|Year : 2022 | Volume
| Issue : 2 | Page : 370-377
SOX7 modulates the progression of hepatoblastoma through the regulation of Wnt/β-catenin signaling pathway
Juntao Ge1, Qipeng Zheng2, Hongyi Qu3, Zuohui Zhao3, Yue Xu3, Hao Wang3, Huayu Gao3, Jianghua Zhan4
1 Graduate School, Tianjin Medical University, Tianjin; Department of Pediatrics, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Engineering and Technology Research Center for Pediatric Drug Development, Jinan; Department of General Surgery, Tianjin Children's Hospital, Tianjin, China
2 Graduate School, Tianjin Medical University; Department of General Surgery, Tianjin Children's Hospital, Tianjin, China
3 Department of Pediatrics, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Engineering and Technology Research Center for Pediatric Drug Development, Jinan, China
4 Department of General Surgery, Tianjin Children's Hospital, Tianjin, China
|Date of Submission||06-Oct-2021|
|Date of Acceptance||12-Jan-2022|
|Date of Web Publication||20-May-2022|
Department of General Surgery, Tianjin Children's Hospital, LongYan Road 238, Beichen District, Tianjin, 300134
Source of Support: None, Conflict of Interest: None
Aims: Hepatoblastoma (HB) was reported as the frequently diagnosed primary hepatic malignant tumor among children. No reports have shown the function of SOX7 and its relationship with the Wnt/β-catenin pathway in HB.
Materials and Methods: SOX7 and factors related to Wnt/β-catenin pathway were detected using reverse transcription–quantitative polymerase chain reaction (RT-PCR) and Western blotting. MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium and flow cytometry were used to detect HB cell proliferation and apoptosis. The transwell assay uses cell invasion.
Results: In this study, RT-PCR, Western blotting, and immunohistochemistry results indicated that the expression of SOX7 was significantly reduced in HB tissues compared with adjacent noncancerous tissues, while the β-catenin was significantly increased in HB tissues compared with adjacent noncancerous tissues. There were significant differences in the PRETEXT stage and tumor metastasis between patients with low expression and high expression of SOX7. Moreover, it was found that the overexpression of SOX7 and inhibiting Wnt/β-catenin pathway significantly reduced the cell proliferation and invasion, while the cell apoptosis was significantly increased compared with the control group.
Conclusions: This study shows that SOX7 was downexpressed in HB tumor tissues. Moreover, ex vivo experiments indicated that SOX7 was related to β-catenin and regulated the progression of HB cells.
Keywords: Hepatoblastoma, SOX7, Wnt/β-catenin
|How to cite this article:|
Ge J, Zheng Q, Qu H, Zhao Z, Xu Y, Wang H, Gao H, Zhan J. SOX7 modulates the progression of hepatoblastoma through the regulation of Wnt/β-catenin signaling pathway. J Can Res Ther 2022;18:370-7
|How to cite this URL:|
Ge J, Zheng Q, Qu H, Zhao Z, Xu Y, Wang H, Gao H, Zhan J. SOX7 modulates the progression of hepatoblastoma through the regulation of Wnt/β-catenin signaling pathway. J Can Res Ther [serial online] 2022 [cited 2022 Jul 7];18:370-7. Available from: https://www.cancerjournal.net/text.asp?2022/18/2/370/345530
| > Introduction|| |
Hepatoblastoma (HB) was reported as the frequently diagnosed primary hepatic malignant tumor among children. The number of patients with HB accounts for about 0.8%–2.0% of all malignancies in children and almost all malignant hepatic tumors., Currently, although most patients underwent routinely combinatorial chemotherapy and radiotherapy, surgical resection of the HB tumors combined with other options, such as immunotherapy, was the major treatment for patients with HB. Even after surgery, HB patients still have a high possibility of tumor recurrence or distant metastasis., The overall survival of patients with HB has no significant improvement. The primary reason for that is that most children with HB are diagnosed during the late stage, such as PRETEXT (Pre Treatment of extent of disease staging system) III or IV., Lacking effective means of early diagnosis and intervention is a pivotal reason that contributed to the relatively worse prognosis for patients with HB. Novel biomarkers are required for patients with HB to develop diagnostic and prognostic prediction.
