|Year : 2023 | Volume
| Issue : 5 | Page : 365-371
SPAG5 promotes the proliferation, migration, invasion, and epithelial-mesenchymal transformation of colorectal cancer cells by activating the PI3K/AKT signaling pathway
Xuelian Zhang1, Weiyu Wu1, Xiaohui Li1, Feng He1, Lei Zhang2
1 Department of Gastroenterology, The First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan, China
2 Department of Traditional Chinese Medicine, Jinshan Hospital of Fudan University, Shanghai, China
|Date of Submission||10-Jan-2023|
|Date of Decision||05-Apr-2023|
|Date of Acceptance||17-Apr-2023|
|Date of Web Publication||02-Aug-2023|
Dr. Lei Zhang
Department of Traditional Chinese Medicine, Jinshan Hospital of Fudan University, No. 1508, Longhang Road, Shanyang, Jinshan, Shanghai
Source of Support: None, Conflict of Interest: None
Colorectal cancer (CRC) is a cancer that occurs in the rectum or colon with a high incidence. Sperm-associated antigen 5 (SPAG5), a gene that regulates cell division, has been observed highly expressed in a variety of cancers, but its role in CRC is unclear. This study aimed to investigate the regulatory role of SPAG5 in CRC. The expression of SPAG5 in multiple cancers and normal tissues was predicted by The Cancer Genome Atlas and Tumor Immune Estimation Resource, and the expression of SPAG5 in human normal intestinal epithelial cells NCM460 and human CRC cell lines Caco2, HT29, SW480, and LOVO was verified by western blotting (WB). The effects of silencing SPAG5 on cell viability, proliferation, and apoptosis were then investigated by cell counting kit-8, WB, and flow cytometry. The effects of silencing SPAG5 on cell migration and invasion were investigated by scratch assay and transwell assay. Finally, the phosphorylation levels of phosphoinositide 3-kinase (PI3K) and AKT in cells were detected by WB. The results showed that SPAG5 was highly expressed in CRC and was verified by WB. Silencing of SPAG5 inhibited cell viability and proliferation and increased the cell apoptosis rate. Furthermore, both cell invasion and migration abilities were suppressed by the low expression of SPAG5. Finally, WB results found that the phosphorylation levels of PI3K and AKT were reduced after SPAG5 silencing. In summary, the results showed that SPAG5 can promote the proliferation and invasion of CRC cells by targeting the PI3K/AKT signaling pathway.
Keywords: Cancer, colorectal cancer, PI3K/AKT, sperm-associated antigen 5
|How to cite this article:|
Zhang X, Wu W, Li X, He F, Zhang L. SPAG5 promotes the proliferation, migration, invasion, and epithelial-mesenchymal transformation of colorectal cancer cells by activating the PI3K/AKT signaling pathway. Chin J Physiol 2023;66:365-71
|How to cite this URL:|
Zhang X, Wu W, Li X, He F, Zhang L. SPAG5 promotes the proliferation, migration, invasion, and epithelial-mesenchymal transformation of colorectal cancer cells by activating the PI3K/AKT signaling pathway. Chin J Physiol [serial online] 2023 [cited 2023 Dec 4];66:365-71. Available from: https://www.cjphysiology.org/text.asp?2023/66/5/365/382855
| Introduction|| |
Colorectal cancer (CRC) is a common malignant tumor with high morbidity and occurs in the rectum or colon. In recent years, the incidence of CRC is still increasing. The 5-year survival rate of CRC has also been improved in recent years due to the continuous improvement of the level of diagnosis and treatment, but the prognosis is affected by the stage of the cancer, and the outcomes in different periods are often different. Patients with advanced CRC are usually accompanied by metastasis of cancer cells like other cancer types, which greatly decreased the survival rate. The current treatment still adopts a strategy of integrating multiple treatment methods, but the therapeutic efficacy is limited. Therefore, it is still necessary to study the pathogenesis of CRC and the molecular mechanism of metastasis to carry out targeted therapy.
