Novel regulatory network of PS-1/β-catenin/p-PTEN axis in gastric cancer invasion

Abstract

Gastric cancer (GC) is the fifth most prevalent malignancy globally, characterized by abnormal mutant genes, high heterogeneity, and poor prognosis. A recent study focused on the expression, regulatory relationships, and effects on cell invasion of presenilin-1 (PS-1), β-catenin, and phosphorylated phosphatase and tensin homolog (p-PTEN) in GC. This study is the first integration of the tripartite regulatory network involving PS-1, β-catenin, and p-PTEN in GC. It revealed that PS-1 serves as a novel regulatory component that modulates p-PTEN through β-catenin-mediated mechanisms, thereby facilitating GC cell invasion. While this study provides valuable insights, several limitations should be noted: (1) The exclusive use of the MGC-803 cell line may not fully capture the biological diversity across different GC molecular subtypes; and (2) The precise molecular mechanisms underlying the interaction between PS-1 and β-catenin remain to be elucidated. Nevertheless, these findings significantly advance our understanding of GC metastasis mechanisms and substantiate the potential therapeutic value of targeting PS-1, β-catenin, and p-PTEN in GC treatment.

Key Words: Gastric cancer; Presenilin-1; Phosphatase and tensin homolog; β-Catenin; Tumor metastasis; γ-secretase inhibitor

Core Tip: Gastric cancer (GC) is a type of malignant tumor with high mortality and morbidity rates. Tumor metastasis and recurrence are among the main causes of death for GC patients, yet the specific mechanisms behind them remain unclear. This paper comments on a recent study that revealed the regulatory correlation among presenilin-1, β-catenin, and phosphorylated phosphatase and tensin homolog in GC and their combined role in GC cell invasion.

INTRODUCTION

Gastric cancer (GC) is one of the major global health challenges, with nearly one million new cases each year and over 650000 deaths[1,2]. The key risk factors for GC include Helicobacter pylori infection (particularly closely associated with non-cardia GC), dietary patterns, obesity, smoking, and genetic susceptibility[3-5]. The epidemiology shows significant regional differences, with high incidence areas concentrated in Asia, South America, and Eastern Europe[2]. Although advances in early screening, surgical resection, and adjuvant therapy in recent decades, the overall prognosis of GC remains unsatisfactory[6-8]. This is mainly due to the lack of specific early diagnostic biomarkers and the high rate of advanced-stage diagnosis, where tumor invasion and distant metastasis have already occurred[9,10]. The identification of molecular pathways driving GC invasion and metastasis is critical for developing actionable biomarkers and targeted therapies[11,12]. The study by Lin et al[13] focuses on the expression, regulatory relationships, and effects on cell invasion of presenilin-1 (PS-1), β-catenin, and phosphorylated phosphatase and tensin homolog (p-PTEN) in GC. By investigating their regulatory relationships and functional impact on GC cell invasion, the study addresses two fundamental questions: (1) How do PS-1, β-catenin, and p-PTEN correlate in clinical GC tissues? and (2) What is the mechanistic basis for their role in GC cell invasion and metastasis? The rationale is scientifically sound, as prior work has implicated each molecule in GC progression but failed to integrate them into a unified pathway. PS-1 has been shown to promote GC invasion via β-catenin[14], while phosphatase and tensin homolog (PTEN) is often inactivated due to phosphorylation in GC[15]. However, the link between PS-1/β-catenin signaling and PTEN phosphorylation remained unexplored. This study fills this gap, making it a valuable addition to the field.

WHAT IS THE CORRELATION BETWEEN THE PHOSPHORYLATION OF β-CATENIN, PS-1, AND p-PTEN?

