcium and phosphate regulation during the development of cancer. The role of STC2 in endometrial cancer (EC) remains unclear. The data from the bioinformatic and immunohistochemical analysis showed that STC2 was upregulated in the EC tissues. The EC cells were treated with 17β-estradiol (E2), and 0.1 μmol/L E2 increased the expression of STC2 in the EC cells. E2 also increased cell viability, promoted proliferation, and inhibited apoptosis of EC. However, the knockdown of STC2 decreased cell viability, reduced proliferation, and promoted apoptosis of E2-stimulated EC. Moreover, silencing of STC2 attenuated E2-induced downregulation of phosphorylated-AMP-activated protein kinase (AMPK) in the EC cells. The loss of STC2 reduced E2-stimulated tumor growth EC in vivo. In conclusion, STC2 deficiency suppressed E2-stimulated proliferation and tumor growth of EC through the activation of AMPK signaling.
Keywords: AMP-activated protein kinase, apoptosis, endometrial cancer, estrogen, proliferation, stanniocalcin 2
|How to cite this article:|
Wang Q, Wang Q, Zhao Y. Stanniocalcin 2 is induced by estrogen and promotes growth in endometrial cancer via AMPK pathway. Chin J Physiol 2023;66:111-7
| Introduction|| |
Endometrial cancer (EC) is a common gynecological malignancy worldwide with an increasing incidence. EC includes Type I and Type II based on estrogen dependency, and Type I, with increased estrogen dependency, is the major type of EC. Therapeutic strategies, including radiotherapy, chemotherapy, and standard surgery, have been widely used in the treatment of patients with early-stage EC. The 5-year survival rate for patients with early-stage EC is approximately 80%, while the prognosis for patients with advanced EC remains poor. Therefore, exploring the novel diagnostic and prognostic biomarkers of EC and understanding the underlying mechanisms involved in tumor progression are essential for the improvement of patients with advanced EC.
Estrogen has been widely known as a risk factor for tumorigenesis of the endometrium. Estrogen signaling through ERs (ERs), including ER-α and ER-β, is an oncogenic signaling in the development of EC. Estrogen signaling enhanced cell proliferation, invasion, and epithelial–mesenchymal transformation of EC.,, Estrogen also inhibited autophagy and promoted tumor growth of EC. The suppression of estrogen-induced endometrial growth showed promising inhibitory effects on the EC progression.
Stanniocalcin 2 (STC2) is identified as a glycosylated peptide hormone and plays a pivotal role in angiogenesis, cell development, cytoprotection, and calcium and phosphate regulation during the development of cancer. A high expression of STC2 was associated with a poor prognosis of solid cancers, and overexpression of STC2 promoted cell proliferation, metastasis, and chemo- or radioresistance of cancer cells. Therefore, STC2 is a potential therapeutic target for distinct tumors. It has been reported that STC2 was upregulated in EC, and an elevated expression of STC2 was associated with the recurrence and predicted poor prognosis in EC. However, the role of STC2 in EC progression remains unclear. Moreover, estrogen exposure stimulated the upregulation of STC2 in breast cancer cells, and STC2 was regarded as an estrogen-responsive gene in tumorigenesis. STC2 might also be triggered by estrogen and contributes to cell proliferation and metastasis of EC.
In this study, the effects of STC2 on cell proliferation and apoptosis of estrogen-induced EC were investigated, and the effect of STC2 on in vivo tumor growth of EC was also assessed.
| Materials and Methods|| |
The expression of STC2 in the EC tissues was analyzed by TIMER (https://cistrome.shinyapps.io/timer/), GEPIA (http://gepia.cancer-pku.cn/index.html), and UALCAN (http://ualcan.path.uab.edu/cgi-bin/TCGAExResultNew2.pl?genenam=MED27andctype=STAD).