SOX7 is a member of the SOX (SRY-related HMG-box) family of transcription factors involved in various physiological processes, including cell survival, proliferation, and cell death.,, Recently, SOX7 has drawn more attention since it is related to different malignant cancers, including breast cancer, ovarian cancer, liver, and pancreatic cancer,,,, but the mechanisms are largely unclear. The human SOX7 gene is located at the chromosomal region of 8p23.1 and is about 7.7 kbps in length., Based on previous reports, on the one hand, genome-wide promoter analysis indicated that SOX7 was associated with numerous transcription factors, including E2F1, E2F4, and c-MYC., which were closely related to tumorigenesis., Alternatively, a few studies have reported that SOX7 overexpression was related to a favorable prognosis and SOX7 functioned as a tumor suppressor gene. Moreover, SOX7 was reported to associate with the aberrant activation of the Wnt/β-catenin pathway.,, The Wnt/β-catenin pathway used Wnt ligand and correlated receptors to initiate intracellular signaling through nuclear translocation of β-catenin.,,,,, The Wnt/β-catenin pathway had been repeatedly reported in patients with HB, while no study focused on the SOX family., SOX7 has a significant role in influencing the factors related to the Wnt/β-catenin signaling pathway, especially the β-catenin, in the cacogenesis. Nevertheless, no reports have demonstrated the function of SOX7 and its interaction with the β-catenin in HB.
In this study, an analysis of the expression of SOX7 and β-catenin in patient samples with HB was conducted and the potential interaction between SOX7 and β-catenin in cell proliferation and survival was further explored.
| > Materials and Methods|| |
Samples from children with hepatoblastoma
Twelve paired HB tissues accompanied by adjacent noncancerous tissues were obtained and analyzed from patients with HB who received hepatic surgical resection at the hospital. Patients did not receive any treatment before tumor resection. There are five female and seven male patients. The stages of patients with HB were based on the pretreatment extension stage (PRETEXT) system. This PRETEXT system was identified as the essential and significant assessment method for risk stratification and prognostic prediction for patients with HB. It described the potential extent of HB tumor and the location of all tumors in the liver. Moreover, it included many annotation factors to involve the related tumor characters, such as vascular involvement and lymph invasions, portal vein or hepatic vein invasion or destruction, distant metastasis, the number of tumors, and tumor rupture.,, Two independent pathologists conducted the histology and pathology evaluation of the tumors from all children. In this study, the adjacent noncancerous tissues were based on the literature and defined as sampled ≥1-cm away from the primary tumor and the tumor margin also identified by two independent pathologists. This study was approved by the local ethics committee of the hospital.
Cell culture and transfection
HB cell lines (HepG2 and Huh6) were purchased from the American Type Culture Collection (ATCC; Rockville, Md, USA). The cell culture methods and selecting the appropriate medium and other materials were followed with the manufacturer's instructions and previously published articles.,, The lentivirus packaging of SOX7 mimics, NC mimics, or β-catenin inhibitors were purchased from the company of RiboBio, and the transfection of these lentiviruses with HepG2 and Huh6 followed the reagent instructions supplied by the company.
Extract the total RNA
The Recover All™ Total Nucleic Acid Isolation Kits were used to conduct total RNA extraction. All noncancerous samples, tumor samples, and samples from transfection of these lentiviruses with HepG2 and Huh6 were extracted. The maximum absorption wavelength of nucleic acid is 260 nm, which can be used to calculate the concentration of nucleic acid samples. We used Recover All™, the Total Nucleic Acid Isolation Kit to extracts total RNA from all HB tissues and adjacent noncancerous tissue samples. The maximum absorption wavelength of nucleic acid is 260 nm, which can be used to calculate the concentration of nucleic acid samples. The purity of nucleic acid can be estimated by measuring the ratio of optical density (OD) values at 260 nm and 280 nm. Our experimental result indicated that the extracted RNA content is higher. 260/280 analysis shows that the RNA is not degraded, the purity is higher, and there is no DNA pollution.