Sperm-associated antigen 5 (SPAG5, also known as astrin and hMAP126), located at Ch17q11.2. Mitotic spindle-associated proteins are encoded by SPAG5. It interacts with many other proteins during mitosis, such as CLASP1, astrin and Kif2b, to regulate centromere-microtubule dynamics, thereby promoting the mitotic process. SPAG5 has been reported to be involved in the growth and progression of a variety of tumors,, including but not limited to breast cancer, osteosarcoma, lung cancer,, bladder urothelial carcinoma, and cervical cancer., In these cancers, abnormal activation of phosphoinositide 3-kinase (PI3K)/AKT can be observed,, and site mutations in PI3K and AKT are also observed, which further leads to cancer cell dysfunction and uncontrolled development. This signaling pathway not only regulates cell growth and differentiation, but its abnormal activation can also activate cells to develop into cancer cells. However, whether SPAG5 is involved in the regulation of CRC remains unclear.
In addition, the current treatment methods for CRC are relatively limited, and the study of the molecular mechanism of CRC is conducive to the development of targeted therapy strategies, and clinical diagnosis and treatment. Therefore, this study aimed to study how SPAG5 regulates CRC through the regulation of PI3K/AKT signaling pathway.
| Materials and Methods|| |
Prediction through Tumor Immune Estimation Resource and The Cancer Genome Atlas
The expression level of SPAG5 in tumor was analyzed by Tumor Immune Estimation Resource (TIMER) 2.0 website, and the expression level of SPAG5 in CRC tissue and normal tissue was analyzed by The Cancer Genome Atlas (TCGA) online platform Gene Expression Profiling Interactive Analysis (GEPIA) and UALCAN website.
Cells and treatment
Human normal intestinal epithelial cells NCM460, human CRC cell lines Caco2, HT29, SW480, LOVO were obtained from Biodee, Co. Ltd. Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% fetal bovine serum (FBS) and 1% penicillin and streptomycin (Corning, Somerville, MA, USA) were used to culture cells at 37°C and 5% CO2 atmosphere.
SPAG5 overexpression plasmid and knockdown plasmid (Binoway, Beijing, China) were used to co-transfect 293T cells with packaging plasmid (10 μg) and transmembrane plasmid (15 μg) via Lipofectamine® 2000 (Biodee, Beijing, China). 293T medium supernatant (containing virus) was collected at 48 h and 72 h and used to infect Caco2 and SW480 cells to stably overexpress and knock down SPAG5. The grouping scheme was NC, SPAG5 (overexpression group), si NC (empty transfection group), si SPAG5#1 and si SPAG5#2. The knockdown efficiency was detected by the western blotting (WB).
Cell proliferation assay
Cell counting kit-8 (CCK-8) kits (Biodee, Beijing, China) were used to analyze the changes in cell viability at various time points after silencing SPAG5. The transfected cells were grown to 70% confluency and then passaged, prepared into 103 cells and seeded in 96-well plates and tested for cell viability at 0 h, 24 h, 48 h, and 72 h. 10 μL of CCK-8 was added to the wells and the absorbance was read at 490 nm in a microplate reader after waiting for 1 h to generate the growth curves. Each time point has three repeats. 5-Ethynyl-2'-deoxyuridine (EdU, Biodee, Beijing, China) was used to detect the cell growth in CRC. Cells were incubated with 50 nM EdU for 2 h and fixed with 4% paraformaldehyde. Nuclei were stained with DAPI, and then, an inverted fluorescence microscope (Axiocam 702 mono, Zeiss, Germany) was used to observe fluorescence.
Proteins were extracted from the indicated treated cells. Subsequently, the loading buffer was mixed with the protein and boiled for 5 min to denature the protein. After the protein was subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis, it was transferred to a polyvinylidene fluoride (PVDF) membrane with the constant electricity set at 300 mA for 60–90 min. Subsequently, PVDF membranes were sealed with 5% nonfat dry milk for 2 h, and the membranes were incubated primary antibodies including SPAG5 (1:1000, Bioway), N-cadherin (1:1000, Bioway), E-cadherin (1:1000, Bioway), AKT (1:1000, Bioway), p-AKT (1:1000, Binoway), PI3K (1:8000, Bioway), and p-PI3K (1:1000, Bioway) overnight incubation at 4°C. Then, horseradish peroxidase-conjugated secondary antibody (1:10,000, Bioway) was incubated with membranes. Finally, the freshly prepared enhanced chemiluminescence (ECL) luminescence solution was added for gray value analysis.