Human tissues and immunohistochemistry
Patients with type I estrogen-related EC (n = 30) and type II estrogen-independent EC (n = 15) were recruited at the Medical Ethics Committee of Zhejiang Provincial People's Hospital. Tissues were surgically collected from these patients. Benign endometrial tissues were also harvested from the volunteers (n = 20). The experiment was approved by the Medical Ethics Committee of Zhejiang Provincial People's Hospital (approval no. 20220063) and in accordance with those of the 1964 Helsinki Declaration and its later amendments for the ethical research involving human subjects. Tissues were fixed with 10% formalin and embedded in paraffin. The paraffin-embedded tissues were sliced into 4-μm thick sections. Sections were deparaffinized, rehydrated, and then immersed in tris-ethylenediaminetetraacetic acid buffer containing 0.05% Tween 20. After incubated with 3% hydrogen peroxide and blocked in 5% dry milk, the sections were probed overnight with rabbit antihuman STC2 antibody (1:50; Santa Cruz Biotechnology, Santa Cruz, CA, USA). Sections were then incubated with horseradish peroxidase-labeled goat anti-rabbit secondary antibody (Santa Cruz Biotechnology, Santa Cruz, CA, USA). Slides were incubated with 3,3'-diaminobenzidine and counterstained with hematoxylin before measurement under microscope (Olympus, Tokyo, Japan).
Cell culture and transfection
Ishikawa and RL95-2 cells were grown in Dulbecco's Modified Eagle's Medium containing 10% fetal bovine serum (Gibco, Gaithersburg, MD, USA). Cells were transfected with sh-STC2 or shNC (RiboBio, Guangzhou, China) using lipofectamine 2000 (Invitrogen, Carlsbad, CA, USA) for 48 h and then treated with 0.001, 0.01, 0.1, 1, or 10 μmol/L 17β-estradiol (E2; Sigma-Aldrich, St. Louis, MO, USA) or 10 μmol/L compound C for 24 h.
Cell viability assay
Ishikawa and RL95-2 cells were seeded in 96-well plates for 24 h and cultured in medium for 24, 48, 72, or 96 h. Cells were treated with CCK8 solution (Beyotime, Beijing, China) for 2 h. Absorbance at 450 nm was examined through a microplate autoreader (Thermo Fisher, Waltham, MA, USA).
Colony formation assay
Ishikawa was seeded in 6-well plates and cultured in medium for 10 days. Cells were fixed in methanol and then stained with crystal violet. The colonies were photographed under the light microscope.
Ishikawa was harvested after trypsin digestion and resuspended in 100 μL binding buffer (KeyGEN BioTech, Jiangning, Nanjing, China). Cells were treated with 100 μg/mL propidium iodide and then incubated with fluorescein isothiocyanate-conjugated annexin V. Cells were analyzed by FACS flow cytometer (Attune, Life Technologies, Darmstadt, Germany).
Cells and tumor tissues were lysed in RIPA buffer (KeyGEN BioTech, Jiangning, Nanjing, China) and centrifuged at 12,000 × g for 60 min to collect the protein samples. Samples were separated by SDS-PAGE, and electrotransferred onto PVDF membrane. Membranes were blocked with 5% skim milk and probed with primary antibodies, including anti-STC2, anti-β-actin (1:3000), antiphosphorylated-AMP-activated protein kinase (anti-p-AMPK), and anti-AMPK (1:4000). Membranes were incubated with horseradish peroxidase-labeled secondary antibody (1:5000) and subjected to enhanced chemiluminescence (KeyGEN BioTech) to detect the immunoreactivities. All the proteins were purchased from Santa Cruz Biotechnology.