MTT assays were used to detect the cell proliferation for HepG2 and Huh6 transfected with various lentiviruses and divided into different groups. After being transfected with SOX7 mimics, NC mimics, or β-catenin inhibitor, the HepG2 and Huh6 cells were harvested and the plantation of cells into a 96-well plate was performed. After that, the OD 490 was detected and analyzed using the related software in the microplate reader (Bio-Rad, Hercules, CA, USA).
Using the tissue slice digital scanner or imaging system to obtain the scanned files or images on the immunohistochemical slices, Seville image analysis system was used to automatically read the tissue measurement area, analyze, and calculate the number of weak, medium, and strong positive cells in the measurement area (negative no Coloring, 0 points; weak positive light yellow, 1 point; medium positive brown, 2 points; and strong positive tan, 3 points), the total cell number, positive cumulative OD IOD value, positive pixel area, and tissue area mm2. The following results were calculated separately to reflect the degree of positiveness. The following indicators can be selected to evaluate the intensity of positive cells according to the slice conditions.
Histochemistry score (H-score) was used to identify the expression of SOX7 and β-catenin. It is a histological scoring method for immunohistochemistry (IHC), which converts the number of positives in each section and its staining intensity into corresponding values to achieve half of the staining of tissue quantitative purposes. H-Score (H-SCORE=Σ(pi × i) = (percentage of weak intensity cells × 1) + (percentage of moderate-intensity cells × 2) + (percentage of strong intensity cells × 3), where i means positive cell grade division: negative without staining, score 0; weak positive light yellow, score 1; medium positive brown, score 2; strong positive tan, score 3. pi represents the percentage of positive cells). H-score is a value between 0 and 300; the larger the value, the stronger the comprehensive positive strength.
Flow cytometry for apoptosis detection
The treated cells were digested and collected and 50,000–100,000 cells (1000 R/min, 5 min) were centrifuged. The supernatant was abandoned and 195-μ L annexin V-FITC binding solution was joined, the cells were gently resuspended. Subsequently, 5-μ L annexin V-FITC reagent was added, gently mixed well, and placed in the dark at room temperature for ten minutes. Then, propidium iodide staining solution 10 μL was added. It was mixed well and kept away from light at room temperature for 10 min. Then, by gently adding 200-μ L annexin V-FITC binding solution, resuspended cells, the cell suspension was then detected using flow cytometry.
Reverse transcription–quantitative polymerase chain reaction
Total RNA was extracted from HB tissues and adjacent noncancerous tissues, and HepG2 and Huh6 cells, followed by the manufacturer's instructions. The following primer pairs were used to perform quantitative polymerase chain reaction (qPCR): β-catenin forward, 5'-GCTGAAGGTGCTATCTGTCTGC-3' and reverse, 5'-CCTTCCATCCCTTCCTGTTTAG-3'; SOX7 forward, 5'-CGAGCTGTCGGATGGACAATC-3' and reverse, 5'-CCACGACTTTCCCAGCATCTT-3'; ACTIN forward, 5'-CACCCAGCACAATGAAGATCAAGAT-3' and reverse, and 5'-CCAGTTTTTAAATCCTGAGTCAAGC-3'.
Western blotting analysis
Tumor tissue was collected from patients and adjacent noncancerous tissues in radioimmunoprecipitation assay; total protein was buffered and extracted. The protein concentration was calculated using the bicinchoninic acid protein determination kit (Thermo Fisher Scientific, Waltham, MA, USA). Then, the protein was electrophoresed and transferred to a polyvinylidene fluoride membrane (Roche, Basel, Switzerland) and sealed with 5% skim milk. Buffered Saline Tween (tbst) was placed at room temperature for 2 h and incubated with a specific primary antibody at 4°C overnight. The following primary antibodies were used: SOX7 (Abcam, 1:200), β-catenin (Abcam, 1:400 and Thermo Scientific, 1:200), E-cad (BD, 1:300), and bcl-2 (Abcam, ab92574, 1:400). ImageJ software was used to calculate the gray value of the Western blotting result band and to conduct statistical analysis. The gray value of the target protein is divided by the gray value of the internal reference to correct the error. The result represents the relative content of the target protein of a sample.
