Abstract
Invasive pituitary neuroendocrine tumors (PitNETs) are the most prevalent types of intracranial and neuroendocrine tumors. Their aggressive growth and difficulty in complete resection result in a high recurrence rate. Cystine transporter solute carrier family 7 member 11 (SLC7A11) is overexpressed in various cancers, which contributes to tumor growth, progression, and metastasis by promoting cystine uptake and glutathione biosynthesis. We identified SLC7A11 as an invasive biomarker based on three Gene Expression Omnibus cohorts. This study aimed to investigate the role of SLC7A11 in invasive PitNETs. Cell proliferation was assessed using CCK-8 and colony formation assays, while cell apoptosis was estimated with flow cytometry. Wound healing assays and transwell assays were utilized to evaluate migration and invasion ability. Our findings demonstrated that SLC7A11 was markedly upregulated in invasive PitNETs, and was associated with the invasiveness of PitNETs. Knockdown of SLC7A11 could largely suppress tumor cell proliferation, migration, and invasion, while inducing apoptosis. Furthermore, SLC7A11 depletion was implicated in regulating epithelial–mesenchymal transition and inactivating the PI3K/AKT signaling pathway. These insights suggest SLC7A11 as a potential therapeutic target for invasive PitNETs.
Introduction
Pituitary neuroendocrine tumors, representing 10–20% of intracranial tumors in adults, are the second most prevalent benign neuroendocrine tumors in the central nervous system (1, 2, 3). Most pituitary neuroendocrine tumors (PitNETs) are non-invasive, grow slowly, and remain in the sella turcica (4). However, as many as 25–55% of PitNETs may display infiltrative features, such as invasion of the cavernous and sphenoid sinuses, along with either focal or extensive bone erosion, thereby classifying them as invasive PitNETs (4, 5). Invasive PitNETs may demonstrate a rapid growth rate, frequent recurrences, resistance to conventional treatments, and a poorer prognosis (6, 7). In 2017, the World Health Organization classified them as ‘high-risk’ PitNETs (8, 9). The surgical resection of invasive PitNETs poses significant challenges. Typically, patients require post-surgery interventions such as radiotherapy, medication, and occasionally chemotherapy. Therefore, investigating the underlying mechanisms and identifying potential therapeutic targets for invasive PitNETs patients is essential.
Metastasizing cancer cells frequently encounter elevated oxidative stress, necessitating a high demand for extracellular cysteine to bolster their antioxidant defenses (10). Solute carrier family 7 member 11 (SLC7A11) functions as a constituent of the cysteine/glutamate transporter, facilitates cystine import for glutathione biosynthesis and antioxidant defense (11, 12). Previous studies have demonstrated that expression of SLC7A11 was linked to tumor invasion and lymph node metastasis. The study by Chen et al. indicated that SLC7A11 might serve as a potential target to inhibit cancer metastasis (13). Ruiu et al. revealed that deficiency of SLC7A11 reduces metastasis in breast cancer mouse models (14). However, it is unclear whether SLC7A11 regulates metastasis in invasive PitNETs.
In the present study, we explored the function of SLC7A11 in invasive PitNETs. We found that SLC7A11 functions as an invasive biomarker and was highly expressed in invasive PitNETs. In addition, knockdown of SLC7A11 inhibited epithelial–mesenchymal transition (EMT) through the PI3K/AKT signaling pathway.
Materials and methods
Patient data analysis
Transcriptional datasets for PitNETs were acquired from the Gene Expression Omnibus (GEO) database (https://www.ncbi.nlm.nih.gov/geo/), including GSE51618, GSE26966 and GSE169498. These datasets were then normalized as one cohort using the ‘limma’ package in R software. To remove batch effects and other unwanted variation between the three datasets, data were corrected with the ‘sva’ package.
Differential expression analysis
Using these datasets, we identified differentially expressed genes (DEGs) using the Edge R package. Heatmaps were generated using the heatmap package, and volcano plots were depicted with the ggplot2 package in R software. The criteria for DEG selection were set as log fold change (FC) >1 and adjusted P < 0.05. Further functional annotation and pathway enrichment analysis were conducted on DEGs using the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways.
