Role of FBXW7 in esophageal squamous cell carcinoma: a potential biomarker for tumor progression and prognosis

Introduction

Esophageal cancer (ESC) is a fatal gastrointestinal malignancy, comprising two main histological subtypes: esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EADC) (1). ESCC accounts for approximately 90% of all ESC cases and is characterised by non-specific early symptoms, high invasiveness, and rapid progression. As a result, most patients present with advanced-stage disease at the time of diagnosis (2,3). To date, the treatment options for ESCC patients mainly include surgery, radiotherapy, chemotherapy, and targeted therapy. However, the prognosis of ESCC patients remains unfavorable, with a 5-year survival rate of less than 50% (4). Given the aggressive behavior of ESCC and the limited therapeutic benefit, there is an urgent need to identify key molecular regulators involved in its pathogenesis and progression.

F-box and WD repeat domain containing 7 (FBXW7) protein is a substrate recognition component of the Skp1-Cul1-F-box protein (SCF) E3 ubiquitin ligase complex, which plays a critical role in regulating cell cycle progression, differentiation, and tumorigenesis (5,6). It is widely recognized as a tumor suppressor due to its ability to mediate the ubiquitination and subsequent proteasomal degradation of several oncogenic proteins, including c-Myc, Cyclin E, Notch1, and mTOR (7,8). FBXW7 plays a critical role in controlling cell proliferation, differentiation, and apoptosis (9). However, emerging evidence suggests that the function of FBXW7 may vary depending on cancer type and progression stage. Under certain conditions, FBXW7 may even exhibit oncogenic functions. For instance, it may promote tumor metastasis via epithelial-mesenchymal transition (EMT), thereby enhancing cell migration and invasion (10). Moreover, FBXW7 has been implicated in the maintenance of cancer cell stemness, which may contribute to tumor recurrence and drug resistance (11,12). These findings suggest that the dual role of FBXW7 in tumor development highlights the complexity of its biological functions.

This study was designed to investigate the roles of FBXW7 in the pathogenesis and progression of ESCC. We assessed FBXW7 protein expression in ESCC tissues and adjacent nontumor tissues. Then we evaluated the effects of FBXW7 knockdown or overexpression on the proliferation and invasion of ESCC cell lines in vitro. In addition, tumor-bearing nude mice models were established to validate its role of FBXW7 in ESCC tumorigenesis. We present this article in accordance with the ARRIVE and REMARK reporting checklists (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-aw-2294/rc).

Methods

Patients and samples

In this study, 69 paired ESCC tissues and matched adjacent non-tumorous tissues were collected from patients diagnosed at The First Affiliated Hospital of Xinjiang Medical University between March 2014 and January 2017. Patients were eligible if they had archived paraffin-embedded ESCC specimens, a histopathologically confirmed diagnosis, and no prior radiotherapy, chemotherapy, or immunotherapy before tissue collection. Patients were excluded if they had acute infection, allergy, or autoimmune disease, malignancies in other organs, secondary ESCC, or a family history of genetic diseases.

Clinicopathological characteristics of the ESCC patients, including sex, age, ethnicity, history of Barret’s disease, tumor differentiation, tumor-node-metastasis (TNM) stage and other data, were extracted from medical records. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the ethics board of The First Affiliated Hospital of Xinjiang Medical University (No. 20220308-091), and informed consent was obtained from all individual participants.

Immunohistochemistry (IHC)

Paraffin-embedded tissue sections (3 µm) were deparaffinized in xylene and dehydrated in a graded ethanol series (95%, 85%, and 75%). The sections were rinsed in 0.01 mol/L phosphate-buffered saline (PBS) for 10 min. After antigen retrieval and quenching of endogenous peroxidase activity, the sections were incubated with a primary antibody (1:200; Santa Cruz Biotechnology, CA, USA) overnight at 4 ℃. Slides were then washed three times in PBS and incubated with a biotinylated secondary antibody for 30 min at room temperature. Antigen-antibody complexes were visualized using the streptavidin-peroxidase method with 3,3'-diaminobenzidine (DAB) as the chromogenic substrate (Vector Laboratories, Burlingame, CA, USA). Slides were subsequently rinsed with distilled water, counterstained with hematoxylin for 3–5 min, dehydrated and mounted. Finally, sections were observed under a microscope with a magnification of ×400. FBXW7 expression was quantified as the mean percentage of positively stained cells in five randomly selected fields.