PS-1 is the catalytic core subunit of the γ-secretase complex, responsible for intramembranous proteolytic cleavage of various type I transmembrane proteins, including amyloid precursor protein, Notch-1, N-and E-cadherins, etc.[16-18]. PS-1 was initially identified to be closely associated with familial Alzheimer’s disease due to its role in the cleavage of β-amyloid precursor protein[17,19]. However, PS-1 plays an opposite role in different types of tumors. For instance, PS-1 is significantly upregulated and amplified in GC tissues and cell lines, and its high expression is positively correlated with lymph node metastasis and poor overall survival of GC patients[14]. On the contrary, in glioblastoma, PS-1 cleaves and degrades sortilin to inhibit the activity of β-catenin, thereby suppressing the migration, invasion, and mesenchymal transformation of tumor cells[20]. Moreover, PS-1 exerts an anti-proliferative effect in glioblastoma by inhibiting the Wnt/β-catenin pathway[21]. β-catenin is a key component of the Wnt signaling pathway and plays a dual role in cells: It acts as an adhesion molecule to maintain cell-cell junctions when combined with E-cadherin on the cell membrane, and it functions as a transcriptional co-activator to regulate the expression of downstream target genes when translocated into the nucleus[22,23]. The dysregulation of β-catenin is a common molecular event in GC, which is closely related to the occurrence, progression, chemotherapy resistance, and ferroptosis resistance of GC[24,25]. In normal gastric mucosal cells, β-catenin is tightly regulated by the destruction complex, and its cytoplasmic level is maintained at a low level[26]. However, abnormal expression of β-catenin can lead to the proliferation, invasion, metastasis, and anti-apoptotic phenomena of GC cells[26,27]. PTEN is a dual-specificity phosphatase that can dephosphorylate both tyrosine and serine/threonine residues, and it plays a key role in regulating the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT)/mammalian target of rapamycin (mTOR) signaling pathway[28]. The abnormal phosphorylation of PTEN can lead to its cytoplasmic retention or degradation, thereby inhibiting its phosphatase activity and losing tumor suppressor function in tumors[29,30]. PTEN can also interact with other signaling pathways to jointly regulate the biological behavior of tumor cells[31]. Therefore, there may be potential crosstalk between these three molecules: PS-1 regulates the activity of β-catenin, and both may interact with the PI3K/AKT/mTOR pathway mediated by PTEN phosphorylation to jointly regulate the biological behavior of GC cells. However, the specific regulatory mechanisms among them still need to be further clarified.

Lin et al[13] identified a novel regulatory network involving PS-1, β-catenin, and p-PTEN in GC cells (Figure 1). They found that PS-1 is overexpressed in GC and stabilizes β-catenin, promoting its nuclear translocation to activate Wnt target genes associated with invasion[13]. Meanwhile, nuclear βcatenin further induces PTEN phosphorylation, leading to PTEN inactivation and sustained PI3K/AKT activation. As we all known, the PI3K/Akt/mTOR pathway is frequently activated in various types of cancer[32,33], which contributes to tumorigenesis, cell invasion, and chemotherapy resistance[34,35]. Furthermore, phosphorylation of PTEN plays a critical role in the pathogenesis of various diseases, including cancer[15]. For instance, phosphorylation of PTEN at Ser380/Thr382/Thr383 results in the loss of its lipid phosphatase activity and tumor suppressor function[36]. Moreover, the absence of PDZ domain-containing 1 can activate PI3K/AKT signaling by inhibiting PTEN phosphorylation at the S380/T382/T383 cluster, thereby enhancing its tumor-suppressive function[37]. Helicobacter pylori, a known risk factor for GC, has been shown to induce PTEN phosphorylation and inactivation, promoting gastric epithelial cell survival[36]. In this study, PS-1 influences PTEN phosphorylation and cytoplasmic localization, which effectively reduces PTEN’s tumor-suppressive activity and enhances cell invasion. Therefore, a positive feedback loop is formed among PS1, β-catenin, and p-PTEN, which synergistically enhances cell invasion and metastasis in GC.

Figure 1 Schematic diagram of the presenilin-1/β-catenin/phosphorylated phosphatase and tensin homolog axis regulating invasion and metastasis in gastric cancer. Presenilin-1 upregulates β-catenin to promote phosphatase and tensin homolog phosphorylation and cytoplasmic retention, thereby inactivating its tumor suppressor function and enhancing gastric cancer cell invasion and metastasis. γ-secretase inhibitor blocks this pathway and inhibits tumor metastasis. PS-1: Presenilin-1; PTEN: Phosphatase and tensin homolog; GSI: γ-secretase inhibitor; TCF: T cell factor; LEF: Lymphoid enhancer-binding factor.