Transwell assays were performed using a BD Matrigel™ Invasion Chamber (MA, USA). A single cell suspension (50,000) was prepared and resuspended in serum-free DMEM and added to the upper chamber filled with 0.7 mL of DMEM containing 10% FBS. Cells were stained with 0.8 mL of crystal violet (Bioway, Beijing, China) 30 min after incubation. Three selected fields of view were then counted under a light microscope. For invasion, use chambers were precoated with matrix adhesive.
The best passage time is when the cells grow to a confluence of more than 70%, prepared a 5 × 105 cell suspension and inoculated it in a 6-well plate, and culture it for 24 h. Then, a vertical scratch was made in the center of the well and the cells gently rinsed twice with sterile phosphate-buffered saline to remove cell debris, and the incubation was continued for 24 h. The migration of cells was observed under an inverted microscope, and ImageJ software was used to analyze the cell migration.
To assess the rate of apoptosis, a Northern Lights full-spectrum flow cytometer (Cytek, Fremont, CA, USA) was used. Annexin V-fluorescein isothiocyanate/propidium iodide apoptosis detection kit (Bioway, Beijing, China) was used to detect the ratio of apoptosis, and then, the results were analyzed according to the manufacturer's protocol. The rate of apoptosis was calculated using FlowJo software (Ashland, OR, USA).
All data analyses were performed by GraphPad software Graphpad Prism version 9 (Dotmatics, Boston, MA, USA). Specifically, normality test and variance homogeneity test were performed on the data. If the data were normal and variance homogeneous, t-test or one-way ANOVA was performed; otherwise, Wilcoxon signed-rank test was used. P < 0.05 was considered statistically significant.
| Results|| |
Sperm-associated antigen 5 is upregulated in colorectal cancer
TCGA and TIMER are network analysis tools that can be used to analyze the gene expression differences between tumors and normal tissues. Combined with experimental verification, differentially expressed genes can be mined. TIMER 2.0 analyzed multiple tumors and found that SPAG5 was upregulated in most tumors, including CRC. Combined with the prediction of TCGA, it was found that SPAG5 expression was significantly increased in cancer tissues (n = 275/n = 286) compared with normal tissues (n = 349/n = 41) [Figure 1]a, [Figure 1]b, [Figure 1]c. Overall, the expression of SPAG5 has a tendency of increasing in CRC, which needs further verification. WB results showed that the protein expression of SPAG5 in Caco2, HT29, SW480, and LOVO cells was significantly higher than that in NCM460 cells. Caco2 and SW480 cells with relatively high expression of SPAG5 were chosen for subsequent experiments [Figure 1]d.
|Figure 1: TIMER2.0 and TCGA platform predict SPAG5 expression difference between tumor tissue and normal tissue. (a) TIMER2.0 predicted the expression of SPAG5 in multiple tumors including CRC. (b) TCGA predicts the expression of SPAG5 in normal tissues (n = 41) and cancer tissues (n = 288). (c) GEPIA predicted the expression of SPAG5 in normal tissues (n = 275) and cancer tissues (n = 349). (d) The protein expression level of SPAG5 in SPAG5 cell lines in Caco2, HT29, SW480, LOVO. n = 3. *P < 0.05 versus normal tissues group, **P < 0.01 versus normal tissues group, ***P < 0.001 versus normal tissues group, ^^^P < 0.001 versus normal tissues group. TCGA: The Cancer Genome Atlas, TIMER: Tumor Immune Estimation Resource, SPAG5: Sperm-associated antigen 5, CRC: Colorectal cancer, GEPIA: Gene Expression Profiling Interactive Analysis.|
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Knockdown of sperm-associated antigen 5 inhibits colorectal cancer cell proliferation
By silencing SPAG5, and detecting cell viability, proliferation, apoptosis, etc., the regulatory role of SPAG5 in CRC was investigated. The efficiency of SPAG5 knockdown in Caco2 and SW480 cells was first examined. It was found that in these two cell lines, SPAG5 overexpression group had higher expression levels than NC. Compared with the si NC group, the expressions of SPAG5 in the si SPAG5#1 group and the si SPAG5#2 group were significantly decreased, indicating the successful silencing efficiency [Figure 2]a. The changes of cell viability after knocking down SPAG5 were further detected at the time points of 0 h, 24 h, 48 h, and 72 h. Compared with NC, the expression level of SPAG5 was higher, and the cell viability of si SPAG5#1 group and si SPAG5#2 group was significantly lower than that of si NC group [Figure 2]b. The detection of cell proliferation by EdU also showed consistent results. The EdU positive cells was obviously increased by SPAG5 overexpression and decreased in si SPAG5#1 group and si SPAG5#2 group [Figure 2]c and [Figure 2]e. The results of flow cytometry showed that apoptosis in SPAG5 group was the lowest compared to NC group, and si SPAG5#1 group and si SPAG5#2 group had higher apoptosis rate than si NC group [Figure 2]d. Taken together, these results suggest that SPAG5 can enhance the cell viability, proliferation, and inhibit apoptosis in CRC cells. Since the si SPAG5#2 group had better downregulation efficiency, it was used for subsequent experiments.