All data were indicated as the mean ± standard error of mean. Statistical analysis was conducted using GraphPad Prism software. Continuous variables were expressed as mean ± standard deviation and compared using a two-tailed unpaired Student's t-test; categorical variables were compared using Chi-Squared 2 or Fisher analysis.
| > Results|| |
Comparison of SOX7 and β-catenin expression in adjacent noncancerous and tumor tissues in Hepatoblastoma patients
The qPCR assay results indicated that the expression of SOX7 was significantly reduced in HB tissues compared with adjacent noncancerous tissues, while the β-catenin was significantly increased in HB tissues compared with adjacent noncancerous tissues [Figure 1]a. Furthermore, IHC and Western blotting were conducted, and it was found that the expression of SOX7 was significantly reduced in HB tissues compared with adjacent noncancerous tissues, while the β-catenin was significantly increased in HB tissues compared with adjacent noncancerous tissues [Figure 1]b and [Figure 1]c. This finding suggested that SOX7 and β-catenin were related and involved in the development of HB. The expression levels of SOX7 and β-catenin were significantly negatively correlated, which was consistent in the reverse transcription–PCR (RT-PCR), IHC, and Western blotting results.
|Figure 1: Comparison of SOX7 and β-catenin expression in adjacent noncancerous and tumor tissues in patients with hepatoblastoma. (a) SOX7, β-catenin, and other related factors detected by reverse transcription–polymerase chain reaction; (b) IHC for SOX7 and β-catenin expression; (c): SOX7, β-catenin, and other related factors detected by Western blotting|
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Cell transfection was then found and the relative expression of SOX7 and β-catenin using RT-PCR was detected. It was explored that the expression of SOX7 and β-catenin in different groups showed significant differences, proving the transfection rate of SOX7 and β-catenin.
After detection using RT-PCR and IHC, expression of SOX7 and b-catenin-related markers were confirmed by Western blotting in all 12 patients. It was found that the protein levels of SOX7 in the tumor tissues were significantly decreased compared with those in the adjacent noncancerous tissues (P < 0.05), while β-catenin in the tumor tissues was significantly increased compared with those in the adjacent noncancerous tissues.
SOX7 expression was associated with clinical characteristics in patients with hepatoblastoma
In this study, the expression of SOX7 in 12 patients was detected. The baseline characteristics of patients during diagnosis are summarized in [Table 1]. Overall, these patients had a median age of 1.8 years. The gender distribution was roughly equal (male: female: 58.3%:41.7%). The PRETEXT status of most patients was PRETEXT III (six patients, 50%), and PRETEXT 3 (25%). Most patients had solitary tumors (85.7%), with no metastases (75%). Most patients had epithelial histological subtypes (58.3%). After being detected by IHC and Western blotting, it was found that seven patients had low expression of SOX7 and five patients had high expression of SOX7. Particularly, there were significant differences in the PRETEXT stage and tumor metastasis between patients with low expression and high expression of SOX7 [P < 0.05 [Figure 2]].
|Figure 2: SOX7 expression was associated with clinical characteristics in patients with hepatoblastoma. (a) SOX7 expression was related to PRETEXT staging; (b) SOX7 expression was related to tumor metastasis|
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SOX7 is closely related to the β-catenin expression in HEPG2 and HUH6 cell lines
Gene overexpression is the process that leads to the abundant target protein expression subsequently. In this study, the SOX7 has been overexpressed through the construction of an expression vector and then transfected with HEPG2 and HUH6 cell lines. It was found that SOX7 was significantly increased and β-catenin was significantly decreased in the overexpression SOX7 group [Figure 3]a and [Figure 3]b. In addition, β-catenin was downexpressed through shRNA in HEPG2 and HUH6 cell lines. It was found that compared with the control group, SOX7 was significantly increased and β-catenin was significantly reduced in the overexpression SOX7 group [Figure 3]c and [Figure 3]d.
