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| ORIGINAL ARTICLE |
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| Year : 2023 | Volume
: 66
| Issue : 4 | Page : 257-265 |
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Stomatin-like protein-2 contributes the migration and invasion of breast cancer cells via regulating ERK/FOXO3a signaling pathway
Shengming Wu1, Lingang Zhao2, Qian Li3
1 Department of Breast Surgery, Nanjing Liuhe District Hospital of Traditional Chinese Medicine, Nanjing, Jiangsu, China
2 Department of Pharmacy, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
3 Key Laboratory of Particle and Radiation Imaging, Ministry of Education, Department of Engineering Physics, Tsinghua University, Beijing, China
| Date of Submission | 24-Oct-2022 |
| Date of Decision | 07-Mar-2023 |
| Date of Acceptance | 17-Apr-2023 |
| Date of Web Publication | 29-Jul-2023 |
Correspondence Address:
Dr. Lingang Zhao
Department of Pharmacy, Affiliated Hospital of Nanjing University of Chinese Medicine, No. 155, Hanzhong Road, Nanjing, Jiangsu
China
 Source of Support: None, Conflict of Interest: None
DOI: 10.4103/cjop.CJOP-D-22-00117
Breast cancer (BC) is the most common tumor in women, and its incidence is increasing, ranking first among female malignant tumors. It is urgently needed to find new and reliable biomarkers of BC and to understand the cellular changes that cause metastasis. Stomatin-like protein-2 (SLP-2) is a member of the stomatin protein superfamily. Studies have shown that SLP-2 was highly expressed in some tumors and played an important role in tumor genesis and development. SLP-2 regulated the extracellular signal-regulated kinase (ERK) pathway, and activation of ERK phosphorylated FOXO3a, which was involved in BC progression. However, its possible role in the progression of BC remains unclear. In this study, we found the high expression of SLP-2 in BC tissues and cells. SLP-2 promoted the viability of BC cells. In addition, we found that SLP-2 stimulated the motility of BC cells in vitro. Mechanically, our results revealed that SLP-2 could mediate FOXO3a expression and ERK signaling pathway, thereby contributing to the viability and motility of BC cells. Therefore, SLP-2 has the potential to serve as a promising target for BC treatment.
Keywords: Breast cancer, ERK pathway, FOXO3a, motility, stomatin-like protein 2, viability
How to cite this article:
Wu S, Zhao L, Li Q. Stomatin-like protein-2 contributes the migration and invasion of breast cancer cells via regulating ERK/FOXO3a signaling pathway. Chin J Physiol 2023;66:257-65 |
How to cite this URL:
Wu S, Zhao L, Li Q. Stomatin-like protein-2 contributes the migration and invasion of breast cancer cells via regulating ERK/FOXO3a signaling pathway. Chin J Physiol [serial online] 2023 [cited 2023 Sep 26];66:257-65. Available from: https://www.cjphysiology.org/text.asp?2023/66/4/257/382479 |
| Introduction | |  |
Breast cancer (BC) is the most common tumor in women, and its incidence is increasing year by year, ranking first among female malignant tumors, and the survival rate of metastatic BC patients is low.[1],[2] BC belongs to heterogeneous tumor characterized by hormone receptor (estrogen receptor) and human epidermal growth factor receptor 2 (HER2) expression.[3] The prognosis and treatment of BC are mainly based on the state of tumor lymph node metastasis.[4] At present, the main method is the combined treatment of surgery, radiotherapy, and chemotherapy.[5] With the improvement of medical treatment, targeted therapies such as trastuzumab can significantly improve survival of the metastasis patients with HER2-positive BC.[6],[7] In-depth understanding of the biological characteristics of BC and finding new and reliable biomarkers are very important for the diagnosis, treatment, and prognosis of BC and to understand the cell changes that cause metastasis.
