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BDNF facilitates ectopic endometrial stromal cell growth, invasion, migration and glycolysis in endometriosis via upregulating GLUT1
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Received: ,
Accepted: ,
How to cite this article: Han Y, Yu Y, Han Y, Guan W, Li J, Feng B, et al. BDNF facilitates ectopic endometrial stromal cell growth, invasion, migration and glycolysis in endometriosis via upregulating GLUT1. CytoJournal. 2026;23:19. doi: 10.25259/Cytojournal_169_2024
Abstract
Objective:
Brain-derived neurotrophic factor (BDNF) is considered to participate in regulating the endometriosis (EM) process. However, other functions and mechanisms of BDNF in EM progression still need to be further studied.
Material and Methods:
Ectopic/normal endometrial stromal cells (ESCs) were isolated from EM tissues/normal control endometrial tissues. BDNF mRNA expression in EM tissues and normal control endometrial tissues was analyzed through quantitative real-time polymerase chain reaction. The protein levels of BDNF and glucose transporter 1 (GLUT1) were detected by Western blot. The function of ESCs was determined through cell counting kit 8 assay, 5-ethynyl-2’-deoxyuridine assay, flow cytometry, Transwell assay, and wound healing assay. The interaction between BDNF and GLUT1 was assessed through a co-immunoprecipitation assay and immunofluorescence staining.
Results:
BDNF expression was elevated in EM tissues and ectopic ESCs. Functional experiments revealed that BDNF knockdown repressed ectopic ESC proliferation, invasion, migration, and glycolysis and promoted apoptosis. In terms of mechanism, BDNF interacted with GLUT1 to enhance its protein expression. In addition, the repressing effect of BDNF knockdown on ectopic ESCs’ growth, invasion, migration, and glycolysis was abolished by GLUT1 overexpression.
Conclusion:
Our study showed that BDNF could facilitate ectopic ESC function by interacting with GLUT1, thereby providing basic information for finding an effective therapeutic target of EM.
Keywords
Brain-derived neurotrophic factor
Endometriosis
Glucose transporter 1
INTRODUCTION
Endometriosis (EM), which mostly occurs in women of reproductive age, is characterized by abnormal growth of endometrial tissue outside the uterus.[1] Although EM is a benign gynecological disease, it can exhibit biological behaviors similar to tumors and may lead to the development of ovarian cancer.[2,3] Endometrial stromal cells (ESCs) are among the important functional cells in the endometrium, and their abnormal activation is closely related to EM occurrence.[4-6] Therefore, understanding the molecular mechanisms that affect ESC function may help find potential targets for EM treatment.
Brain-derived neurotrophic factor (BDNF) plays a vital role in neuron survival, differentiation, and synaptic plasticity regulation.[7] Considerable research confirms that abnormal BDNF expression is associated with human disease progression.[8] For example, BDNF exerts a neuroprotective role in neurodegenerative disease and psychosis.[9] Activated BDNF expression can induce the epithelial–mesenchymal transition of endometrial cancer cells to accelerate malignant cancer behaviors.[10] Moreover, high BDNF expression is overexpressed in EM lesions[11] and patients’ blood samples.[12] A previous study showed that T-cell immunoglobulin and mucin domain 3 facilitated ESC proliferation and migration by activating the BDNF,[13] thereby confirming the positive role of BDNF in the EM process. Therefore, BDNF is likely to be a potential regulator for EM, and its related molecular mechanisms need to be further revealed.
Glucose transporter 1 (GLUT1) is a unimodal transporter responsible for transporting glucose into mammalian cells.[14] GLUT1 enhances glucose metabolism to accelerate lung cancer cell proliferation and migration.[15] Abnormal GLUT1 expression is associated with the progression of EM-related ovarian clear cell carcinoma.[16,17] A study suggests that GLUT1 is overexpressed in transforming growth factor-beta 1-induced mesothelial cells; this scenario may contribute to the development of peritoneal EM.[18] We found that BDNF may interact with GLUT1 by analyzing the STRING protein interaction database. However, whether BDNF interacts with GLUT1 to regulate ESC function and mediate EM progression remains unclear.
Our study aims to explore the molecular mechanisms by which BDNF regulates EM progression. In this research, we hypothesized that BDNF regulates GLUT1-mediated glycolysis to promote ESC function, thereby accelerating the EM process.