WHAT ARE THE THERAPEUTIC IMPLICATIONS OF THE PS-1/β-CATENIN/ p-PTEN SIGNALING AXIS IN GC?

GC is one of the most prevalent malignant tumors globally, ranking fourth in cancer-related mortality and fifth in incidence, and poses a severe threat to human health[38,39]. The pathogenesis of GC is a complex, multistep process characterized by extensive molecular abnormalities, dysregulated signaling pathways, and interactions between genetic factors and environmental stimuli[40,41]. These molecular alterations drive the transformation of normal gastric epithelial cells into malignant phenotypes, and further promote tumor progression, invasion, and metastasis[41,42]. Among the numerous dysregulated molecules and signaling cascades involved in GC pathogenesis, the abnormal expression and functional disorder of PS-1 and β-catenin have been increasingly recognized as crucial contributors[14,43]. In the study by Lin et al[13], the results demonstrated high expression rates of PS-1 (60.3%, 70/116), β-catenin (56.9%, 66/116), and p-PTEN (47.4%, 55/116) in 116 clinical GC specimens. Notably, the co-high expression of PS1, β-catenin, and p-PTEN was not only closely associated with aggressive clinicopathological features, but also significantly correlated with poorer 5-year overall survival rates in GC patients. These findings strongly indicate that the PS-1/β-catenin/p-PTEN axis serves as a reliable combined prognostic biomarker for predicting tumor invasion, metastasis, and unfavorable clinical outcomes in GC, laying a solid foundation for its potential therapeutic application.

The Wnt/β-catenin pathway is well recognized as a key driver in the initiation and progression of various cancers, including GC[44]. Its abnormal activation is known to promote epithelial-mesenchymal transition, a critical process that enhances tumor cell migration and invasion, as well as facilitates lymph node metastasis and overall tumor progression[23,44,45]. Unlike many other cancer types where constitutively activated mutations in the Wnt/β-catenin pathway are common, such mutations are relatively rare in GC[46]. Instead, environmental factors such as Helicobacter pylori infection can indirectly activate this pathway, leading to aberrant accumulation and nuclear translocation of β-catenin[36]. In this background, the PS-1/β-catenin/p-PTEN axis emerges as a promising therapeutic target for GC, given its central role in regulating both the Wnt/β-catenin and PI3K/AKT signaling pathways. As an upstream triggering factor of this axis, PS-1 plays a pivotal role in stabilizing β-catenin and promoting its nuclear translocation. Therefore, targeting PS-1 can effectively block the upstream initiation of the axis, thereby decreasing the stability and nuclear translocation of β-catenin and further inhibiting the activation of downstream Wnt/β-catenin target genes associated with tumor invasion. Furthermore, direct inhibition of β-catenin can simultaneously block the Wnt/β-catenin pathway and the subsequent induction of p-PTEN, breaking the positive feedback loop formed among PS-1, β-catenin, and p-PTEN. In addition, reducing the expression of p-PTEN or restoring the activity of PTEN can reactivate its tumor-suppressing function[47]. Therefore, targeted intervention to decrease p-PTEN levels or dephosphorylate PTEN can inhibit the PI3K/AKT signaling pathway—another key oncogenic pathway involved in tumor cell survival, migration, and metastasis[48,49]. Collectively, targeting different components of the PS-1/β-catenin/p-PTEN axis can synergistically suppress GC cell invasion and metastasis, providing multiple potential therapeutic strategies for the clinical management of GC, especially for patients with high expression of PS-1, β-catenin, and p-PTEN who have poor prognosis.

WHAT ARE THE LIMITATIONS OF LIN’S STUDY AND WHAT ARE THE FUTURE RESEARCH DIRECTIONS?

