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PTEN suppresses renal cell carcinoma proliferation and migration via inhibition of the PI3K/AKT pathway

World Journal of Surgical Oncology volume 23, Article number: 42 (2025) Cite this article

Abstract

Background

Renal cell carcinoma (RCC) is a frequent and aggressive type of kidney cancer with limited therapeutic options. Although phosphatase and tensin homolog (PTEN) have been recognized as a potential tumor suppressor in all kinds of cancers, its function in RCC remains to be thoroughly elucidated.

Objective

This article was recruited to examine the PTEN’s role in managing the PI3K/AKT pathway and its impact on the RCC cell proliferation and migration.

Methods

This study collected renal cancer and adjacent non-cancerous tissue samples from our hospital. HK-2 and 786-O cells were used, with 786-O cells divided into control, vector, and oe-PTEN groups. PTEN and related protein levels were detected using RT-qPCR and Western blot. Statistical analyses were performed using the Mann-Whitney U test and Kruskal-Wallis H test. Cell viability and migration were assessed using the CCK-8 assay and wound healing assay. All analyses were conducted with SPSS 22.0 software, with statistical significance defined as p < 0.05.

Results

RT-qPCR results showed that PTEN expression was significantly increased in RCC tumor tissues compared to normal tissues (p < 0.01). However, PTEN mRNA levels were significantly reduced in 786-O cells compared to HK-2 cells (p < 0.01). In 786-O cells with low PTEN expression, further induction of PTEN overexpression significantly inhibited PI3K/AKT signaling activity (p < 0.01), accompanied by decreased cell viability and migration ability. These results indicate that the expression pattern of PTEN in RCC is complex, but its overexpression can exert tumor-suppressive effects by inhibiting the PI3K/AKT signaling pathway.

Conclusion

Our findings demonstrate that PTEN overexpression in RCC cells leads to decreased PI3K/AKT signaling, decreasing cell viability and migration. This study highlights the critical role of PTEN in RCC progression and suggests potential therapeutic targets for intervention.

Introduction

Renal cell carcinoma (RCC) is the most common type of malignant kidney tumor, accounting for about 90% of all kidney malignancies [1]. RCC is characterized by a high recurrence rate and resistance to conventional treatments, making it a significant challenge in clinical therapy. Despite advancements in surgery and targeted therapies in recent years, the five-year survival rate for patients with advanced RCC remains below 10% [2, 3]. This underscores the urgent need to explore the molecular mechanisms underlying RCC to develop more effective treatment strategies. Phosphatase and tensin homolog (PTEN) is a crucial tumor suppressor gene that plays a key role in several cancers [4, 5]. PTEN not only regulates tumor cell proliferation but is also involved in cellular metabolism, genomic stability maintenance, and immune regulation [6]. For example, in breast cancer [4], glioblastoma [7], and prostate cancer [8], PTEN loss is often associated with increased tumor malignancy, enhanced drug resistance, and poor clinical prognosis [9,10,11]. Additionally, research has shown that PTEN can regulate drug resistance in cancer cells [12], and it also modulates apoptosis by increasing the stability and cytoplasmic localization of P21 [13]. Furthermore, PTEN can protect the kidneys by interacting with inflammatory factors to inhibit the progression of nephritis [14]. PTEN encodes a lipid phosphatase responsible for dephosphorylating PIP3, a key molecule in the PI3K/AKT signaling pathway [15]. By converting PIP3 to PIP2, PTEN negatively regulates the PI3K/AKT pathway, thereby affecting critical cellular processes of such as growth, proliferation, survival, and migration [16]. However, the specific role of PTEN in RCC remains controversial. In recent years, significant progress has been made in RCC research. Tumkur et al. (2021) found that clear cell renal cell carcinoma is closely related to VHL and HIF status, suggesting potential molecular mechanisms of this cancer type [17]. Meanwhile, Roldan et al. (2020) discovered that chromophobe renal cell carcinoma is associated with poor prognosis, revealing the aggressive nature of this rare cancer type [18]. However, the precise mechanisms by which PTEN influences RCC cell behavior through the regulation of the PI3K/AKT pathway have not been fully explored. Addressing this gap in knowledge will provide a foundation for investigating PTEN’s potential as a therapeutic target in RCC.

This study aims to clarify the function of PTEN in RCC by investigating its impact on the PI3K/AKT pathway and exploring its potential influence on RCC cell growth and motility. The findings of this study may provide new insights into the molecular mechanisms of RCC and suggest potential innovative strategies for the development of RCC therapies.