MATERIAL AND METHODS
Sample collection
A total of 27 patients with EM and 21 normal control women without EM were recruited from The First Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine. EM tissues and normal control endometrial tissues were collected and stored in a liquid nitrogen container. For this study, each participant provided written informed consent. The study was approved by the Ethics Committee of The First Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine and was performed in accordance with the Declaration of Helsinki.[19]
Cell isolation, culture, and transfection
As previously described,[13] the harvested EM tissues/normal control endometrial tissues were washed, homogenized, and centrifuged, followed by incubation with type I collagenase for 40 min. After the termination of digestion, the suspension was filtered through cell sieves, and the collected ectopic/control ESCs were cultured in the Dulbecco’s Modified Eagle Medium/F12 medium (PM150312, Procell, Wuhan, China) containing 10% fetal bovine serum (164210-50, Procell) and 1% penicillin–streptomycin (PB180120, Procell). The isolated human ectopic/control ESCs were identified using IF staining. For transfection, the ectopic ESCs were transfected with small interfering RNA against BDNF (siBDNF: F 5'-UUUUACUAGAGAUGUUCUCUC-3', R 5'-GAGAACAUCUCUAGUAAAAAG-3'), pcDNA3.1 GLUT1 overexpression vector, and negative controls using lipofectamine 3000 (Invitrogen, Waltham, MA, USA). Ectopic/control ESCs were identified through short tandem repeat and were tested to confirm the absence of mycoplasma contamination.
Quantitative real-time polymerase chain reaction (PCR)
TRIzol reagent (15596026CN, Invitrogen) was utilized to isolate total RNAs, and the PrimeScript Reverse Transcription Reagent Kit (RR037A, Takara, Tokyo, Japan) was used to synthesize cDNA. PCR assay was conducted in the PCR system (CFX96, Bio-Rad, Hercules, CA, USA) by mixing SYBR Green (RR820A, Takara) with cDNA and specific primers, including the following: BDNF, F 5'-GCTGATGGGGTGCGAGTATT3', R5'-AGTCTTTGGTGCCCGGTATG-3'; GLUT1, F5'-GGCCA AGAGTGTGCTAAAGAA-3', R 5'-ACAGCGTTGATGCCAG CAG-3'; β-actin, F 5'-TGGATCAGCAAGCAGGAGTA-3', R 5'-TCGGCCACATTGTGAACTTT-3'. The relative BDNF mRNA expression was calculated by using the 2−ΔΔCt method.
Western blot (WB)
The protein samples were isolated by radio immunoprecipitation assay buffer (P0013B, Beyotime, Shanghai, China), quantified by bicinchoninic acid assay kit (P0009, Beyotime), separated by gel, and transferred onto membranes (FFP24, Beyotime). After blockage, the membranes were incubated with primary antibodies (Abcam, Cambridge, MA, USA), including anti-BDNF (1:1000, ab108319), anti-GLUT1 (1:100000, ab115730), anti-alpha-smooth muscle actin (α-SMA;1:1000, ab7817), anti-hexokinase 2 (HK2, 1:1000, ab209847), anti-β-actin (1:1000, ab8227), and secondary antibody (1:50000, ab205718). Finally, protein bands were visualized.
Cell counting kit 8 (CCK8) assay
Ectopic ESCs were inoculated in 96-well plates and incubated with CCK8 solution (CK04, Dojindo, Kumamoto, Japan), and cell viability was evaluated under a SpectraMax i3x microplate reader at 450 nm.
5-ethynyl-2’-deoxyuridine (EdU) assay
Ectopic ESCs in 24-well plates were incubated with EdU solution and stained with Apollo solution using EdU Kit (C10310-1, Ribobio, Guangzhou, China). 4’,6-Diamidino-2-phenylindole (DAPI) staining (C1005, Beyotime) was employed to visualize cell nuclei. Finally, positive cells were visualized under a BX53 fluorescence microscope.
Flow cytometry
Ectopic ESCs were resuspended in a binding buffer. The cells were mixed with Annexin V-Fluorescein isothiocyanate and propidium iodide (C1062S, Beyotime) and were incubated for 10 min in the dark. The cell apoptosis rate was analyzed using a FACScalibur flow cytometer.