|Figure 2: Effects of SPAG5 silencing on viability, proliferation and apoptosis of CRC cells. (a) The expression level of SPAG5 was detected by WB to evaluate the silencing efficiency. (b) The changes of cell viability in each group at each time point after silencing SPAG5. (c) The proliferation of cells in each group after silencing SPAG5. (d) It is expressed as the proportion of red fluorescent cells in the field of view. (e) Apoptosis of each group after silencing SPAG5 expressed as apoptotic proportion. n = 3, *P < 0.05 versus si NC group, **P < 0.01 versus si NC group, ***P < 0.001 versus si NC group, ^P < 0.05 versus NC group, ^^P < 0.01 versus NC group, ^^^P < 0.001 versus NC group. WB: Western blotting, SPAG5: Sperm-associated antigen 5, CRC: Colorectal cancer.|
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Knockdown of sperm-associated antigen 5 inhibits colorectal cancer cell migration, invasion, and mesenchymalization
Cell migration and invasion are the hallmarks of cancer cells metastasis. Next, we explored the effects of silencing of SPAG5 on CRC cell motility. The results showed that, compared with the NC group, overexpression of SPAG5 enhanced the migration and invasion at 24 h of CRC cells [Figure 3]a and [Figure 3]b. The colony number was also increased in CRC cells by the overexpression of SPAG5 [Figure 3]c and [Figure 3]d. Compared with the si NC group, downregulation of SPAG5 significantly reduced migration and invasion, as well as the colony formation in si SPAG5#2 group. N-cadherin and E-cadherin are closely related to tumor cell invasion. Our results indicated that the expression of N-cadherin was higher in the SPAG5 group than that of the NC group, and the protein expression level of N-cadherin was relatively lower in si SPAG5#2 group than that of the si NC group. The expression of E-cadherin was opposite [Figure 3]e and [Figure 3]f. Taken together these results suggest that silencing of SPAG5 reduced the migratory and invasive abilities of CRC cells.
|Figure 3: Effects of SPAG5 silencing on cell invasion and migration. (a) Scratch test shows the width of cell invasion and migration within 24 h. (b) The width of cell invasion and migration within 24 h is expressed as a percentage of the entire area. (c) Crystal violet shows cell invasion. (d) The number of cells invaded is expressed as the proportion of the total number of cells. (e) The protein expression of N-cadherin and E-cadherin. (f) The protein expression is expressed as the relative expression of GAPDH. n = 3. **P < 0.01 versus si NC group, ***P < 0.001 versus si NC group, ^^^P < 0.001 versus NC group. SPAG5: Sperm-associated antigen 5.|
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Sperm-associated antigen 5 activates PI3K/AKT signaling pathway
The PI3K-Akt pathway is an intracellular signal transduction pathway that is closely related to cell proliferation, survival, angiogenesis, etc., and it is usually abnormally activated in cancer. In order to deeply understand the regulation of SPAG5 on CRC, the signaling pathways regulated by SPAG5 were detected by WB. The expression trends of all proteins were consistent in both cell lines. The expression of phosphorylated AKT and PI3K was increased in the SPAG5 overexpression group compared with NC group and was decreased in the si SPAG5#2 group compared with NC group [Figure 4].