|Figure 3: SOX7 is closely related to the β-catenin expression in HepG2 and HUH6 cell lines. (a) Comparison of SOX7 expression between the overexpressed SOX7 group by lentivirus and control groups; (b) Comparison of β-catenin expression between the overexpressed SOX7 group by lentivirus and control groups; (c) Comparison of β-catenin expression between the Sh-β-catenin group and sh-NC group; (d) Comparison of SOX7 expression between the Sh-β-catenin group and sh-NC group|
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SOX7 regulates the β-catenin expression to inhibit proliferation and invasion and to promote apoptosis of HepG2 and Huh6 cells
HepG2 and Huh6 cells were successfully transfected with lentivirus of SOX7 mimic, NC mimic, β-catenin inhibitor, and NC inhibitor. The MTT assay, transwell assay, and flow cytometry were performed. The results showed that overexpression of SOX7 significantly decreased cell proliferation and cell invasion. Knockdown β-catenin significantly inhibited cell proliferation and cell invasion. The apoptosis results were opposite in these two groups (P < 0.05) [Figure 4] and [Figure 5].
|Figure 4: SOX7 regulates β-catenin expression to inhibit the cell proliferation of HepG2 and Huh6 cells. (a) SOX7 mRNA expression level in the overexpressed SOX7 group by lentivirus and control groups; (b) β-catenin mRNA expression level in the Sh-β-catenin group and sh-NC group; (c and d) Cell proliferation detected using MTT in HepG2 and Huh6 cells|
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|Figure 5: SOX7 regulates β-catenin expression to inhibit cell invasion ability and promote cell apoptosis. (a and b) Cell invasion was significantly inhibited by overexpressed SOX7 and Sh-β-catenin; (c and d) Cell apoptosis was significantly promoted by overexpressed SOX7 and Sh-β-catenin|
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| > Discussion|| |
Among children, HB is reported as the most commonly diagnosed primary malignant live tumor in children. Although most patients underwent routinely combinatorial chemotherapy and radiotherapy, patients with HB have a slight improvement in prognosis.
The Wnt/β-catenin signaling pathway has been reported as a significant pathway related to cancer genesis in various cancers.,,,, Nevertheless, activation of this pathway can cause oncogenic or tumor-suppressive effects of different cancer entities. Several studies have revealed different effects of the Wnt/β-catenin signaling pathway. In HB, there is much conflicting evidence on the role of Wnt/β-catenin signaling, and the activation and inhibition of this pathway are considered a potential treatment strategy., In this study, in vitro and in vivo experiments were conducted. RT-PCR, Western blotting, and IHC results showed that the expression of SOX7 was significantly reduced in HB tissues compared with adjacent noncancerous tissues, while the β-catenin was significantly increased in HB tissues compared with adjacent noncancerous tissues. Concerning the clinical relationship of the expression of SOX7 and β-catenin, the clinical characteristics of patients with HB, there were significant differences in the PRETEXT stage and tumor metastasis between patients with low expression and high expression of SOX7.
SOX7 protein contains a β-catenin interaction region, which can suppress Wnt signaling., This is the theoretical basis of our study to perform in patients with HB. It was discovered that SOX7 is frequently inactivated in HB cell lines, and it was hypothesized that it might act as a tumor suppressor. Suppression of the Wnt/β-catenin signaling pathway by SOX7 has now been observed in many other cancer types, and the down-regulation of SOX7 expression is also correlated with the progression of patients with various cancers. In this study, the expression of SOX7 and factors in the Wnt/β-catenin signaling pathway were detected in patients with HB. However, progression analysis was not performed since there was a limited sample size.
By the way, this study has some limitations, and future studies should be conducted. First, this was a retrospective study, and more patients should be recruited to verify these results. Second, the association between SOX7 and the potential possibilities of β-catenin suppressing HB was not clearly explained. Therefore, further research is needed to explore the potential mechanism for this significant phenomenon.
| > Conclusions|| |
Our study demonstrates that SOX7 was downexpressed in HB tumor tissues, and the overexpression of SOX7 related to the early stage of patients with HB. Moreover, ex vivo experiments demonstrated that SOX7 was related to β-catenin and regulated the progression of HB cells.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]