Methods

Participants

The study was conducted at the Department of Haematology, The First Affiliated Hospital of Naval Medical University, Shanghai, China, under project number KYSY-2024-0112. All experimental procedures were approved by the Ethics Committee and adhered to relevant ethical guidelines. Tissue samples were collected from ten human renal cancer cases, along with adjacent non-cancerous areas. Human renal cancer 786-O cells and human renal tubular epithelial HK-2 cells were obtained from the Cell Bank of the Chinese Academy of Sciences (Shanghai, China). The 786-O cell line originates from primary clear cell carcinoma, while the HK-2 cells, derived from the proximal tubule cells of normal kidneys, served as normal controls. Both cell lines exhibit epithelial-like characteristics. The sample size was determined based on the availability of tissue samples and cell lines.

Setting

Cell culture

The HK-2 and 786-O cell lines were cultured in Dulbecco’s Modified Eagle Medium (DMEM, Gibco, Carlsbad, CA, USA), supplemented with 10% fetal bovine serum (FBS, Gibco) and 1% penicillin/streptomycin. The cells were maintained at 37 °C in a humidified atmosphere containing 5% CO2. The Institutional Review Board of our hospital approved the study protocol, and informed consent was obtained from each patient prior to participating.

Cell transfection

The full-length human PTEN cDNA was amplified via polymerase chain reaction (PCR) and subsequently cloned into the pcDNA3.1 expression vector. Sequencing was performed to confirm the successful construction of both the recombinant plasmid (pcDNA3.1-PTEN) and the empty vector (pcDNA3.1). The control plasmid was custom-designed and produced by Shanghai IBS Biotech Co., Ltd. For the transfection, 786-O cells were seeded in six-well plates at a density of 2 × 10^5 cells per well. Cells were then transfected with 2 µg of either pcDNA3.1-PTEN or pcDNA3.1 using Lipofectamine™ 3000 Transfection Reagent (Invitrogen), followed by a 48 h incubation to ensure efficient transfection.

Data sources/ measurement

Quantitative reverse transcription PCR (RT‑qPCR)

Total RNA from tissues and cells was extracted using the TRIzol reagent (Invitrogen), following the manufacturer’s instructions. Reverse transcription and quantitative PCR (qPCR) were performed using the Quant One Step qRT-PCR Kit (Probe) (LM-0102; LMai Biotech Co., Ltd.). Specific primers for miR-25-3p and U6 snRNA (as an internal control) were utilized to quantify expression levels. The primer sequences, designed by Tsingke Biotech Ltd., are listed in Table 1.

Table 1 Sequences of the primers used in the present study. The forward and reverse primers for PTEN and GAPDH genes are listed. GAPDH was used as the internal control for normalization
Full size table

Cell viability assay

For the Cell Counting Kit-8 (CCK-8) assay, 5,000 cells per well were seeded into a 96-well plate and allowed to attach for 24 h. Following this, the cells were treated with varying concentrations of paclitaxel, gained from the National Institute for the Control of Pharmaceutical and Biological Products (Beijing, China), for 24, 48, and 72 h. Subsequently, 10 µl of CCK-8 solution (Sant Biotechnology, Shanghai, China) was added to each well, and the cells were incubated at 37 °C. After 1 h, the absorbance at 450 nm was measured using an enzyme-linked immunosorbent assay (ELISA) reader.

Scratch wound healing assay

Cells were grown in a 6-well plate until they reached confluence. A uniform scratch was made using a sterile pipette tip, and the wells were rinsed with Phosphate Buffered Saline (PBS) to remove any debris. The cells were then treated with various concentrations of paclitaxel. Images of the scratch were captured at 0 and 24 h. The extent of wound closure was quantified by measuring the initial and final wound widths using ImageJ software.

Western blot analysis

For protein extraction, cells were lysed using a RIPA lysis buffer kit (Jrdun Biotechnology, CA, USA), and the supernatants were collected after centrifugation. Protein concentrations were determined using a BCA protein quantification kit (Thermo Scientific, USA). Proteins were then separated by 10% or 15% sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) gels and transferred onto nitrocellulose membranes. The membranes were blocked with 5% fat-free milk at room temperature for 1 h, followed by overnight incubation at 4 °C with primary antibodies specific for PI3K (abcam, ab191606), p-PI3K (abcam, ab182651), p-AKT (abcam, ab192623), AKT (abcam, ab179463), PTEN (abcam, ab267787), and GAPDH (abcam, ab181602). After washing with Tris-Buffered Saline with Tween (TBST), the membranes were incubated with Horseradish Peroxidase (HRP)-conjugated secondary goat anti-rabbit antibodies for 1 h at room temperature. Chemiluminescent signals were generated using an enhanced chemiluminescence kit (Millipore, USA) and captured with the Tanon-5200 Imaging system. Band intensities were quantified using ImageJ software (National Institutes of Health, Bethesda, MD, USA).