|Figure 4: Effects of SPAG5 silencing on protein expression levels (phosphorylation levels) of AKT/p-AKT, PI3K/p-PI3K, expressed relative to GAPDH expression. n = 3. ***P < 0.001 versus si NC group, ^^^P < 0.001 versus NC group. PI3K: Phosphoinositide 3-kinase, SPAG5: Sperm-associated antigen 5.|
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| Discussion|| |
This study investigated the regulatory role of SPAG5 in CRC. The prediction of SPAG5 expression in tumors by TCGA and TIMER found that SPAG5 is highly expressed in CRC. This is consistent with current findings in other cancers. For example, Liu et al. found that abnormal expression of SPAG5 was often found in gastric cancer, and the survival rate of patients was significantly reduced; Jiang et al. found that high expression of SPAG5 in breast cancer was also negatively correlated with the quality of life of patients. However, how SPAG5 regulates CRC remains unclear, and the mechanism needs to be studied to provide new strategies for drug development.
The effects of silencing SPAG5 expression on Caco2, SW480 cell viability, proliferation and apoptosis were examined. The results showed that downregulation of SPAG5 significantly inhibited cell viability and proliferation, and promoted cell apoptosis. This result indicates that SPAG5 plays an important role in regulating cell survival, which is accordance with previous studies. For example, Liu et al. found that SPAG5 can down-regulate the expression of SCARA5 by modifying β-catenin to promote its degradation, thereby promoting the development of hepatocellular carcinoma, and this promoting effect was weakened by silencing of SPAG5; Li et al. found that knockdown of SPAG5 inhibited breast cancer progression. These findings suggest that silencing SPAG5 may inhibit cell survival. Further, we also tested the cell invasion and migration abilities after silencing SPAG5. These abilities are closely related to the metastasis of cancer cells. The result showed that cell invasion and migration abilities were supressed by the silencing of SPAG5. Wang et al. found that SPAG5 is involved in human gliomagenesis by regulating cell proliferation and apoptosis. Li et al. found that SPAG5 promotes osteosarcoma metastasis by activating the FOXM1/MMP2 axis. Therefore, SPAG5 might be a potential target for the therapy of CRC.
Finally, we also investigated the signaling pathways involved in the regulation of SPAG5 in CRC cells. The results showed that the phosphorylation levels of AKT and PI3K were attenuated by SPAG5 silencing, suggesting that the PI3K/AKT signaling pathway may be regulated by SPAG5, which is consistent with other studies. For example, Yang et al. found that SPAG5 interacts with CEP55 and exerts oncogenic activity in hepatocellular carcinoma through the PI3K/AKT pathway. Zeng et al. found that SPAG5 regulates the AKT pathway in multiple myeloma, suggesting that SPAG5 may serve as a novel biomarker and potential therapeutic target. Therefore, SPAG5 can regulate CRC by targeting the PI3K/AKT signaling pathway.
However, this study still has limitations. First, we only performed in vitro experiments in this study, and an animal model of CRC needs to be established to verify the effect of silencing SPAG5 on the survival of CRC. Second, this study failed to investigate whether SPAG5 directly acts on the PI3K/AKT signaling pathway, and there may be interactions with other genes, which may affect the efficiency of targeted therapy. Second, it was reported that silencing SPAG5 would inhibit the epithelial-mesenchymal transition process in multiple cancer cells.,,,, However, relevance experiments such as loss-of-function assays were not included in this study, which would be involved in our study. Third, the direct effect of SPAG5 on cell progression, migration, and invasion was unknown and further research would be needed. Finally, this study needs to be further verified, and some identified genes that are highly expressed in CRC also need to be knocked out, and further verify whether the effect on cell behavior is consistent with the results obtained in this study, which is conductive to supporting our conclusions.
| Conclusion|| |
Collectively, this study concluded that SPAG5 can promote the proliferation and invasion of CRC cells by regulating the PI3K/AKT signaling pathway.
This article does not contain any studies with human participants or animals performed by any of the authors.
Data availability statement
The authors declare that all the 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.
Xuelian Zhang designed the study and carried them out; Xuelian Zhang, Weiyu Wu, Xiaohui Li and Feng He supervised the data collection, analyzed the data and interpreted the data; Xuelian Zhang and Lei Zhang prepared the manuscript for publication and reviewed the draft of the manuscript. All authors have read and approved the manuscript.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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