Our study combines various technical approaches, including network toxicology, 117 combinations of machine learning algorithms, molecular docking, kinetic simulations, and targeted therapy experiments to investigate the toxic effects of dioxin exposure on liposarcoma development. Based on the PubChem database, we investigated the properties of dioxin-like pollutants, especially their high lipophilicity, which can promote accumulation in human adipose tissue and pose serious health risks.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) has been widely studied19its potential harm is mainly focused on the occurrence of liver cancer, breast cancer, lung cancer, stomach cancer, and pancreatic cancer. However, despite the confirmed carcinogenicity in these organs, there are few studies on the carcinogenicity of dioxins in adipose tissue. The biological properties of adipose tissue as an important metabolic organ make it a favorable environment for the accumulation and long-term presence of dioxin-like pollutants.20providing an environment conducive to carcinogenic effects. Therefore, adipose tissue is a potential target for the carcinogenic effects of these pollutants. AhR, recognized as a receptor for dioxin-like compounds, is known to play an important role in cell proliferation and metastasis, and is closely associated with the development of various cancers.twenty one. In our study, we identified AhR through network toxicology analysis and subsequently revealed the oncogenic process of receptor AhR in liposarcoma through phenotypic studies. We further validated this finding using a clinical cohort, thereby filling a gap in this research field.
Previous studies have mainly focused on the molecular function of the single gene AhR in TCDD-related carcinogenesis.twenty two. Our results show that although AhR receptors are certainly involved in part of the carcinogenic process in adipose tissue, relying on single genes alone to predict liposarcoma outcome is insufficient, as a single gene approach may not fully reflect the complex pathological process of liposarcoma, a tumor with multiple genetic mutations.twenty three. Therefore, we established a predictive model and validated it using techniques such as molecular docking and kinetic simulation. Finally, we used proteins such as CDH3, ADORA2B, MMP14, IP6K2, and HTR2A to predict recurrence of dioxin-related liposarcoma.
P-cadherin (CDH3), a classical cadherin, is considered an important component of the Wnt pathway. Yiting Li and his friendstwenty four We show that genes of the Wnt pathway, including LeF1, CDH2, and CDH3, are involved in TCDD-induced cellular changes. Further research by Vivek Subbiatwenty five We observed that P-cadherin overexpression represents a potential target for tumor radioimmunotherapy, including liposarcoma. Kim Seung Tae’s study26 found that the adenosine receptor A2B (ADORA2B) gene is one of the putative primary response genes induced by TCDD and is associated with signal transduction. The binding pocket selected by molecular docking is very similar to previously reported binding pockets27 It is formed by residues such as Ala64, Val85, Leu86, Phe173, and Val250 of human A2BAR. Hydrophobic subpockets within this region play an important role in high-affinity binding of small molecules, making it a potential target for drug development.
Xiaolan Feng et al.28 found that amplification on 17p11-12 was highly tumor specific, including DDLPS, and that ADORA2B gene expression was associated with this amplification. Matrix metalloproteinase 14 (MMP-14) promotes invasive growth and metastasis of tumor cells by degrading extracellular matrix (ECM) components such as collagen and matrix proteins. Cheri L. Lamb and colleagues29 found that TCDD induced the expression of MMP-3 and MMP-14, both of which exhibit collagenase and gelatinase activities. Research by Jordi Gonzalez Molina30 Furthermore, we revealed that MMP-14 is highly expressed in most sarcomas, is closely associated with the sarcomatoid phenotype, and controls key processes in this disease. In previous research31Amino acid residues Met-328 and Arg-330 in the PEX domain of MMP-14 are important for selective recognition and binding of NSC405020. The structural features of these residues resemble the binding pocket we selected and allow tight interactions with the compounds that play a role.
Research by Julian Krauskopf32 found that polychlorinated biphenyls significantly disrupted inositol hexaphosphate kinase 2 (IP6K2) gene expression at certain concentrations. David S. Shames33 We believe that IP6K2 is a target of HSP90 and may be a potential target for cancer drug development. Research by Glancis Luzeena Raja34 TCDD is an endocrine disrupting chemical (EDC), suggesting that some EDCs may affect serotonin receptors (HTR1A and HTR2A) and cause modifications in a region-specific, sexually dimorphic, and experience-dependent manner. Yesenia Ballou’s research35 demonstrated that treatment with a 5-HT antagonist in the SW872 liposarcoma cell line led to a significant decrease in cell density. This indicates that serotonin receptors play an important role in liposarcoma cell proliferation and provides a theoretical basis for further research on 5-HT receptor inhibitors in TCDD-related liposarcoma treatment. Similar to the hydrophobic pocket of the HTR2A receptor that we selected, particularly the SER159 position, 6-PPDQ could exert neurotoxic effects by binding to this critical region.36provides the basis for selecting this site for investigation.
These findings suggest that proteins such as CDH3, ADORA2B, MMP14, IP6K2, and HTR2A may serve as potential therapeutic targets for dioxin exposure-related cancers, especially in regulating cancer cell behavior and improving the efficacy of anticancer therapy.
It is important to note that our study innovatively used ketanserin, a selective HTR2A receptor antagonist, in combination with doxorubicin, a first-line chemotherapeutic drug, for the treatment of TCDD exposure-related liposarcoma. Ketanserin, commonly used to treat high blood pressure and certain cardiovascular diseases37blocks HTR2A receptors and inhibits vasoconstriction, which dilates blood vessels and lowers blood pressure. Because its action is primarily confined to peripheral tissues, it has relatively little effect on the central nervous system, reducing side effects. Recent studies suggest that ketanserin may have potential in cancer therapy, particularly in inhibiting tumor cell proliferation and promoting apoptosis. It has been shown to promote apoptosis in gastric cancer cells by blocking the HTR2A receptor.38. Additionally, ketanserin exhibits significant inhibitory effects on the proliferation of certain cancer cell lines, such as MCF-7.39suggesting its potential as an adjunctive anticancer agent. Although its role in cancer therapy is still in the early stages of research, its function as an HTR2A receptor antagonist provides a new approach for adjuvant treatment of TCDD-related liposarcoma.
Our study of potential mechanisms linking TCDD and liposarcoma has several limitations. First, there is currently a lack of clinical cohort studies on dioxin exposure and liposarcoma. Because the amount and duration of exposure to dioxin plays an important role in the development of the disease.40The chronic nature of this process makes it difficult for researchers to fully reflect real exposure scenarios through short-term studies and models, especially when observing liposarcoma development. Second, there is a lack of animal models41 For interspecies comparative studies simulating long-term, low-dose dioxin exposures that reflect real-world chronic exposure situations. Therefore, although our study provides valuable mechanistic insight regarding dioxin-related liposarcoma, direct evidence from real-world environmental exposures is still lacking.
Despite the aforementioned limitations, our study has essential advantages. We comprehensively applied a variety of techniques, including network toxicology, 117 combinations of machine learning algorithms, molecular docking, dynamic simulations, and pharmacological experiments. This multi-layered research approach not only increases research comprehensiveness and accuracy, but also greatly improves the efficiency of toxicity assessment of environmental pollutants such as dioxins through the integration of bioinformatics and big data. Improved toxicity assessment efficiency will enable the rapid development of pollutant-related tumor prognostic biomarkers and the trial of targeted therapies based on these biomarkers, further accelerating the optimization of therapeutic strategies. Compared to traditional methods, our study provides a more efficient and cost-effective alternative through network toxicology. Through our comprehensive analysis and innovative approach, we not only provide a new perspective on the pathogenesis of dioxin-related liposarcoma, but also provide new tools and theoretical foundations to assess the health effects of environmental pollutants.