Stomatin-like protein-2 (SLP-2) is a member of the Stomatin protein superfamily.[8] Due to the absence of a hydrophobic region at the amino terminus, it can be distinguished from other members of the family and it localizes in the cytoplasm.[8] It was considered as a potential target for the treatment of mitochondrial cardiomyopathy.[9] In addition, SLP-2 conferred neuroprotection effects in oxygen-glucose deprivation/reoxygenation-injured neurons.[10]
In recent years, studies have shown that SLP-2 was highly expressed in some tumors and played an important role in tumor genesis and development.[8],[11] For example, SLP-2 is used as a new prognostic marker in esophageal cell carcinoma to regulate cell proliferation and migration.[12] SLP-2 can inhibit the apoptosis of cervical cancer cells through the activation of MEK/ERK signaling pathway.[13] SLP-2 regulates the Wnt/β-catenin pathway to promote colorectal cancer invasion and metastasis.[14] Interestingly, SLP-2 expression is higher in BC than in normal tissue and is closely related to tumor size, stage, and prognosis.[15] Previous studies have demonstrated that SLP-2 regulated the extracellular signal-regulated kinase (ERK) pathway, and activated ERK phosphorylated FOXO3a, which was involved in BC progression.[16],[17] However, its possible role in the progression of BC remains unclear.
In this study, we investigated the role of SLP-2 in BC. Our data confirmed that SLP-2 affected the viability and the motility of BC cells via mediating FOXO3a expression and ERK pathway. Therefore, our findings suggested that SLP-2 has the potential to serve as a therapeutic target for BC treatment.
| Materials and Methods | | |
Bioinformation analysis and clinical specimens
For bioinformation analysis, the transcriptome data were obtained from The Cancer Genome Atlas (TCGA), Genodo-Tissue Expression Project, and Sarcoma databases. For clinical specimens, our study was authorized by the Ethics Committee of Affiliated Hospital of Nanjing University of Chinese Medicine (Approval No. 2017-ky021), and subjects were required to sign informed consent before conducting this study. We obtained 50 BC tissue samples and normal control tissue samples. Tissue collected during surgery was stored in liquid nitrogen and 4% paraformaldehyde (Beyotime, Shanghai, China), respectively, for subsequent testing of gene and protein levels.
Antibodies
SLP-2 antibody (1:500 dilution, ab191883, Abcam, Cambridge, UK), FOXO3a antibody (1:500 dilution, ab109629, Abcam), p-FOXO3a (Ser253) antibody (1:1000 dilution, ab47285, Abcam), ERK antibody (1:500 dilution, ab184699, Abcam), p-ERK antibody (1:500 dilution, ab201015, Abcam), Lamin B antibody (1:500 dilution, ab133741, Abcam), and beta-actin antibody (1:3000 dilution, ab8226, Abcam) were acquired from the indicated companies.
Cell culture and transfection
A total of 4 BC cell lines, including MCF-7, MDA-MB-231, BT-474, and MX-1, and a normal BC cell line, MCF-10A, were purchased from ATCC and maintained in DMEM (with 10% of fetal bovine serum) at 37°C in a 5% CO2 incubator. The negative control shRNAs and SLP-2 shRNAs plasmids were bought from Addgene (USA). The plasmids including pcDNA3.1 and pcDNA3.1-SLP-2 were constructed in our lab and the overexpression plasmids or shRNAs were transfected into BC cells using Lipofectamine® 3000 (Invitrogen; Thermo Fisher, MA, USA).
Quantitative polymerase chain reaction assays
Total RNA was extracted from bladder cancer cells using Trizol reagent (15596-018, Invitrogen). Then, total RNA was reverse-transcribed into cDNA using M-MLV reverse transcriptase kit (M1701, Promega). Quantitative polymerase chain reaction (qPCR) was then performed through SYBR mixture (RR420A, Takara). SLP-2 mRNA levels were normalized to GAPDH. The sequences of SLP-2 qPCR primers were listed as following: forward, 5'-GCAGAAGGGAAGAAACAGGC-3' and reverse, 5'-GAGAACGCGCTGACATACTG-3'; the sequences of GAPDH were: 5'-CGACCACTTTGTCAAGCTCA-3' and reverse, 5'-GGTTGAGCACAGGGTACTTTATT-3'.