The study by Lin et al[13] contributes to a deeper understanding of the molecular mechanisms driving GC invasion and provides a rationale for developing targeted therapies against the PS-1, β-catenin, and p-PTEN. Nevertheless, this research also has certain limitations: The experiment was conducted based on a single GC cell line (MGC-803). Given that GC is a highly heterogeneous malignant tumor, its molecular characteristics, histological manifestations, and clinical behaviors vary significantly[50,51]. A single-cell model is unable to comprehensively reflect the overall characteristics of the disease[52,53]. Currently, the internationally recognized mainstream molecular classification systems for GC mainly include The Cancer Genome Atlas classification system and the Asian Cancer Research Group classification system[54]. According to The Cancer Genome Atlas, GC is classified into four subtypes: Epstein-Barr virus-positive, which is characterized by viral integration and unique epigenetic changes[55]; microsatellite instability-high, which exhibits high tumor mutational burden and potential sensitivity to immunotherapy[56]; chromosomally unstable, which is marked by significant chromosomal copy number variations[57]; and genomically stable, which is mostly associated with diffuse histology and often presents an immunologically inert tumor microenvironment[50]. On the other hand, the Asian Cancer Research Group classification consists of four subtypes: Microsatellite instability; microsatellite stable (MSS)/epithelial-mesenchymal transition, which is associated with poor prognosis and closely related to invasion and metastasis; MSS/TP53-deficient (MSS/TP53-); and MSS/TP53-wild type (MSS/TP53+)[54]. Notably, the PS1/β-catenin/p-PTEN signaling axis may not be conserved across different GC molecular subtypes. Therefore, validation in additional GC cell lines (such as SGC-7901 and BGC-823) is necessary to confirm the universal relevance of this axis in GC, thereby enhancing the reliability and generalizability of the study’s findings.

Furthermore, PTEN is mainly phosphorylated at multiple residues (Ser370/380/385 and Thr382/383) on the C-terminus, resulting in alterations in the phosphatase activity and stability of PTEN[58]. Among them, the phosphorylation at the Thr383 site of the PTEN protein leads to the loss of its phosphatase activity[59]. They also found that the phosphorylation states of Thr383 and Ser380/Ser385 of PTEN are closely related to the migration of human glioma cells[59]. Apart from the C-terminal tail, the C2 domain has also been demonstrated to be the main target for the functionally phosphorylation-dependent regulation of PTEN. The phosphorylation of Ser229, Thr232, Thr319, and Thr321 within the C2 domain seems to regulate the intracellular localization of PTEN and the chemotaxis mediated by PTEN[60]. Lin et al[13] used a non-specific pan-p-PTEN antibody, thus unable to determine which phosphorylation events were crucial for the PTEN inactivation mediated by PS-1/β-catenin. The author can use specific PTEN phosphorylation antibodies for detection, thereby determining the specific phosphorylation of the PTEN sites caused by abnormal expression of PS-1. Furthermore, γ-secretase is a multi-substrate protease, and its inhibitors exert biological effects through the simultaneous inhibition of multiple signaling pathways including PS-1 and Notch[61,62]. Therefore, γ-secretase inhibitor (GSI) treatment cannot be exclusively attributed to PS-1 inhibition. They need to further increase the detection of Notch signaling pathway activation status in tumor tissues of the GSI treatment group and the control group. If GSI treatment leads to a significant reduction in the activation of Notch signaling, this will confirm that the inhibition of Notch is also involved in the anti-metastatic effect.

Therefore, future research should address the following gaps: (1) To investigate whether PS-1 regulates the phosphorylation and cytoplasmic localization of PTEN through β-catenin in different GC subtypes to determine its universality; (2) To use phosphor-specific antibodies or mass spectrometry to identify which PTEN residues are phosphorylated by the PS-1/β-catenin pathway, enabling targeted inhibition of the responsible kinase; and (3) To further elucidate the role of PS-1 in inhibiting GC metastasis by employing substrate-specific intervention strategies (such as PS-1-specific knockout or Notch-specific inhibitors).

CONCLUSION

Overall, Lin et al’s study[13] reveals a novel PS-1/β-catenin/p-PTEN signaling in GC cell invasion. In this study, they found a positive correlation between PS-1, β-catenin, and p-PTEN in GC. They also confirmed that PS-1 can regulate PTEN phosphorylation and cytoplasmic localization by β-catenin. Furthermore, using a multi-tiered approach (clinical, in vitro, and in vivo), they provide valuable insights into GC pathogenesis. While methodological limitations (single cell line and unspecified PTEN phosphorylation sites) exist, the study’s core findings are scientifically robust and clinically relevant. By linking PS-1, β-catenin, and p-PTEN in a cohesive pathway, the work advances our understanding of GC progression and identifies potential biomarkers and therapeutic targets for this malignancy.