Cell culture
The rat pituitary tumor cell line GH3 was obtained from Procell Life Science & Technology (Wuhan, China) and cultured in F-12K (Gibco) supplemented with 15% horse serum (HS) (Procell) and 2.5% fetal bovine serum (FBS) (Procell). The mouse pituitary tumor cell line GT1-1 was obtained from Cellverse Science & Technology (Shanghai, China) and cultured in DMEM/F12 (Gibco) containing 5% HS (Procell) and 5% FBS (Procell, China). Cells were routinely cultured under standard conditions in a humidified 37°C incubator with 5% CO2.
Lentivirus infection
Short hairpin SLC7A11 (shSLC7A11, sequence: 5′-CCGGAAATCCTCTCTATGA-3′) lentiviral particles and the short hairpin negative control (shNC, sequence: 5′-UUCUCCGAACGUGUCAGU-3′) lentiviral particles were purchased from Sigma-Aldrich. Cells were transfected with lentiviral particles and then subjected to selection using puromycin-containing culture medium (1 mg/mL) for 2 weeks. The knockdown efficiency of SLC7A11 expression was examined by Western blot.
Cell viability assay
Transfected GH3 and GT1-1 cells were seeded in a 96-well plate at a density of 4 × 103 cells/well and cultured for 24, 48, 72, or 96 h. Subsequently, 10 μL of CCK-8 solution was added to each well, followed by a 2-hour incubation at 37°C. The absorbance was measured at 450 nm using a microplate reader.
Colony formation assay
The gene-transfected cells (2 × 103 cells/well) were plated in a six-well plate and were incubated in complete medium for an additional 10–14 days until colonies formed. The colonies were then fixed with 4% paraformaldehyde and stained with 2% crystal violet. Colonies comprising 50 or more cells were counted under a microscope.
Apoptosis assay
Cell apoptosis was detected using the Apoptosis Detection Kit (KeyGEN BioTECH, Nanjing, China). A mixture of 100 µL cells and 400 µL annexin V binding buffer, containing 10 µL PI solution and 5 µL FITC annexin V, was incubated for 30 min at room temperature. The apoptotic rates of stained cells were analyzed by a flow cytometer.
Wound healing assay
Transfected GH3 and GT1-1 cells were maintained in a six-well plate. Upon reaching 90% confluency, the cell monolayer was scratched with a 200 µL pipette tip. After 24 h, the migration distance of the cells was documented using an optical microscope, and cell migration was quantified as the percentage of wound closure.
Cell migration assay and invasion assay
For the migration assay, we seeded 5 × 104 transfected cells in the upper chamber (Costar, Cambridge, MA, USA) with 200 µL of serum-free medium, while the lower chamber contained 500 µL of medium supplemented with 15% horse serum and 5% FBS as a chemoattractant. For the invasion assay, the procedure was similar to the steps of the cell migration assay, with the exception of precoating the chamber with 50 µL Matrigel (BD Biosciences). After 24 h (for the migration assay) or 48 h (for the invasion assay) of incubation, cells adhered to the lower surface were fixed with 4% paraformaldehyde for 15 min, then stained with 2% crystal violet and counted under a microscope.
Western blot
Cell proteins were lysed and extracted using RIPA buffer supplemented with a protease inhibitor. Protein concentrations were measured with the BCA Protein Assay (Beyotime, Nanjing, China). The samples were separated by SDS-PAGE gel and transferred to the PVDF membrane. The membrane was blocked in 5% skim milk and then incubated with primary antibodies followed by horseradish peroxidase-conjugated secondary antibodies. Finally, the protein bands were quantified using an ECL kit. Antibody information is as follows: SLC7A11 (Proteintech), GAPDH (Proteintech), phospho-PI3 kinase (Affinity Biosciences), PI3K (Proteintech), phospho-AKT (Affinity Biosciences), AKT (Proteintech), vimentin (Proteintech), N-cadherin (Proteintech), E-cadherin (Proteintech).
Statistical analysis
Data were analyzed by GraphPad Prism 9 software. Continuous variables across the two subgroups were analyzed using the independent Student’s t-test. Correlation was examined using Pearson’s correlation analysis. When the P-value falls below 0.05, the result was deemed statistically significant.