Cell culture

Two human ESCC cell lines (Ecal09 and EC9706), obtained from Wuhan University (Wuhan, China), were used in this study. Cells were cultured in RPMI-1640 (Roswell Park Memorial Institute) supplemented with 10% fetal bovine serum (FBS) and 1% penicillin/streptomycin at 37 ℃ in a humidified incubator with 5% CO₂.

Cellular transfection

A fusion expression vector containing full-length FBXW7 complementary DNA (cDNA) with a C-terminal flag tag was purchased from Invitrogen (Shanghai, China). The primer sequences for FBXW7 were: 5'-CCAACTTTGTGCCAACCGGTCGCCATGAATCAGGAACTGCTCTC-3'; 5'-AATGCCAACTCTGAGCTTCTTCATGTCCACATCAAAGTC-3'. Cells in the logarithmic growth phase were transfected with plasmids or small interfering RNA (siRNA) using the Lipofectamine^TM 2000. After 12 h of transfection, the medium was replaced with complete culture medium containing antibiotics, and the cells were cultured at 37 ℃ in a humidified incubator with 5% CO₂.

For overexpression experiments, cells transfected with the recombinant FBXW7 expression vector were defined as the overexpression group, whereas cells transfected with the corresponding empty vector were used as the vector control group. For knockdown experiments, cells transfected with FBXW7 siRNA (sense: 5'-GGAAGGAGCUACAGCUAAATT-3'; antisense: 5'-UUUAGCUGUAGCUCCUUCCTT-3') were defined as the knockdown group, while cells transfected with a scrambled negative control siRNA were used as the negative control (siRNA-NC) group. In addition, Eca109 and EC9706 cells without transfection served as the blank control.

Would healing assay

Cells (5×10⁵) were seeded into 6-well plates and cultured in serum-free RPMI-1640 medium. A linear wound was created by scraping the center of the cell monolayer using a pipette tip. Cells were then incubated at 37 ℃ in a humidified atmosphere containing 5% CO₂. Wound closure was imaged under an optical microscope at 0 and 12 h in the FBXW7 overexpression group, and at 0 and 24 h in the FBXW7 knockdown group.

Transwell assay

A Transwell chamber (Corning, USA) was used to assess the migration and invasion of cells. Cells were seeded in 100 mL serum-free media in the upper chamber, while the lower chamber contained 600 µL culture medium supplemented with 10% FBS. After incubation at 37 ℃ for 10 h, non-migrated cells on the upper membrane surface were removed with a cotton swab. Migrated cells on the lower membrane surface were visualized using an inverted microscope (Nikon ECLIPSE TS100, Japan). Cell counts were averaged across five randomly selected fields per well.

Establishing a tumor xenograft model in athymic nude mice

A tumor-bearing mouse model was established to evaluate the effects of FBXW7 overexpression and knockdown on the proliferation and tumorigenicity. Thirty-nine female BALB/C nude mice of specific pathogen-free grade (3 weeks old, 13–15 g) were purchased from Weitong Lihua (Beijing, China) and acclimatized for 1 week prior to experiments at the Animal Center of Xinjiang Medical University. The mice were randomly divided into 6 groups: (I) Eca109 group (n=6), injected with untransfected Eca109 cells; (II) LV-NON group (n=7), injected with Eca109 cells transfected with an empty vector; (III) LV-FBXW7 group (n=7), injected with Eca109 cells transfected with FBXW7 overexpression vector; (IV) EC9706 group (n=6), injected with untransfected EC9706 cells; (V) shNON group (n=6), injected with EC9706 cells transfected with an empty vector; and (VI) shFBXW7 group (n=7), injected with EC9706 cells transfected with FBXW7-targeting siRNA. Animal experiments were performed under a project license (No. IACUC-20160218-031) granted by the ethics board of The First Affiliated Hospital of Xinjiang Medical University, in compliance with national guidelines for the care and use of animals. A protocol was prepared before the study without registration.