Immunoblot assay
This experiment has been approved by the Ethics Committee of Affiliated Hospital of Nanjing University of Chinese Medicine (Approval No. 2017-ky021). Tumor tissues or cells were used to isolate the total proteins. The cytoplasm and nuclear of cells were separated by ultracentrifugation (800 rpm, 5 min, 4°C) to achieve the supernatant (cytoplasm) and precipitation (nuclear). Then, the samples were lysed using radioimmunoprecipitation assay (RIPA) buffer (9800; Cell Signaling, MA, USA). All samples were used to separate proteins via the 8% sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), and transferred onto polyvinylidene difluoride (PVDF) membranes. Then, the membranes were blocked using 5% fat-free milk/TBST. The PVDF membranes were blotted with the primary antibodies for 1.5 h. Subsequently the membranes were treated with secondary antibodies for another 1 h. Blots were then measured.
Cell counting kit-8 assay
BC cells were plated into the 96-well plates with 1000 cell per well and maintained for 48 h in the medium after transfection. The cells were then treated with CCK-8 for 4 h, and then, in the absorbance of each well was measured at 450 nm.
Scratch wound assay
The BC cells after transfection for 48 h were grown to 100% confluency. Then, scratches were produced using a pipette tip, after which cells were washed with phosphate-buffered saline buffer. Serum-free culture medium was added to induce wound healing. Images were taken at 0 and 24 h time point.
Transwell assays
Cells after transfection for 48 h were seeded into the upper chamber of chambers in culture medium without serum. Then, complete culture medium was added into the bottom to induce cell invasion. After 24 h, cells in the upper were manually removed, and the remaining was fixed, stained with 0.1% crystal violet and the cell number was counted.
Statistics
GraphPad 5.0 software (USA) was used to perform the statistical analysis. Data were represented as mean ± standard error of the mean (SEM). Student's t-test was used for comparison and P < 0.05 was thought as statistically significant.
| Results | | |
SLP-2 expression was upregulated in human breast cancer tissues
To uncover the possible effects of SLP-2 on the progression and metastasis of BC, we first detected its expression, the log2 TPM of SLP-2, in different types of tumor tissues and the corresponding normal tissues via searching TCGA database. According to the data, we noticed that SLP-2 was obviously highly expressed in several types of tumor tissues, such as BC (BRCA), esophageal cancer, and lung cancer [Figure 1]a. We further found that the expression of SLP-2 was correlated with the prognosis of patients with BC [Figure 1]b. Therefore, these analyses indicated that SLP-2 was highly expressed in BC. Through qPCR assays, we found that SLP-2 mRNA levels were dramatically up-regulated in BC tissues collected in our hospital [Figure 1]c. Similarly, the immunoblot assays confirmed that SLP-2 protein was highly expressed in BC tissues [Figure 1]d. Therefore, these results showed that SLP-2 expression was upregulated in human BC tissues. | Figure 1: SLP-2 expression was upregulated in human breast cancer tissues. (a) TCGA database confirmed SLP-2 was high expression in multiple types of tumors, with the increased log2 TPM value compared to the corresponding normal tissues. Red, tumor tissues, blue, normal tissues. The data were from TCGA database. (b) The expression of SLP-2 was correlated with the prognosis of patients with breast cancer. (c) qPCR assays showed the mRNA levels of SLP-2 in 50 tumor tissues and normal tissues from patients in our hospital. (d) Immunoblot assays showed the protein levels of SLP-2 in tumor tissues and normal tissues from patients in our hospital. Data are presented as mean ± SEM, ***P < 0.001. SLP-2: Stomatin-like protein-2, TCGA: The Cancer Genome Atlas, qPCR: Quantitative polymerase chain reaction, SEM: Standard error of the mean.