Transwell assay
Ectopic ESCs were seeded into the upper chamber of the 24-well Transwell plate with Matrigel-coated filters (354230, Corning Inc., Corning, NY, USA). After 24 h, the invaded cells number was counted under a microscope (IX71, Olympus).
Wound healing assay
Ectopic ESCs in six-well plates were cultured, and 90% confluences were reached. Then, a straight wound was created using a 200 μL pipette tip. After being washed, the cells were cultivated in a serum-free medium for 24 h. Wound width was visualized under an IX71 microscope to measure migration distance.
Detection of cell glycolysis
Glucose consumption, lactate production, and adenosine triphosphate (ATP)/adenosine diphosphate (ADP) ratio were evaluated in ectopic ESCs using the glucose assay kit (ab65333, Abcam), L-Lactate assay kit (ab65331, Abcam), and ADP/ATP ratio assay kit (ab65313, Abcam), respectively.
Co-immunoprecipitation (Co-IP) assay
The STRING protein interaction database (https://cn.string-db.org/cgi/input?sessionId=bcZcZKlR5wHb&input_page_active_form=multiple_identifiers) was used to analyze the interaction between BDNF and GLUT1. The lysates of ectopic ESCs were treated with anti-GLUT1 (1:100, ab115730, Abcam) or anti-BDNF (1:100, ab108319, Abcam), precoated with protein A/G agarose beads (Pierce, Rockford, IL, USA) for 2 h with rotation. The samples were washed with PBS and eluted using 2 × lithium dodecyl sulfate buffer. After being boiled, the proteins were collected for WB assay to detect GLUT1 and BDNF protein signals for analyzing the interaction between GLUT1 and BDNF.
Immunofluorescence (IF) staining
Ectopic ESCs transfected with si-NC/si-BDNF were fixed and permeabilized. After blockage, the cells were incubated with anti-BDNF (1:500, ab205067, Abcam) and anti-GLUT1 (1:1000, ab115730, Abcam) on a shaking table overnight, followed by incubation with fluorescent Cy3-conjugated goat anti-rabbit Immunoglobulin G (IgG) (1:1000, ab6939, Abcam) and Alexa Fluor 488 goat anti-mouse IgG (1:1000, ab150113, Abcam). After being stained with DAPI (C1005, Beyotime), the images were obtained under a fluorescence microscope (BX53, Olympus) to explore the colocalization of BDNF and GLUT1 in ectopic ESCs, as well as the effect of BDNF knockdown on GLUT1 signal.
Statistical analysis
All experiments were performed in triplicate. All data were expressed as mean ± SD. Statistical analysis was conducted through GraphPad Prism software (version 8.0, GraphPad, San Diego, CA, USA). Student’s t-test or Analysis of Variance, followed by Bonferroni post hoc test, was conducted to analyze group differences. P <0.05 was deemed statistically significant.
RESULTS
BDNF was upregulated in EM tissues and ectopic ESCs
We determined the BDNF expression in EM tissues and normal endometrial tissues. BDNF mRNA and protein levels were enhanced in EM tissues (P <0.05; [Figure 1a and b]). Then, we isolated the ectopic and normal ESCs from EM tissues and normal endometrial tissues, respectively. As shown in Supplementary Figure 1, we detected the surface marker α-SMA expression in ectopic ESCs. We also confirmed that the α-SMA protein level was highly expressed in ectopic ESCs. These data suggested that the extraction of ectopic ESCs was successful. BDNF expression was markedly increased in ectopic ESCs at the mRNA and protein levels (P <0.05; [Figure 1c and d]). The above data confirmed the abnormal expression of BDNF in EM tissues and ectopic ESCs, suggesting that BDNF might participate in EM development.
- BDNF expression in EM tissues. (a and b) BDNF levels were examined in EM tissues and normal endometrial tissues. (c and d) BDNF mRNA and protein levels in ectopic ESCs and normal ESCs were detected (n = 3). ESCs: Endometrial stromal cells, BDNF: Brain-derived neurotrophic factor, EM: Endometriosis. ✶P <0.05.