Results
Identification of DEGs between invasive PitNETs and non-invasive PitNETs
First, we successfully integrated three PitNET (GSE51618, GSE26966, and GSE169498) datasets (Supplementary Table S1, see section on supplementary materials given at the end of this article), then normalized as one cohort. To remove batch effects and other unwanted variation between the three datasets, data were corrected with the ‘sva’ package. Differential expression analysis was performed on invasive PitNETs and non-invasive PitNETs, and 74 downregulated genes and 21 upregulated genes were identified (Supplementary Table S2). The volcano plots (Fig. 1A) and heatmap (Fig. 1B) depict the distribution of DEGs, applying P < 0.05 and |log2FC| >1 as selection thresholds. Therefore, we screened novel genes related to invasiveness in PitNETs.
Identification of DEGs between invasive PitNETs and non-invasive PitNETs. (A) Volcano map of DEGs. (B) Heatmap of DEGs. (C–E) GO enrichment analysis of DEGs. (F) KEGG enrichment analysis of DEGs.
Citation: Endocrine Connections 13, 7; 10.1530/EC-24-0097
GO and KEGG enrichment analysis
Next, we performed functional and pathway enrichment analysis on these DEGs employing GO and KEGG analysis. In terms of biological processes, DEGs were involved in regulation of trans-synaptic signaling and sex differentiation (Fig. 1C). For cellular components, the DEGs were enriched in protein complexes involved in cell-matrix adhesion, collagen-containing extracellular matrix, and basement membrane (Fig. 1D). For molecular functions, the DEGs played roles in extracellular matrix structural constituent, heparin binding, and ion channel activity (Fig. 1E). KEGG analysis indicated an enrichment of DEGs in the PI3K-AKT signaling pathway, neuroactive ligand-receptor interaction, extracellular matrix–receptor interaction, and focal adhesion (Fig. 1F) (Supplementary Table S3). Function enrichment analyses suggested that these DEGs are mainly associated with cell adhesion and extracellular matrix structure.
SLC7A11 as a potential biomarker in invasive PitNETs
SLC7A11 is one of the upregulated genes widely reported in cancer, but it has not been fully elucidated in invasive PitNETs. The preoperative MRI performance of non-invasive and invasive PitNETs was depicted in Fig. 2A. To further evaluate SLC7A11 as a biomarker in invasive PitNETs, we performed immunohistochemical staining to detect SLC7A11 expression in non-invasive and invasive PitNETs. The results revealed that SLC7A11 was highly expressed in invasive PitNETs (Fig. 2B and C). Additionally, SLC7A11 expression was prominently higher in invasive PitNETs based on the three GEO datasets (Fig. 2D, E, and F). The area under the receiver operating characteristic (ROC) curve for predicting invasiveness by SLC7A11 in GSE26966, GSE51618 and GSE169498 was 0.714, 0.762 and 0.697, respectively (Fig. 2G, H, and I). The findings suggested that the SLC7A11 could be used to predict the invasiveness of PitNETs.
SLC7A11 as a potential biomarker in invasive PitNETs. (A) The preoperative MRI performance of non-invasive PitNETs. (B) The preoperative MRI performance of invasive PitNETs. (C) IHC scores of SLC7A11 in non-invasive and invasive PitNETs. (D) SLC7A11 expression in GSE26966. (E) SLC7A11 expression in GSE51618. (F) SLC7A11 expression in GSE169498. (G) ROC curve predicting invasiveness in GSE26966. (H) ROC curve predicting invasiveness in GSE51618. (I) ROC curve predicting invasiveness in GSE169498. Statistical analysis was performed using a two-tailed Student’s t-test. *P < 0.05, **P < 0.01 and ***P < 0.001.
Citation: Endocrine Connections 13, 7; 10.1530/EC-24-0097
Knockdown of SLC7A11 inhibits PitNET cell proliferation and induces apoptosis
SLC7A11 knockdown in GH3 and GT1-1 stable cell lines were successfully established, and the knockdown efficiency was confirmed by Western blot. The results showed the SLC7A11 protein level was obviously decreased (Fig. 3A and B). To examine the role of SLC7A11 on the proliferation of PitNETs, CCK8 and colony formation assays were performed. Our data indicated that the knockdown of SLC7A11 significantly reduced the proliferation of GH3 and GT1-1 cells (Fig. 3C, D, E, and F). Annexin V/PI staining demonstrated that the proportion of apoptotic cells after SLC7A11 knocking down was significantly higher compared to the control group in GH3 and GT1-1 cells. These data illustrated that SLC7A11 was critical for the tumorigenicity of PitNET cells.