A tumor with a diameter of no less than 5 mm was considered indictive of successful xenograft establishment. Tumor size and body weight were measured every 3 days using a vernier caliper and an electronic balance, respectively. After 4 weeks, all mice were euthanized by cervical dislocation, and the tumor tissues were harvested. The tumor volume was calculated using the formula: volume = 0.5 × length × width2.

Statistical analysis

All data were analyzed using SPSS 20.0 statistical software. Quantitative data were presented as mean ± standard deviation from experiments conducted at least in triplicate. Comparisons between groups were made using the Chi-squared test for categorical variables and Student’s t-test for continuous variables. A P value of less than 0.05 was considered to be statistically significant.

Results

FBXW7 expression differed across clinicopathological features in ESCC

FBXW7 protein showed significant up-regulation in ESCC tissues compared with that in adjacent nontumor tissues (66.7% vs. 31.9%, P<0.05) (Table 1). FBXW7 expression tended to be higher in patients aged ≤60 years than in those aged >60 years (P<0.05; Table 2); however, this finding should be interpreted with caution given the limited sample size, and further validation in larger cohorts is warranted. There was no statistical difference in the FBXW7 expression between male and female (P=0.386). FBXW7 expression differed significantly between poorly differentiated tumors and non-poorly differentiated tumors (P<0.001). FBXW7 expression was also significantly different between patients with advanced tumor stage (T3–T4) and those with early-stage disease (T1–T2) (P<0.001). Furthermore, patients with lymph node metastasis exhibited significantly different FBXW7 expression compared with those without lymph node metastasis (P<0.001).

FBXW7 overexpression promoted the migration of ESCC cells

Wound healing assay was performed to evaluate the effects of FBXW7 overexpression on the migration of ESCC cells. In Eca109 and EC9706 cells, the wound healing rate at 12 h post-transfection was significantly increased in FBXW7 overexpression group compared to the blank control (Eca109 cells: 52.8% vs. 27.5%, P<0.05; EC9706 cells: 88.4% vs. 69.0%, P<0.05) and negative control group (Eca109 cells: 52.8% vs. 33.2%, P<0.05; EC9706 cells: 88.4% vs. 74.8%, P<0.05) (Figure 1). The wound healing rate at 24 h of transfection of FBXW7 knockdown group in Eca109 cells was significantly decreased than that of the blank control group (12.9% vs. 22.3%, P<0.05) and the negative control group (12.9% vs. 21.5%, P<0.05) (Figure 2).

Figure 1 Representative images of cell migration in the wound healing assay following FBXW7 overexpression. FBXW7, F-box and WD repeat domain-containing protein 7.

Figure 2 Representative images of cell migration in wound healing assay following FBXW7 knockdown. Scale bar =200 µm. FBXW7, F-box and WD repeat domain-containing protein 7.

Transwell assay indicated that the number of migrated cells showed significant increase in FBXW7 overexpression group compared with blank group and negative group (Figure 3A,3B, P<0.01). In contrast, the number of migrated cells in FBXW7 knockdown group was significantly reduced than that in blank and negative control groups (Figure 3C,3D, P<0.01). These data indicated that FBXW7 overexpression could promote the migration of Eca109 and EC9706 cells, while its knockdown could inhibit the migration accordingly.