Mouse xenograft assay
To stable silencing STC2, shRNA targeting STC2 or shNC was inserted into the pAAV-U6-GFP vector (Cell Biolabs, San Diego, CA, USA). HEK-293T cells were co-transfected with pAAV-shSTC2 or pAAV-shNC with pHelper and pAAV-DJ Rep-Cap. Viruses were harvested and then infected with Ishikawa cells to obtain stable cells. BALB/c nude mice (n = 20; 4–6 weeks old, 18–20 g weight) were divided into four groups: sh-NC (n = 5), sh-STC2 (n = 5), sh-NC with E2 (n = 5), and sh-STC2 with E2 (n = 5). The experiment was approved by the Medical Ethics Committee of Zhejiang Provincial People's Hospital (Approval no. 20220063) and in accordance with the National Institutes of Health Laboratory Animal Care and Use Guidelines. Stable STC2-silencing Ishikawa cells or the negative control was subcutaneously injected into the nude mice. Mice in the sh-NC with E2 or sh-STC2 with E2 groups were subcutaneously injected with 500 mg/kg E2 once a week 2 days after cell injection. The tumor volume was calculated every week and weighed 5 weeks later.
All the data were expressed as the mean ± standard error of the mean and analyzed via the Student's t-test or one-way analysis of variance in GraphPad Prism software (GraphPad Software, San Diego, CA, USA). P < 0.05 was considered statistically significant.
| Results|| |
Stanniocalcin 2 was elevated in the estrogen-related endometrial cancer tissues
To investigate the role of STC2 in EC, bioinformatic analysis was performed to detect the expression of STC2 in EC. Results showed that STC2 was upregulated in the EC tissues compared to the normal tissues based on TIMER [Figure 1]a, GEPIA [Figure 1]b, and UALCAN [Figure 1]c. Immunohistochemistry confirmed the upregulation of STC2 in the EC tissues [Figure 1]d. The type I estrogen-related EC tissues showed a higher expression of STC2 than the type II estrogen-independent EC tissues [Figure 1]d. Ishikawa and RL95-2 cells were then treated with increasing concentrations of E2 in 0.001, 0.01, 0.1, 1, or 10 μM. Treatment with E2 significantly increased STC2 in Ishikawa and RL95-2 cells [Figure 1]e compared to that in cells without E2 treatment, and E2 treatment (0.1 μM) showed the highest expression of STC2 [Figure 1]e.
|Figure 1: STC2 was elevated in the estrogen-related EC tissues. (a) The expression level of STC2 in the EC tissues and normal tissues based on TIMER analysis (https://cistrome.shinyapps.io/timer/). (b) STC2 was upregulated in the EC tissues (n = 174) compared to the normal tissues (n = 91) based on GEPIA analysis (http://gepia.cancer-pku.cn/index.html). Red color represents the EC tissues, and black color represents the normal tissues. UCEC represents uterine corpus endometrial cancer. (c) The expression levels of STC2 in the EC tissues (n = 546) and normal tissues (n = 35) based on UALCAN analysis (http://ualcan.path.uab.edu/cgi-bin/TCGAExResultNew2.pl?genenam=MED27&ctype=STAD). (d) Immunohistochemistry confirmed the upregulation of STC2 in the EC tissues, and the type I estrogen-related EC tissues demonstrated a higher expression of STC2 than the type II estrogen-independent EC tissues. (e) Treatment with E2 significantly increased STC2 in Ishikawa and RL95-2 compared to that without E2 treatment, and E2 treatment (0.1 μM) showed the highest expression of STC2. (n = 3). *P < 0.05, **P < 0.01, ***P < 0.001. STC2: Stanniocalcin 2, EC: Endometrial cancer.|
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Knockdown of stanniocalcin 2 reduced the proliferation of 17β-estradiol-induced endometrial cancer cells
Loss-of-functional assays were used to detect the effect of STC2 on the proliferation of EC. Ishikawa [Figure 2]a and RL95-2 cells, with or without 0.1 μM E2 treatment, were transfected with sh-STC2 to decrease the protein expression of STC2. Treatment with E2 increased the cell viability of Ishikawa and RL95-2 cells [Figure 2]b and promoted the proliferation of Ishikawa cells [Figure 2]c. However, silencing of STC2 decreased the cell viability of E2-induced Ishikawa and RL95-2 cells [Figure 2]b and inhibited the proliferation of E2-induced Ishikawa [Figure 2]c.