Knockdown of SLC7A11 inhibits PitNET cell proliferation and induces apoptosis. (A–B) SLC7A11 knockdown efficiency was examined by Western blot. (C–D) Cell viability was detected by CCK-8 assay. (E–F) Cell proliferation was measured by colony formation assay. (G–J) Cell apoptosis was measured by flow cytometry using annexin V/PI staining. Statistical analysis was performed using a two-tailed Student’s t-test. *P < 0.05, **P < 0.01 and ***P < 0.001.
Citation: Endocrine Connections 13, 7; 10.1530/EC-24-0097
SLC7A11 knockdown inhibits migration, invasion, and EMT in PitNET cells
We then evaluated the effects of SLC7A11 on cell migration and invasion. The wound healing assay demonstrated that SLC7A11 knockdown significantly attenuated PitNET cell migration (Fig. 4A, B, and C). Moreover, depletion of SLC7A11 also notably inhibited cell migration and invasion in PitNET cells (Fig. 4D, E, and F). These results underscore the pivotal role of SLC7A11 in promoting PitNET cell migration and invasion. The EMT represents a morphogenetic process associated with the invasiveness and metastasis of malignant tumors (15). The correlation between SLC7A11 and EMT biomarkers in PitNETs was explored using co-expression correlation analysis. We found a positive expression correlation of SLC7A11 with N-cadherin and vimentin and a negative correlation of SLC7A11 with E-cadherin (Fig. 4G, H, and I). Next, we detected EMT markers by Western blot and revealed that SLC7A11 knockdown resulted in increased expression of the epithelial marker E-cadherin and decreased expression of the mesenchymal markers N-cadherin and vimentin (Fig. 4J, K, and L). These results suggested that depletion of SLC7A11 can inhibit the EMT process.
Downregulation of SLC7A11 inhibits PitNET cell migration, invasion, and EMT. (A–C) Cell migration was detected by wound-healing assays. (D–F) Cell migration and cell invasion ability were detected by transwell assays. (G) Correlation between SLC7A11 expression and E-cadherin. (H) Correlation between SLC7A11 expression and N-cadherin. (I) Correlation between SLC7A11 expression and vimentin. (J–L) Expression of EMT-related molecules was detected by Western blotting. Statistical analysis was performed using a two-tailed Student’s t-test. *P < 0.05, **P < 0.01 and ***P < 0.001.
Citation: Endocrine Connections 13, 7; 10.1530/EC-24-0097
SLC7A11 knockdown inhibits the EMT process via PI3K/AKT pathway in PitNET cells
The KEGG enrichment analysis revealed that the DEGs were significantly enriched in the PI3K/AKT signaling pathway. Emerging evidence suggests that the PI3K/AKT pathway is often dysregulated in cancer and controls core cellular processes, such as proliferation and metastasis (16, 17). Additionally, SLC7A11 was reported to mediate invasion and metastasis through the PI3K/AKT signaling pathway in pancreatic carcinoma (18). Here, we examined whether SLC7A11 promotes EMT through the PI3K/AKT signaling pathway. Western blot analysis revealed that knocking down SLC7A11 resulted in a decrease in the protein levels of phosphorylated PI3K and AKT without altering their total protein levels (Fig. 5A, B, C, and D). This data suggests that SLC7A11 knockdown inhibits EMT by modulating the PI3K/AKT signaling pathway in PitNET cells.
Downregulation of SLC7A11 inhibits the EMT process via the PI3K/AKT pathway in PitNET cells. (A–D) Expression of PI3K/AKT signaling pathway-related proteins and EMT-related molecules was detected by Western blotting. Statistical analysis was performed using a two-tailed Student’s t-test. *P < 0.05, **P < 0.01 and ***P < 0.001.
Citation: Endocrine Connections 13, 7; 10.1530/EC-24-0097
Discussion
Invasive PitNETs present significant challenges and have emerged as a prominent research area within neurological tumors. Invasive PitNETs often invade surrounding structures and cannot be cured with standard therapies (19). There is currently little research focused on the prognosis and mechanisms of invasive PitNETs, with most studies being clinical and imaging (20). Investigating the molecular mechanisms that drive the progression, invasion, and metastasis of PitNETs can contribute to the development of effective treatments.