Statistical methods

Data are presented as median (Q1–Q3) or as ranges (minimum–maximum). Group comparisons between two groups were conducted using the Mann-Whitney U test, while comparisons among multiple groups were performed using the Kruskal-Wallis H test, followed by Dunn’s post hoc test with Bonferroni correction for multiple comparisons [19, 20]. All statistical analyses were performed using SPSS software version 22.0 (IBM Corporation, USA), with statistical significance set as p < 0.05.

Results

PTEN mRNA and protein expression in RCC tissues and cell lines

We examined the involvement of PTEN in RCC tissues and cells compared to normal kidney tissues and cells. PTEN mRNA levels were significantly increased in tumor tissues (p < 0.01) (Fig. 1A; Table 1, S1). However, in the 786-O RCC cell line compared to the HK-2 normal renal epithelial cell line, the level of PTEN reduced significantly (p < 0.01) (Fig. 1B; Table 2, S2). Western blot analysis also showed a similar reduction in PTEN protein levels in the 786-O cells (p < 0.01) (Fig. 1C; Table 3, S3). These results indicate that PTEN expression is reduced in RCC, suggesting that PTEN may play a role in the occurrence and development of RCC.

Fig. 1
figure 1

PTEN mRNA and Protein Expression in RCC Tissues and Cell Lines. (A) PTEN mRNA levels in Normal and Tumor tissues; (B) PTEN mRNA levels in HK-2 and 786-O cell lines; (C) PTEN protein levels in HK-2 and 786-O cell lines. Compared to the Normal and HK-2 group, **p < 0.01

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Table 2 The comparison of PTEN mRNA expression levels between the normal group and the Tumor group was evaluated using the Mann-Whitney U test, n, Me (Q1-Q3) (see Fig. 1A)
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Table 3 The comparison of PTEN mRNA expression levels between the HK-2 group and the 786-O group was evaluated using the Mann-Whitney U test, n, Me (min-max) (see Fig. 1B)
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Effects of PTEN overexpression on 786-O cells

In this study, PTEN overexpression in 786-O RCC cells significantly increased both mRNA and protein expression levels compared to the Vector group (p < 0.01) (Fig. 2A-B; Tables 4 and 5, table S4-S5). The CCK-8 assay demonstrated a significant reduction in cell viability in the oe-PTEN group compared to the Vector group (p < 0.01) (Fig. 2C; Table 6, S6). Similarly, the wound healing assay revealed a marked decline in cell migration in the oe-PTEN group relative to the Vector group (p < 0.01) (Fig. 2D; Table 7, S7). No significant differences were observed between the Control and Vector groups. These results indicate that PTEN overexpression inhibits both the proliferation and migration of renal cancer cells.

Fig. 2
figure 2

Effects of PTEN overexpression on RCC cells. (A) PTEN mRNA levels in Control, Vector, and oe-PTEN groups; (B) PTEN protein levels in Control, Vector, and oe-PTEN groups; (C) Cell viability assessed by CCK-8 assay in Control, Vector, and oe-PTEN groups; (D) Cell migration assessed by wound healing assay in Control, Vector, and oe-PTEN groups. Compared to the Vector group, *p < 0.05

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Table 4 The comparison of PTEN protein expression levels between the HK-2 group (normal kidney epithelial cells) and the 786-O group (renal cancer cells) was evaluated using the Mann-Whitney U test. The results are presented as n, Me (min-max)(see Fig. 1C)
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Table 5 The comparison of PTEN mRNA expression levels among the control, Vector, and PTEN groups was evaluated using the Kruskal-Wallis test. The results are presented as n, Me (min-max) (see Fig. 2A)
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Table 6 The comparison of PTEN protein expression levels among the control, Vector, and PTEN groups was evaluated using the Kruskal-Wallis test. The results are presented as n, Me (min-max) (see Fig. 2B)
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Table 7 The comparison of cell viability among the control, Vector, and PTEN groups was evaluated using the Kruskal-Wallis test. The results are presented as n, Me (min-max) (see Fig. 2C)
Full size table

Effects of PTEN overexpression on PI3K/AKT pathway

To investigate the effect of PTEN overexpression on the PI3K/AKT pathway, we analyzed the protein expression levels of p-AKT/AKT and p-PI3K/PI3K in the oe-PTEN, Vector, and Control groups through western blot analysis. As shown in Fig. 3A, PTEN overexpression significantly reduced the phosphorylation levels of both AKT and PI3K, compared to the Vector group, while no significant difference was observed between the Control and the Vector groups. The quantitative analysis in Fig. 3B further confirmed that the p-AKT/AKT and p-PI3K/PI3K ratios were significantly lower in the oe-PTEN group (p < 0.01) (Tables 8 and 9, S8-S9). These results indicate that PTEN overexpression effectively inhibits the activation of the PI3K/AKT pathway in 786-O cells (See Table 10).