|Figure 2: Knockdown of STC2 reduced the proliferation of E2-induced EC cells. (a) Ishikawa cells were transfected with sh-STC2 or sh-NC for 48 h, then treated with E2 or vehicle for 24 h, and STC2 protein expression was detected by western blot. (b) Silencing of STC2 reduced the cell viability of Ishikawa and RL95-2 and attenuated E2-induced increase of the cell viability in Ishikawa and RL95-2 based on the CCK8 assay. (c) Silencing of STC2 reduced the cell proliferation of Ishikawa and attenuated E2-induced increase of cell proliferation in Ishikawa based on the colony formation assay. (n = 3). *P < 0.05, **P < 0.01, ***P < 0.001. STC2: Stanniocalcin 2, EC: Endometrial cancer, E2: 17β-estradiol.|
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Knockdown of stanniocalcin 2 promoted apoptosis of 17β-estradiol-induced endometrial cancer cells
The effect of STC2 on apoptosis of EC was assessed using flow cytometry. Knockdown of STC2 promoted cell apoptosis of Ishikawa cells [Figure 3], while treatment with E2 reduced cell apoptosis of Ishikawa cells [Figure 3]. However, the loss of STC2 promoted cell apoptosis of E2-induced Ishikawa cells [Figure 3].
|Figure 3: Knockdown of STC2 promoted apoptosis of E2-induced EC cells. Silencing of STC2 promoted cell apoptosis of Ishikawa and attenuated E2-induced decrease of cell apoptosis in Ishikawa based on the flow cytometry assay. (n = 3). *P < 0.05, **P < 0.01, ***P < 0.001. STC2: Stanniocalcin 2, EC: Endometrial cancer, E2: 17β-estradiol.|
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Knockdown of stanniocalcin 2 promoted the activation of AMP-activated protein kinase in 17β-estradiol-induced endometrial cancer cells
Underlying mechanism involved in STC2-mediated EC was evaluated. Transfection with sh-STC2 increased the protein expression of p-AMPK in Ishikawa cells [Figure 4]a. However, E2 reduced p-AMPK expression in Ishikawa cells [Figure 4]a. Moreover, silencing of STC2 attenuated E2-induced decrease in p-AMPK in Ishikawa cells [Figure 4]a. Treatment with AMPK inhibitor, compound C, attenuated STC2 defciency-induced decrease of cell viability in E2-induced Ishikawa cells [Figure 4]b.
|Figure 4: Knockdown of STC2 promoted the activation of AMPK in E2-induced EC cells. (a) Silencing of STC2 enhanced the protein expression of p-AMPK in Ishikawa, and attenuated E2-induced decrease of p-AMPK expression in Ishikawa. (b) Treatment with AMPK inhibitor and compound C attenuated an STC2 deficiency-induced decrease of the cell viability in E2-induced Ishikawa. (n = 3). ***P < 0.001. AMPK: AMP-activated protein kinase, p-AMPK: Phosphorylated-AMPK, STC2: Stanniocalcin 2, EC: Endometrial cancer, E2: 17β-estradiol.|
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Knockdown of stanniocalcin 2 suppressed 17β-estradiol-induced tumor growth of endometrial cancer
Mouse xenograft assay was conducted to evaluate the effect of STC2 on the tumor growth of EC. Mice were injected with stable STC2-silencing Ishikawa cells, and then treated with E2. The loss of STC2 inhibited in vivo tumor growth of EC through decreasing of tumor weight and volume [Figure 5]a. E2 treatment promoted the tumor weight and volume of EC [Figure 5]a. However, the loss of STC2 repressed E2-induced tumor growth of EC with the reduction of tumor weight and volume [Figure 5]a. Transfection with sh-STC2 increased the protein expression of p-AMPK in tumor tissues [Figure 5]b. However, E2 reduced p-AMPK expression [Figure 5]b. Moreover, silencing of STC2 attenuated an E2-induced decrease in p-AMPK in the tumor tissues [Figure 5]b.