Knockdown of BDNF repressed the function of ectopic ESCs
We performed loss-of-function experiments to determine the role of BDNF in EM. After the ectopic ESCs were transfected with si-BDNF, we found that the BDNF mRNA and protein expression levels were markedly decreased, thereby confirming the transfection efficiency of si-BDNF in ectopic ESCs (P <0.05; [Figure 2a and b]). BDNF silencing inhibited viability, reduced the EdU-positive cell rate, and promoted the apoptosis rate in ectopic ESCs (P <0.05; [Figure 2c-e]). Moreover, BDNF downregulation decreased the invaded cell numbers and migration distance in ectopic ESCs (P <0.05; [Figure 2f and g]). In addition, we detected the low glucose consumption, lactate production, and ATP/ADP ratios in ectopic ESCs after the BDNF knockdown (P <0.05; [Figure 2h-j]). The above data showed that BDNF might accelerate ectopic ESC growth, invasion, migration, and glycolysis to aggravate EM progression.
- Effect of si-BDNF on the function of ectopic ESCs. Ectopic ESCs were transfected with si-NC/si-BDNF (n = 3). (a and b) BDNF mRNA and protein levels were examined in ectopic ESCs of si-NC and si-BDNF groups (n = 3). (c) CCK8 assay, (d) EdU assay (Scale bar = 50 μm), (e) flow cytometry, (f) Transwell assay (Scale bar = 50 μm), and (g) wound healing assay (Scale bar = 100 μm) were used to examine cell functions. (h-j) Cell glycolysis was determined using a glucose assay kit, L-Lactate assay kit, and ADP/ATP ratio assay kit. ATP: Adenosine triphosphate, ADP: Adenosine diphosphate, CCK8: Cell counting kit 8, EdU: 5-ethynyl-2’-deoxyuridine, BDNF: Brain-derived neurotrophic factor, ESCs: Endometrial stromal cells. ✶P <0.05.
BDNF interacted with GLUT1
Given the positive role of GLUT1 in EM progression,[20,21] we explored its relationship with BDNF. The analysis of the STRING protein interaction database showed that BDNF could interact with GLUT1 [Figure 3a]. Moreover, we discovered that GLUT1 had elevated protein expression in ectopic ESCs isolated from EM tissues (P <0.05; [Figure 3b]), and it could be repressed by BDNF knockdown at the mRNA and protein levels (P <0.05; [Figure 3c and d]). Through the Co-IP assay, GLUT1 was enriched by anti-BDNF, and BDNF was enriched by anti-GLUT1. This observation confirmed the interaction between BDNF and GLUT1 [Figure 3e]. Moreover, IF staining results revealed that BDNF and GLUT1 colocalized in the cytoplasm of ectopic ESCs, and BDNF knockdown led to decreased GLUT1 expression in ectopic ESCs [Figure 3f]. Thus, we believed that BDNF might positively regulate GLUT1 expression by interaction.
- BDNF regulated GLUT1. (a) STRING protein interaction database analyzed the BDNF and GLUT1 interaction. (b and c) GLUT1 mRNA and protein levels were detected in ectopic ESCs and normal ESCs (n = 3). (d) The GLUT1 protein level in ectopic ESCs transfected with si-NC/si-BDNF was examined (n = 3). (e) Co-IP assay and (f) IF staining (Scale bar = 20 μm) were used to confirm BDNF and GLUT1 interaction (n = 3). Co-IP: Co-immunoprecipitation, IF: Immunofluorescence, ESCs: Endometrial stromal cells, BDNF: Brain-derived neurotrophic factor, GLUT1: Glucose transporter 1, EM: Endometriosis.✶P <0.05.
GLUT1 overexpression reversed the function of si-BDNF mediation on ectopic ESCs
In the following experiments, we constructed a GLUT1 overexpression vector to perform a rescue study. The transfection of the GLUT1 vector was used to enhance GLUT1 mRNA and protein expression levels (P <0.05, [Figure 4a and b]). As shown in Figure 4c-e, the decreased viability, reduced EdU-positive cell rate, and increased apoptosis rate in ectopic ESCs caused by si-BDNF could be reversed by GLUT1 overexpression (P <0.05). Furthermore, GLUT1 upregulation eliminated the inhibitory effect of BDNF knockdown on invaded cell numbers, migration distance, glucose consumption, lactate production, ATP/ADP ratio, and HK2 protein expression in ectopic ESCs (P <0.05; [Figure 5a-e, Supplementary Figures 2 and 3]). These results suggested that BDNF might promote the EM process by interacting with GLUT1.