Fig. 3
figure 3

Effects of PTEN overexpression on PI3K/AKT pathway proteins in RCC cells. (A) Western blot analysis of PTEN, p-AKT, AKT, p-PI3K, and PI3K protein levels in Control, Vector, and oe-PTEN groups; (B) Quantification of protein levels, showing significantly lower p-AKT/AKT and p-PI3K/PI3K ratios in the oe-PTEN group. Compared to the Vector group, *p < 0.05

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Table 8 The comparison of migration among the control, Vector, and PTEN groups was evaluated using the Kruskal-Wallis test. The results are presented as n, Me (min-max) (see Fig. 2D)
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Table 9 The comparison of p-AKT/AKT protein expression levels among the control, Vector, and PTEN groups was evaluated using the Kruskal-Wallis test. The results are presented as n, Me (min-max) (see Fig. 3A)
Full size table
Table 10 The comparison of p-PI3K/PI3K protein expression levels among the control, Vector, and PTEN groups was evaluated using the Kruskal-Wallis test. The results are presented as n, Me (min-max) (see Fig. 3A)
Full size table

Discussion

Our research results demonstrated that PTEN is expressed at lower levels in RCC, indicating its potential role in regulating the onset and progression of RCC. This finding aligns with previous observations in pancreatic cancer [21], gastric cancer [22] and endometrial cancer [23], where PTEN has also been shown to function as a tumor suppressor. The significant inhibition of RCC cell proliferation and migration following PTEN overexpression, as observed in this study, supports the notion that PTEN plays a critical role in suppressing tumor growth and metastasis across various cancer types. The PI3K/AKT signaling pathway is a key regulator of cell growth, survival, and migration, and is often abnormally activated in RCC, promoting tumor progression and treatment resistance [24]. PIP3 binds to the cell membrane, recruiting phosphoinositide-dependent kinase-1 (PDK1) and protein kinase B (AKT), which are subsequently phosphorylated and activate AKT. However, PTEN dephosphorylates PIP3 into PI(4,5)P2, thereby preventing AKT activation and inhibiting the PI3K/AKT signaling pathway [25]. Our study demonstrated that PTEN exerts its tumor-suppressive effect in RCC cells through this negative regulatory mechanism. Specifically, PTEN overexpression leads to a marked decrease in phosphorylated AKT (p-AKT) and phosphorylated PI3K (p-PI3K) levels, thereby inhibiting AKT activation by dephosphorylating PIP3 [26, 27]. This result is consistent with findings in other cancer types [28, 29].

The reduction in RCC cell proliferation and migration observed in our experiments can be attributed to the inhibition of key signaling molecules within the PI3K/AKT pathway. This suggests that PTEN plays a major role in regulating the cell cycle, promoting apoptosis, and limiting the invasive behavior of tumor cells [30]. By suppressing the PI3K/AKT pathway, PTEN reduces the metastatic potential of RCC cells, which is often associated with a more aggressive and treatment-resistant phenotype [24]. Our findings also highlight the importance of PTEN in maintaining cellular homeostasis and preventing tumorigenesis. The PI3K/AKT signaling pathway promotes oncogenesis by enhancing cell survival, proliferation, and migration, and its dysregulation is a hallmark of various cancers [24]. Restoring PTEN function or directly targeting the PI3K/AKT pathway could offer promising therapeutic strategies for RCC. In this context, our study adds to the growing body of evidence that suggests the PI3K/AKT pathway as an essential therapeutic target in cancers where PTEN is lost or mutated.

By revealing PTEN’s role in inhibiting the PI3K/AKT pathway in RCC, this study provides crucial insights into the molecular mechanisms underlying RCC progression. These results underscore the therapeutic potential of strategies aimed at restoring PTEN function or inhibiting the PI3K/AKT pathway in RCC treatment. Our findings also suggest that PTEN may have a consistent role in suppressing tumor growth across various cancer types by targeting similar pathways.