Solute carriers (SLCs) represent the second-largest group of membrane proteins within the human genome, following G-protein-coupled receptors (21). According to the HUGO Gene Nomenclature Committee database, there are currently 456 identified SLCs categorized into 52 distinct families (22). SLC is likely to support the demands of cancer cells, not only maintaining a supply of biosynthesis, but also adapting to the constantly changing requirements of cancer cells, such as distant metastasis and the acquisition of chemotherapy resistance (23). Previous research has established the critical function of SLC7A11 in tumor development, progression, metastasis, and resistance to multiple drugs across a range of human cancers (24, 25, 26). However, the specific involvement of SLC7A11 in invasive PitNETs remains poorly understood. Thus, this study aimed to address this gap by performing bioinformatics analysis to identify DEGs between invasive and non-invasive PitNETs, with a focus on SLC7A11. Immunohistochemical staining was conducted to validate the expression feature of SLC7A11 in PitNETs. In the GEO datasets, SLC7A11 was highly expressed in invasive PitNETs. Immunohistochemical staining showed that SLC7A11 expression was elevated in invasive PitNETs compared to non-invasive tissues, which is consistent with our bioinformatics analysis results. In addition, ROC curve analysis showed that SLC7A11 could be used to predict the invasiveness of PitNETs. Meanwhile, knocking down SLC7A11 dramatically inhibited the proliferation in PitNET cells, and resulted in an increase in the percentage of apoptotic cells. These findings indicated that SLC7A11 can serve as an invasive marker, and depletion of SLC7A11 inhibited proliferation and induced apoptosis in PitNET cells.
EMT is a cellular process characterized by the loss of epithelial features, dissolution of tight junction contacts, and acquisition of mesenchymal traits including enhanced motility, invasiveness, resistance to apoptosis, and secretion of extracellular matrix components, which facilitate degradation of the basement membrane (27). This process is linked to the increased expression of vimentin and N-cadherin, accompanied by the concomitant decrease of E-cadherin, and contributes to increased invasiveness, dissemination to distant locations, metastatic colonization, cancer stemness, and chemoresistance (28, 29, 30). Additionally, accumulating studies have suggested that EMT might play a vital role in PitNETs development and metastasis (31). GO and KEGG analyses indicated that the function of DEGs was involved in cell adhesion and extracellular matrix structure. Consequently, the result of wound healing and transwell assays discovered that SLC7A11 knockdown inhibited the migration and invasion of PitNET cells. Co-expression correlation analysis indicated a negative correlation of SLC7A11 with E-cadherin and a positive expression correlation of SLC7A11 with N-cadherin and vimentin. The decreased expression of E-cadherin is considered a hallmark molecule and cellular event of EMT (32). Following SLC7A11 knockdown, increased expression of the epithelial marker E-cadherin and decreased expression of the mesenchymal markers N-cadherin and vimentin were observed. These results indicated that SLC7A11 promotes the migration and invasion of PitNETs by regulating the EMT process.
EMT is driven by complex mechanisms controlled by various signaling pathways, including Wnt/β-Catenin, TGF-β, and PI3K/AKT pathways (33, 34, 35, 36). Notably, the PI3K/AKT pathway significantly influences EMT by activating downstream effectors that govern cellular processes such as cell survival, migration, and invasion (37). For example, Hu’s study showed that SLC4A7 promotes EMT and metastasis via the PI3K/AKT/mTOR pathway in HNSCC (38). In glioblastoma, NQO1 could facilitate EMT through the PI3K/Akt/mTOR pathway (39). Chen also reported POLR3G promotes EMT of BLCA through regulation of the PI3K/AKT pathway (40). KEGG analysis indicated an enrichment of DEGs in the PI3K/AKT signaling pathway. We speculate whether SLC7A11 affects EMT through the PI3K/AKT pathway in PitNETs. Our findings imply that SLC7A11 knockdown decreased the protein level of p-PI3K and p-AKT, suggesting that SLC7A11 knockdown inhibits EMT through the PI3K/AKT signaling pathway in PitNETs.
In conclusion, the present study confirmed that SLC7A11 was an invasive indicator, and showed that SLC7A11 modulates EMT through the PI3K/AKT signaling pathway in PitNETs. Thus, SLC7A11 is a prospective biomarker and therapeutic target for invasive PitNETs.
Supplementary materials
This is linked to the online version of the paper at https://doi.org/10.1530/EC-24-0097.
Declaration of interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Funding
This research was funded by the Chinese Academy of Medical Sciences (ZZ15-WT-04), National Natural Science Foundation of China (No. 82360475), and the Education Department of Jiangxi Province (no. YC2023-B094).
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