Figure 3 Cell migration following FBXW7 overexpression or knockdown. (A,B) Image of the migration and quantitative analysis of migrated cells following FBXW7 overexpression (crystal violet staining). (C,D) Image of the migration and quantitative analysis of migrated cells following FBXW7 knockdown (crystal violet staining). **, P<0.01. FBXW7, F-box and WD repeat domain-containing protein 7.

FBXW7 overexpression enhanced the invasion of ESCC cells

Compared with the blank and negative control groups, the number of cells that passed through the polycarbonate membrane in the Transwell assay was significantly increased in the FBXW7 overexpression group (Figure 4A,4B, P<0.01). In contrast, FBXW7 knockdown significantly reduced the number of invasive cells compared with both control groups (Figure 4C,4D, P<0.01). Collectively, these results demonstrated that FBXW7 overexpression promoted invasion, whereas FBXW7 knockdown inhibited invasion in Eca109 and EC9706 cells.

Figure 4 Cell invasion following FBXW7 overexpression or knockdown. (A,B) Image of the invasion and quantitative analysis after FBXW7 overexpression (crystal violet staining). (C,D) Image of the invasion and quantitative analysis after FBXW7 knockdown (crystal violet staining). **, P<0.01. FBXW7, F-box and WD repeat domain-containing protein 7.

Effect of FBXW7 on the proliferation and tumorigenicity of ESCC xenografts

Approximately 3 days after subcutaneous injection of ESCC cells, the animals developed localized erythematous vesicles and signs of inflammation (Figure 5A). After 1 week, clear subcutaneous tumor nodules were observed in the nude mice (Figure 5B). At 4 weeks, the tumors were markedly enlarged and exhibited irregular morphology, with increased adhesion to the overlying skin and localized skin necrosis (Figure 5C). The tumor size and body weight were compared among three groups. Compared with the Eca109 and LV-NON groups, a significant increase in tumor volume and tumor weight was observed in the LV-FBXW7 group on days 7, 14, 21 and 28 (Figure 6, all P<0.05). Compared with the EC9706 and shNON groups, tumor volume and tumor weight were significantly reduced in the shFBXW7 group on days 7, 14, 21 and 28 (Figure 7, all P<0.05).

Figure 5 Tumor masses in nude mice on day 3 (A), day 7 (B), and day 28 (C) after subcutaneous injection of tumor cells.

Figure 6 FBXW7 overexpression increased tumor mass growth in mice. (A) Tumor volume changes of mice in each group within 30 days. (B) Body weight changes within 30 days. (C) Tumor masses isolated from mice in each group. (D) Tumor weight of mice in each group. *, P<0.05; **, P<0.01. Eca109 group: injected with untransfected Eca109 cells; LV-NON group: injected with Eca109 cells transfected with an empty vector; LV-FBXW7 group: injected with Eca109 cells transfected with FBXW7 overexpression vector. FBXW7, F-box and WD repeat domain-containing protein 7.

Figure 7 FBXW7 knockdown inhibited the tumor growth in mice. (A) Tumor volume changes of mice in each group within 30 days. (B) Body weight changes of mice in each group within 30 days. (C) Isolated tumor masses from mice in each group. (D) Changes of tumor weight in each group. *, P<0.05; **, P<0.01. EC9706 group: injected with untransfected EC9706 cells; shNON group: injected with EC9706 cells transfected with an empty vector; shFBXW7 group: injected with EC9706 cells transfected with FBXW7-targeting siRNA. FBXW7, F-box and WD repeat domain-containing protein 7.

Discussion

There are still disputes on the roles of FBXW7 at different stages of cancers (13-15). At the early stage, FBXW7 showed anti-tumor effects by inducing apoptosis, while at the advanced stages, FBXW7 could stimulate EMT together with inducing proliferation, invasion and metastasis of tumor cells (16,17). These lead us to investigate the potential roles of FBXW7 in ESCC.