While our study offers valuable insights, several limitations should be acknowledged. First, our experiments were conducted in vitro, which may not fully replicate the complexity of the in vivo tumor environment. To better validate our findings, future studies should incorporate animal models that can provide more physiologically relevant data. Second, although we demonstrated PTEN’s suppressive effects on the PI3K/AKT pathway, we did not extensively explore the downstream targets of this pathway. Further investigation into these targets could offer a more comprehensive understanding of the molecular mechanisms driven by PTEN. Additionally, our study primarily focused on the overexpression of PTEN. Future research examining the effects of PTEN knockdown or deletion in RCC cells could provide complementary insights into its tumor suppressive functions.

Renal cell carcinoma (RCC) is an aggressive malignant tumor of the kidney with limited treatment options. As a classical tumor suppressor, PTEN plays a critical role in various cancers by inhibiting the PI3K/AKT signaling pathway; however, its specific function in RCC remains unclear. Studies have shown that the regulation of PTEN function in tumors is influenced not only by its expression levels but also by the modulation of various miRNAs [31]. For instance, miR-92a promotes epithelial-mesenchymal transition (EMT) and metastasis in non-small cell lung cancer by activating the PTEN/PI3K/AKT signaling pathway [32], while miR-23a-3p suppresses the oncogenic effects of the PI3K/AKT pathway by upregulating PTEN expression [33]. These findings suggest that miRNAs exert dual roles in tumor progression through the regulation of PTEN. Therefore, further investigation into the molecular mechanisms of PTEN and its regulatory networks in RCC may help uncover the pathogenesis of RCC and provide a basis for developing new therapeutic strategies.

In conclusion, our study demonstrates that PTEN overexpression in RCC cells inhibits the PI3K/AKT pathway, leading to reduced cell proliferation and migration. These findings highlight the critical role of PTEN in RCC progression and suggest potential therapeutic strategies targeting the PI3K/AKT pathway. Our results contribute to a deeper understanding of PTEN’s functions in cancer biology and emphasize the need for further research to translate these insights into clinical applications. By addressing current limitations and pursuing new research directions, we aim to advance the development of more effective treatments for RCC and other diseases associated with PI3K/AKT pathway dysregulation.

Conclusion

In this study, we found that PTEN inhibits RCC cell proliferation and migration by suppressing the PI3K/AKT pathway, effectively restraining tumor progression. This research further supports the potential of PTEN as a therapeutic target for RCC, providing a basis for the development of therapies that restore PTEN function or compensate for its loss. Future studies should explore the downstream effects of PTEN and its synergy with existing treatment methods to develop more effective RCC therapies.

Data availability

The data used to support the findings of this study are available from the corresponding author upon request.

Abbreviations

RCC:

Renal cell carcinoma

PTEN:

Phosphatase and tensin homolog

ELISA:

Enzyme-linked immunosorbent assay

PBS:

Phosphate Buffered Saline

SDS-PAGE:

Sodium dodecyl sulfate polyacrylamide gel electrophoresis

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Acknowledgements

Not applicable.

Funding

This study supported by Funding Program of the National Natural Science Foundation of China (81970178).

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Author notes

  1. Xu Xu, Yuan-yue Tang and Xiaohong Liang contributed equally to this work as Co-first author.

Authors and Affiliations

  1. Department of Haematology, The First Affiliated Hospital of Naval Medical University, No.168 Changhai Road, Yangpu District, Shanghai, 200433, China

    Xu Xu, Yuan-Yue Tang, Wen Luo, Dong-Mei Jiang & Jie Chen

  2. Department of Urology, Fudan University Shanghai Cancer Center, No. 270 Dongan Road, Xuhui District, Shanghai, 200032, China

    Xiaohong Liang

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Contributions

Study concept and design: X.X., Y.T., X.L., W.L., D.J., J.C.; Analysis and interpretation of data: X.L., W.L.; Drafting of the manuscript: X.X., Y.T., X.L.; Critical revision of the manuscript for important intellectual content: X.X., Y.T.; Statistical analysis: W.L., D.J., J.C.; Study supervision: D.J., J.C.; all authors have read and approved the manuscript.

Corresponding authors

Correspondence to Dong-Mei Jiang or Jie Chen.

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Ethics approval and consent to participate

The study protocol was approved by the Institutional Review Board of The First Affiliated Hospital of Naval Medical University. Informed consent was obtained from all patients participating in the study.

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Not applicable.

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The authors declare no competing interests.

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Xu, X., Tang, YY., Liang, X. et al. PTEN suppresses renal cell carcinoma proliferation and migration via inhibition of the PI3K/AKT pathway. World J Surg Onc 23, 42 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12957-025-03658-9

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  • DOI: https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12957-025-03658-9

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World Journal of Surgical Oncology

ISSN: 1477-7819

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