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SLP-2 was highly expressed in human breast cancer cells and contributed to cell proliferation
We then detected the expression of SLP-2 in BC cell lines and the normal breast cell line. A total of 4 BC cell lines, including MCF-7, MDA-MB-231, BT-474, and MX-1, and a normal BC cell line, MCF-10A, were used to detect the expression of SLP-2. The immunoblot assays results showed that SLP-2 was highly expressed in human BC cell lines, compared to normal cell line [Figure 2]a. | Figure 2: SLP-2 was highly expressed in human breast cancer cells and contributed to cell proliferation. (a) 4 breast cancer cell lines, including MCF-7, MDA-MB-231, BT-474, and MX-1, and a normal breast cancer cell line, MCF-10A were used to detect the expression of SLP-2 through immunoblot assays. (b) qPCR assays showed the mRNA levels of SLP-2 in the indicated types of breast cancer cells and normal breast cells. (c) Immunoblot assays showed the expression of SLP-2 in BT-474 and MX-1 cells upon the transfection of the indicated plasmids. (d) CCK-8 assays showed the effects of SLP-2 overexpression and depletion on BT-474 and MX-1 cells. Data are presented as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001. SLP-2: Stomatin-like protein-2, qPCR: Quantitative polymerase chain reaction, SEM: Standard error of the mean, CCK-8: Cell counting kit-8.
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Subsequently, the overexpression and shRNA plasmids of SLP-2 were transfected into BC cell line, BT-474 and MX-1 cells, to alter its expression in these cells. By performing qPCR assays and immunoblot assays, we found that SLP-2 was obviously highly expressed in BC cells transfected with pcDNA3.1-SLP-2 plasmid and downregulated in cells transfected with SLP-2 shRNA plasmids [Figure 2]b and [Figure 2]c.
Then, we performed CCK-8 assays to confirm the effects of SLP-2 on the viability of BC cells. Interestingly, our data confirmed that SLP-2 overexpression significantly enhanced the viability of BT-474 and MX-1 cells, whereas its depletion suppressed BC cell viability [Figure 2]d. Collectively, SLP-2 was highly expressed in BC cells and contributed to cell proliferation.
SLP-2 promoted the motility of breast cancer cells in vitro
Then, we detected the effects of SLP-2 on the motility of BC cells through wound healing and transwell assays. Our data confirmed that SLP-2 depletion suppressed wound healing in BT-474 and MX-1 cells, indicating that SLP-2 promoted BC cell migration [Figure 3]a. In addition, we found that downregulation of SLP-2 restrained the invasion of BT-474 and MX-1 cells, confirmed by transwell assays [Figure 3]b. Therefore, these results demonstrated that SLP-2 promoted the motility of BC cells in vitro. | Figure 3: SLP-2 promoted the motility of breast cancer cells in vitro. (a) Wound healing assays showed the effects of SLP-2 on the indicated types of breast cancer cells upon the transfection of its overexpression and shRNA plasmids. (b) Transwell assays showed the effects of SLP-2 in BT-474 and MX-1 cells upon the transfection of the indicated plasmids. Data are presented as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001. SLP-2: Stomatin-like protein-2, SEM: Standard error of the mean.
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SLP-2 regulates FOXO3a expression through ERK pathway in breast cancer cells
Since SLP-2 contributed to the viability and motility of BC cells, we therefore investigated the possible mechanism. Through immunoblot assays, we noticed that the depletion of SLP-2 decreased the phosphorylation levels of ERK in BT-474 and MX-1 cells [Figure 4]a. In addition, the downstream protein of ERK pathway, FOXO3a, was dramatically upregulated after SLP-2 depletion in cell lysate [Figure 4]a. Subsequently, the cytoplasm and nuclear of BC cells were separated. Our data confirmed that in the cytoplasm, the phosphorylation levels of FOXO3a were decreased, whereas its total protein levels were increased [Figure 4]a. In addition, in the nuclear, the phosphorylation and expression levels of FOXO3a were all increased [Figure 4]a. | Figure 4: SLP-2 regulates FOXO3a expression through ERK pathway in breast cancer cells. (a) Immunoblot assays showed the phosphorylation levels of ERK and the expression levels of ERK and FOXO3a in BT-474 and MX-1 cells upon the transfection of the indicated plasmids. (b) The expression or phosphorylation levels of the indicated proteins in BT-474 and MX-1 cells upon the transfection of SLP-2 overexpression of SLP-2 and the treatment of U0126. Data are presented as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001. SLP-2: Stomatin-like protein-2, SEM: Standard error of the mean.