In this study, we found that FBXW7 expression was significantly upregulated in ESCC tissues compared with adjacent non-tumor tissues, suggesting its potential involvement in the pathogenesis of ESCC. FBXW7 expression was closely associated with tumor differentiation, T stage, and lymph node metastasis. Specifically, patients with poorly differentiated tumors, advanced T stage (T3 + T4), and lymph node metastasis exhibited significantly higher FBXW7 expression. These findings suggest that FBXW7 may be associated with more aggressive clinicopathological features in ESCC. Given that FBXW7 is traditionally regarded as a tumor suppressor (18-20), its elevated expression in more advanced and poorly differentiated tumors is somewhat paradoxical. This observation supports the notion that FBXW7 may play a context-dependent and potentially dual role in tumor biology (21). Recent evidence suggests that FBXW7 regulates cell cycle arrest and apoptosis and, under certain conditions, promotes EMT and cancer stemness, thereby facilitating tumor invasion, metastasis, and therapy resistance (11,22,23). Therefore, the upregulation of FBXW7 in aggressive ESCC subgroups may reflect a compensatory cellular response, post-translational dysregulation, or even a pro-tumorigenic switch in specific microenvironmental contexts.

FBXW7 has been well acknowledged as a tumor suppressor in many cancers (24-26). However, in this study, we found that the expression of FBXW7 in 69 ESCC tissues was higher than that in adjacent non-tumor tissues. In addition, the expression of FBXW7 protein in ESCC tissues was associated with poor differentiation, advanced tumor stage and lymph node metastasis, which suggested that positive expression of FBXW7 may be associated with malignant ESCC. Based on these findings, we speculated that FBXW7 was a tumor-promoting gene in ESCC. In order to verify our speculation, we performed in vitro experiments in Eca109 and EC9706 cells. FBXW7 overexpression promoted the migration and invasion of ESCC cells in vitro. To further validate these findings in vivo, ESCC xenograft mouse models were established. Mice in the FBXW7 overexpression group developed larger tumors and exhibited increased tumor weight compared to the blank control group. In contrast, mice in the FBXW7 knockdown group showed significantly smaller tumor sizes than those in the control group. These results demonstrate that FBXW7 overexpression enhances the proliferation and tumorigenicity of ESCC cells in vivo.

There are some limitations in this study. First, although in vivo experiments were conducted, the specific signaling pathways involved in FBXW7-mediated tumor promotion were not identified. Future studies including quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blot analyses should be conducted to elucidate the underlying mechanisms. Second, the sample size of clinical ESCC tissues was relatively small, which may limit the statistical power and generalizability of the findings. Larger cohorts and multicenter studies are needed to validate the clinical relevance of FBXW7 expression. Third, the FBXW7 knockdown experiments in EC9706 cells were not performed successfully although we tried several times. Fourth, FBXW7 knockdown experiments in EC9706 cells were not successfully established despite multiple attempts, which limited our ability to comprehensively assess the loss-of-function effects in this cell line. Optimization of transfection conditions or the use of alternative gene silencing strategies (e.g., lentiviral delivery or CRISPR-Cas9) may be necessary in future studies.

Conclusions

FBXW7 promotes tumor cell proliferation, invasion, and migration in ESCC, and may serve as a potential biomarker for its diagnosis and treatment. Further studies are needed to clarify the underlying mechanisms of FBXW7-mediated tumorigenesis in ESCC.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the ARRIVE and REMARK reporting checklists. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-aw-2294/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-aw-2294/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-aw-2294/prf

Funding: This work was supported by the National Natural Science Foundation of China (No. 82260471) and the State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia Fund (No. SKL-HIDCA -2022-SG4).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-aw-2294/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Animal experiments were performed under a project license (No. IACUC-20160218-031) granted by the ethics board of The First Affiliated Hospital of Xinjiang Medical University, in compliance with national guidelines for the care and use of animals. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the ethics board of The First Affiliated Hospital of Xinjiang Medical University (No. 20220308-091), and informed consent was obtained from all individual participants.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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