- Effects of si-BDNF and GLUT1 on the function of ectopic ESCs. (a and b) GLUT1 mRNA and protein levels were examined in ectopic ESCs transfected with vector/GLUT1 (n = 3). Cell functions were examined by (c) CCK8 assay, (d) EdU assay (Scale bar = 50 μm), and (e) flow cytometry in ectopic ESCs of si-NC, si-BDNF, si-BDNF+vector and si-BDNF+GLUT1 groups (n = 3). CCK8: Cell counting kit 8, EdU: 5-ethynyl-2’-deoxyuridine, BDNF: Brain-derived neurotrophic factor, GLUT1, Glucose transporter 1, ESCs: Endometrial stromal cells. ✶P <0.05.
- Effects of si-BDNF and GLUT1 on the invasion, migration, and glycolysis of ectopic ESCs. Cell migration and invasion were detected using (a) Transwell assay (Scale bar = 50 μm) and (b) wound healing assay in in ectopic ESCs of si-NC, si-BDNF, si-BDNF+vector and si-BDNF+GLUT1 groups (n = 3). (c-e) Glucose assay kit, L-Lactate assay kit, and ADP/ATP ratio assay kit were used to test cell glycolysis. ATP: Adenosine triphosphate, ADP: Adenosine diphosphate, BDNF: Brain-derived neurotrophic factor, GLUT1: Glucose transporter 1, ESCs: endometrial stromal cells. ✶P <0.05.
DISCUSSION
EM, which mostly occurs in the peritoneal surface of the pelvic reproductive organs and their adjacent organs, is a common gynecological disease with an increasing incidence. The symptoms caused by EM seriously impact women’s health and quality of life.[22] Previous studies have shown that ectopic ESCs undergo extensive metabolic reprogramming changes, increased invasiveness, decreased apoptotic ability, and changes in immune function, thereby mediating the pathogenesis of EM.[23] Therefore, exploring the molecular mechanisms that affect the functional changes of ectopic ESCs is important. In this study, we pointed out that BDNF may facilitate the growth, invasion, migration, and glycolysis of ectopic ESCs by positively regulating GLUT1, thereby providing a new idea for EM treatment.
BDNF serves as a potent protective factor capable of protecting against neurodegeneration, including Parkinson’s disease.[7] BDNF has increased expression in ovarian cancer, and its upregulation accelerates cell proliferation and invasion by activating the TrkB/PLCgamma1 pathway.[24] High BDNF expression contributes to Schwann cell proliferation, thereby promoting the repair of sciatic nerve crush.[25] BDNF enhances lipopolysaccharide (LPS)-induced normal human astrocyte proliferation, increases glial scar formation, and impedes axonal regeneration.[26] Moreover, BDNF is highly expressed in asthma rat models, which may promote airway smooth muscle cell proliferation and hyperresponsiveness in asthma.[27] BDNF also promotes glioma cell proliferation, migration, and invasion.[28] Eucommia leaf extracts enhance lipid metabolism and aerobic glycolytic to control metabolic syndrome in rats by elevating BDNF expression.[29] These results confirm the proproliferation, promigration, proinvasion, and proglycolysis effects of BDNF. BDNF participates in EM development by mediating various signaling pathways.[30] Moreover, BDNF is considered a biomarker for EM detection.[31,32] Dong et al.[33] revealed that BDNF is a critical growth factor in endometrial cells, which regulates cell proliferation to mediate the EM process. The above data verify the promotion effect of BDNF on EM progression. In the present study, we chose BDNF as the object to explore its effect on ESC function. Our results detected the high BDNF expression in EM tissues and ectopic ESCs. The loss of functional analysis revealed that BDNF silencing could repress ectopic ESC proliferation, invasion, migration, and glycolysis and could promote apoptosis. These data indicate that BDNF may promote the function of ectopic ESCs to accelerate EM progression, and its knockdown may be used to alleviate the EM process.