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We then used the inhibitor of ERK pathway, U0126, to treat BT-474 and MX-1 cells after the overexpression of SLP-2. Immunoblot assays showed that overexpression of SLP-2 increased the phosphorylation of ERK and decreased FOXO3a expression in BC cells [Figure 4]b. Importantly, U0126 treatment obviously reversed the alterations of the phosphorylation of ERK and FOXO3a expression after SLP-2 overexpression [Figure 4]b. In conclusion, these results suggested that SLP-2 regulated FOXO3a expression through ERK pathway in BC cells.
SLP-2 contributed to the viability and motility of breast cancer cells through mediated FOXO3a expression and ERK pathway
We then performed in vitro assays to further confirm the possible mechanisms. CCK-8 assays results showed that SLP-2 overexpression promoted the viability of both BT-474 and MX-1 cells [Figure 5]a. In addition, the treatment of U0126 suppressed the viability of BC cells upon SLP-2 overexpression [Figure 5]a. Furthermore, performing wound closure assays, we found that overexpression of SLP-2 contributed to the migration of BC cells, whereas U0126 treatment attenuated the promoting effects of SLP-2 overexpression on BC cell migration [Figure 5]b. In addition, we further performed CCK-8 and transwell assays. The data showed that U0126 treatment obviously inhibited BC cell viability and invasion [Figure 6]a and [Figure 6]b. Therefore, we thought SLP-2 contributed to the viability and motility of BC cells through mediated FOXO3a expression and ERK pathway. | Figure 5: SLP-2 contributed to the viability and motility of breast cancer cells via mediated FOXO3a expression and ERK pathway. (a) CCK-8 assays were performed to detect the effects of SLP-2 on the viability of BT-474 and MX-1 cells upon the transfection of SLP-2 overexpression of SLP-2 and the treatment of U0126. (b) Wound healing assays were performed to detect the effects of U0126 on the migration of BT-474 and MX-1 cells upon the transfection of SLP-2 overexpression of SLP-2. Data are presented as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001. SLP-2: Stomatin-like protein-2, SEM: Standard error of the mean, CCK-8: Cell counting kit-8.
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 | Figure 6: SLP-2 contributed to the viability and invasion of breast cancer cells via ERK pathway. (a) CCK-8 assays were performed to detect the effects of U0126 on the viability of BT-474 and MX-1 cells upon the transfection of SLP-2 overexpression of SLP-2. (b) Transwell assays were performed to detect the effects of U0126 on the migration of BT-474 and MX-1 cells upon the transfection of SLP-2 overexpression of SLP-2. Data are presented as mean ± SEM. ***P < 0.001. SLP-2: Stomatin-like protein-2, SEM: Standard error of the mean, CCK-8: Cell counting kit-8.
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| Discussion | | |
BC is a malignant tumor in which mammary gland epithelial cells proliferate out of control under the action of various carcinogenic factors.[18] BC is the most common cancer in women.[19] Due to its heterogeneity, further study on its pathogenesis is still needed.[19] The symptoms of early BC are not obvious, but once it develops to the advanced stage, especially triple negative BC, it has a higher mortality.[19] Traditional surgical resection and chemoradiotherapy have limited effects on advanced BC while targeted therapy has broad prospects.[20] To improve the prognosis, more promising therapeutic targets are still urgently needed. In this study, we found that a member of the Stomatin protein superfamily, SLP-2, was highly expressed in human BC tissues. Our data further confirmed that it could promote the viability and motility of BC cells via promoting FOXO3a expression and ERK pathway. Therefore, SLP-2 has the potential to serve as a target for BC treatment.