|Figure 5: Knockdown of STC2 suppressed the E2-induced tumor growth of EC. (a) E2 treatment promoted the tumor weight and volume of EC, while the loss of STC2 repressed the E2-induced tumor growth of EC with a reduction of tumor weight and volume. (b) Silencing of STC2 enhanced the protein expression of p-AMPK in the tumor tissues and attenuated an E2-induced decrease of p-AMPK expression. (n = 3). ***P < 0.001. p-AMPK: Phosphorylated-AMP-activated protein kinase, STC2: Stanniocalcin 2, EC: Endometrial cancer, E2: 17β-estradiol.|
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| Discussion|| |
Estrogen signaling functions as oncogenic signaling in EC. Estrogen stimulated the upregulation of UBE2C through ER-α, and UBE2C promoted cell proliferation, metastasis, and epithelial-mesenchymal transformation of EC. RIZ1 functioned as a tumor suppressor in EC in an estrogen-dependent way. This study showed that STC2 was an estrogen-responsive gene, and STC2 deficiency inhibited estrogen-stimulated tumor growth of EC.
The previous study has shown that STC-1 was reduced in the EC tissues. STC-1 also suppressed cervical cancer proliferation and metastasis. Nuclear factor kappa-B (NF-κB) binds to the promoter region of STC-1 and promotes STC-1 expression in cervical cancer. NF-κB is activated in cervical cancer with a reduced level of nonphosphorylated p65 protein, and reduced p65 resulted in a decrease in STC-1. Considering that NF-κB is also activated in EC, reduced p65 might also inhibit the expression of STC-1 in EC. However, immunohistochemical analysis showed that STC2 was upregulated in the EC tissues. STC2 was identified as an oncogene in the distinct tumors.,,, Results in this study also confirmed the upregulation of STC2 in the EC tissues. Type I estrogen-related EC tissues demonstrated a higher expression of STC2 than type II estrogen-independent EC tissues, and estrogen-stimulated STC2 expression in EC cells suggesting that STC2 was an estrogen-responsive gene in EC. Knockdown of STC2 attenuated estrogen-induced decrease in cell apoptosis and increase in the proliferation in EC cells. Moreover, silencing of STC2 also inhibited estrogen-stimulated in vivo tumor growth of EC. Therefore, STC2 functioned as an oncogene in EC. However, the effects of STC2 on estrogen-induced migration, invasion, and epithelial-mesenchymal transformation of EC should be investigated in further research.
AMPK signaling is known as an energy sensor, and an increased AMP/ATP ratio initiates the activation of AMPK signaling and stimulates the catabolic pathways to maintain energy homeostasis., Therefore, AMPK signaling functioned as a metabolic tumor suppressor to inhibit tumor progression through the regulation of cell growth and metabolism. Estrogen has been reported to mediate glucose homeostasis and energy balance through AMPK signaling, and to induce the downregulation of p-AMPK in EC cells. Furthermore, the activation of AMPK signaling contributed to the suppression of estrogen-dependent EC progression. STC2 modulated AMPK signaling to mediate autophagy and epithelial-mesenchymal transition of trophoblasts. In this study, estrogen reduced the protein expression of p-AMPK to stimulate EC progression. However, the loss of STC2 increased the p-AMPK expression in estrogen-induced EC cells, indicating that STC2 might promote the proliferation and growth of EC through the inactivation of AMPK signaling.
| Conclusion|| |
Collectively, STC2 was an estrogen-responsive gene in EC. STC2 was upregulated by estrogen, and the loss of STC2 repressed the proliferation and growth of EC. The activation of AMPK signaling was involved in the suppressive effect of STC2 deficiency on EC progression. Therefore, STC2 might be a potential target for type I estrogen-related EC. However, the mechanism involved in the STC2-mediated type II estrogen-independent EC should be investigated in further research.
The authors declare that all data supporting the findings of this study are available within the paper and any raw data can be obtained from the corresponding author upon request.
Financial support and sponsorship
This work was supported by the Zhejiang Medical and Health Science and Technology Project (Grant No. 2021KY533).
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]