GLUT1-mediated glycolysis is widely involved in regulating various human diseases. For example, GLUT1 increases gastric cancer cell proliferation and metastasis by enhancing glucose utilization.[34] Dihydroartemisinin suppresses the GLUT1-mediated Warburg effect to inhibit hepatocellular carcinoma malignant behaviors.[35] GLUT1 promoted the secretion of inflammatory cytokines and aggravated caerulein-induced pancreatic acinar cell damage, thereby facilitating acute pancreatitis development.[36] Atorvastatin and resveratrol restrain the neovascularization development in ectopic endometrial tissues to inhibit EM progression by suppressing glycolysis through GLUT1 expression reduction.[20] Moreover, GLUT1 is overexpressed in endometrioid foci, plasma, and fluid exosomes of patients with peritoneal EM.[21] These findings confirmed that the abnormal expression of the glycolysis-related GLUT1 is associated with EM. We discovered the interaction between GLUT1 and BDNF through the STRING protein interaction database and Co-IP assay. Further analysis confirmed the colocalization of BDNF and GLUT1 in ectopic ESCs, and BDNF knockdown inhibited GLUT1 expression. The rescue experiments were performed to further verify whether BDNF regulated ESC function by GLUT1. The results revealed that GLUT1 upregulation reversed the inhibitory effect of si-BDNF mediation on ectopic ESC growth, invasion, migration, and glycolysis. This finding showed that BDNF increased the GLUT1 expression to accelerate EM progression.
This study has some limitations. At present, we confirm the existence of the BDNF/GLUT1 axis only at the cellular level, which is insufficient. In the future, further animal laboratory studies are necessary and may provide additional evidence for the regulation of the BDNF/GLUT1 axis on EM progression. In addition, whether the BDNF/GLUT1 axis is involved in the regulation of ectopic ESC function by mediating signaling pathway activity needs to be further explored. This approach may provide insight into the role of the BDNF/GLUT1 axis in EM progression.
SUMMARY
Our study reveals a novel mechanism regulating EM progression. This research shows that BDNF interacts with GLUT1 to upregulate its expression, thereby promoting ectopic ESC growth, invasion, migration, and glycolysis. Our findings suggest that the targeted inhibition of the BDNF/GLUT1 axis may effectively alleviate the EM process, thereby providing a potential molecular target for EM treatment.
ACKNOWLEDGMENT
Not applicable.
AVAILABILITY OF DATA AND MATERIALS
The analyzed data sets generated during the present study and materials are available from the corresponding author on reasonable request.
ABBREVIATIONS
ADP: Adenosine diphosphate
ATP: Adenosine triphosphate
BDNF: Brain-derived neurotrophic factor
CCK8: Cell counting kit 8
EdU: 5-ethynyl-2’-deoxyuridine
Co-IP: Co-immunoprecipitation
IF: Immunofluorescence
GLUT1: Glucose transporter 1
HK2: hexokinase 2
EM: Endometriosis
ESCs: Endometrial stromal cells
qRT-PCR: Quantitative real-time polymerase chain reaction
WB: Western blot
α-SMA: Alpha-smooth muscle actin
AUTHOR CONTRIBUTIONS
YPH: Designed the research study; YPH, YY, YGH, WG, JML, BYF, CS and HYK: Performed the research, analyzed the data; YPH: Wrote the manuscript; YPH, YY, YGH, WG, JML, BYF, CS and HYK: Contributed to editorial changes in the manuscript, read and approved the final manuscript, possess the ability to be responsible for all aspects of the work, ensuring that any issues related to the accuracy or completeness of the work content can be properly investigated and resolved. All the authors have read and approved the final manuscript. All authors are eligible for ICMJE authorship.
ETHICS APPROVAL AND CONSENT TO PARTICIPATE
This study was approved by the Ethics Committee of the First Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine (Approval number: HZYLLBA2022025) and was performed in accordance with the Declaration of Helsinki. Each participant provided written informed consent.
CONFLICTS OF INTEREST
The authors declare no conflicts of interest.
EDITORIAL/PEER REVIEW STATEMENT
To ensure the integrity and highest quality of CytoJournal publications, the review process of this manuscript was conducted under a double-blind model (authors are blinded for reviewers and vice versa) through an automatic online system.
FUNDING: TCM research subject of Heilongjiang TCM Administration
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