Through performing CCK-8 assays, we noticed the effects of SLP-2 on the viability of BC cells. Further through transwell and wound-healing assays, we confirmed its effects on BC cell motility. Similarly, the effects of SLP-2 on the progression and metastasis of multiple types of tumors have been widely revealed. It affected the apoptosis and autophagy of gastric cancer cells.[21],[22] SLP-2 also promoted the survival of tumor cells through activating JAK2 pathway in colorectal cancer.[14] SLP-2 also attenuated tumor progression as well as inflammatory response through repressing CD14 expression in liver cancer.[23] SLP-2 was highly expressed in colorectal cancer cells and promoted the invasion and metastasis of cancer via mediating Wnt/β-catenin pathway and predicted poor prognosis.[14] These studies, together with our findings, confirmed that SLP-2 could serve as a promising target for cancer treatment.
It was found that SLP-2 could inhibit the apoptosis of cervical cancer cells through the activation of MEK/ERK signaling pathway. Therefore, we hypothesized that SLP-2 also affects the ERK pathway in BC cells. It has been reported that SLP-2 regulated the ERK pathway, and activation of ERK can phosphorylate FOXO3a protein, causing degradation and inactivation. Our data also confirmed that SLP-2 contributed the migration and invasion of BC cells through ERK-FOXO3a axis. In addition, previous study also indicated that FOXO3a transcription factor was associated with BC progression.[24] Therefore, we here mainly focused on the nuclear FOXO3a and detected the nuclear and cytoplasmic expression of FOXO3a. There are also studies confirmed the role of FOXO3a in the migration of BC cells.[25] Therefore, our results suggested that SLP-2 affected the survival and invasion of BC cells via FOXO3a.
In addition to the effects of SLP-2 on tumor growth, its effects on other cellular functions and diseases have also been reported.[10] SLP-2 could confer the neuroprotection effect in oxygen-glucose deprivation/reoxygenation-injured neurons through mediating adenosine 5'-monophosphate (AMP)-activated protein kinase/nuclear factor erythroid 2-related factor 2 (AMPK/Nrf2) pathway.[10] Moreover, it also affected the progression of mitochondrial cardiomyopathy.[9] These studies confirmed the multiple roles of SLP-2 in the progression of different diseases.
In this study, we also noticed that SLP-2 could promote the expression of FOXO3a in BC cells. FOXO3a was involved in the progression of multiple types of cancers, including BC.[26] FOXO3a-induced Linc00926 suppressed BC progression and metastasis through the inhibition of Warburg effect.[27] FOXO3a also inhibited the EMT and the metastasis of BC.[28] Notably, activation of ERK phosphorylated FOXO3a, therefore altering the expression of FOXO3a.[17] We here noticed that SLP-2 could activate the expression of FOXO3a through ERK pathway in BC tissues, thus providing a possible molecular mechanism. In fact, the effects of ERK pathway on the viability, motility, and apoptosis of BC cells have been revealed.[29]
| Conclusion | | |
In conclusion, we investigated the role of SLP-2 in BC progression. Our data confirmed that SLP-2 affected the viability and motility of BC cells via mediating FOXO3a expression and ERK pathway. Therefore, SLP-2 has the potential to serve as a target of BC.
Acknowledgements
Thanks for the editor from English go to polished my paper.
Availability of data and materials
All data generated or analyzed during this study are included in this published article.
Author contributions
Shengming Wu designed the study and supervised the data collection; Lingang Zhao analyzed the data and interpreted the data; Qian Li prepared the manuscript for publication and reviewed the draft of the manuscript. All authors have read and approved the manuscript.
Ethics approval
Ethical approval was obtained from the Ethics Committee of Affiliated Hospital of Nanjing University of Chinese Medicine (Approval No. 2017-ky021).
Statement of informed consent
Written informed consent was obtained from a legally authorized representative(s) for anonymized patient information to be published in this article.
Financial support and sponsorship
This work was supported by the project of Nanjing Health Science and Technology development special fund (Grant No. YKK22235).
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
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