Esophageal Cancer Cells Research Articles

RGS1 targeted by miR-191-3p inhibited the stemness properties of esophageal cancer cells by suppressing CXCR4/PI3K/AKT signaling

BackgroundEsophageal cancer is one of the most common malignant tumors in the world. It is urgent to prevent the development and progression of esophageal cancer. Cancer stem cells (CSCs) were reported to have the ability to initiate tumorigenesis, and reducing the stem cell-like characteristics of tumors is an important strategy to inhibit the occurrence and development of tumors. miRNAs are key regulators of the stemness of cancer. Here, we aimed to investigate the role and regulatory mechanism of miR-191-3p in the stemness properties of esophageal cancer cells. MethodsEsophageal cancer cells with stable expression of miR-191-3p were established by lentivirus system. CCK-8 assay, transwell assay, wound healing assay were used to evaluate the effect of miR-191-3p on proliferation and metastasis of esophageal cancer cells. The expression of stemness-related markers (NANOG, OCT4, SOX2), ALDH activity, sphere-forming assay and subcutaneous tumor model in nude mice were performed to evaluate the stemness properties of esophageal cancer cells in vitro and in vivo. Dual-luciferase reporter assay was used to verify the molecular mechanism. ResultHere we found that overexpression of miR-191-3p promoted the stemness properties of esophageal cancer cells in vitro and in vivo, including increasing esophageal cancer cell proliferation and metastasis ability, the expression of stemness-related markers NANOG, OCT4, and SOX2, ALDH activity, the number of spheres formed and tumor growth. Bioinformatic analysis and dual-luciferase assay demonstrated that regulator of G protein signaling 1 (RGS1) was the directed target gene of miR-191-3p and attenuated the promotion effect of miR-191-3p on the stemness of esophageal cancer cells. Furthermore, we found that RGS1 knockdown activated the PI3K/AKT pathway by negatively regulating CXCR4 to promote the stemness of esophageal cancer cells. ConclusionsOur findings revealed that RGS1 targeted by miR-191-3p inhibited the stemness of esophageal cancer cells by suppressing the CXCR4/PI3K/AKT pathway, which provide potential prognostic markers and therapeutic targets in the future.

Berbamine promotes ferroptosis of esophageal squamous cell carcinoma by facilitating USP51-mediated GPX4 ubiquitination and degradation

Esophageal cancer ranks among the most prevalent malignant tumors globally. The prognosis for esophageal squamous cell carcinoma remains poor, with a 5-year survival rate below 20 % due to limited advances in therapy. Ferroptosis, a novel form of iron-dependent lipid peroxidation-driven regulated cell death (RCD), shows significant promise in cancer treatment. Berbamine (BBM), a natural bisbenzylisoquinoline alkaloid derived from Berberis amurensis, exhibits anti-tumor effects against various cancers, yet its impact on esophageal cancer remains to be elucidated. This study aimed to explore the role of BBM in inducing ferroptosis in the treatment of esophageal cancer, focusing on its molecular mechanisms. Gene set enrichment analysis(GSEA) analysis highlighted the potential of BBM as an anti-cancer agent through ferroptosis induction. We found that BBM inhibited growth and epithelial-mesenchymal transition (EMT) in esophageal cancer cell lines, promoting Fe accumulation, ROS, and malondialdehyde (MDA) production, thereby triggering cell death. These suppressive effects were successfully reversed by Ferrostatin-1 (Fer-1). Mechanistically, BBM decreased deubiquitination enzyme USP51 levels, leading to ubiquitin degradation and glutathione peroxidase 4(GPX4) instability, and it stimulated ferroptosis. The Overexpression of USP51 mitigated the downregulation of GPX4 induced by BBM.BBM significantly inhibited tumor xenograft growth in nude mice. This discovery positions BBM as a promising therapeutic candidate for the treatment of esophageal cancer.

Identifying and validating the roles of the cuproptosis-related gene DKC1 in cancer with a focus on esophageal carcinoma

BackgroundEsophageal cancer is a common malignancy of the digestive tract. Despite remarkable advancements in its treatment, the overall prognosis for patients remains poor. Cuproptosis is a form of programmed cell death that affects the malignant progression of tumors. This study aimed to examine the impact of the cuproptosis-associated gene DKC1 on the malignant progression of esophageal cancer.MethodsClinical and RNA sequencing data of patients with esophageal cancer were extracted from The Cancer Genome Atlas (TCGA). Univariate Cox regression analysis was used to identify the differentially expressed genes related to cuproptosis that are associated with prognosis. We then validated the difference in the expression of DKC1 between tumor and normal tissues via three-dimensional multiomics difference analysis. Subsequently, we investigated the association between DKC1 expression and the tumor microenvironment by employing the TIMER2.0 algorithm, which was further validated in 96 single-cell datasets obtained from the TISCH database. Additionally, the functional role of DKC1 in pancarcinoma was assessed through GSEA. Furthermore, a comprehensive pancancer survival map was constructed, and the expression of DKC1 was verified in various molecular subtypes. By utilizing the CellMiner, GDSC, and CTRP databases, we successfully established a connection between DKC1 and drug sensitivity. Finally, the involvement of DKC1 in the progression of esophageal cancer was investigated through in vivo and in vitro experiments.ResultsIn this study, we identified a copper death-related gene, DKC1, in esophageal cancer. Furthermore, we observed varying levels of DKC1 expression across different tumor types. Additionally, we conducted an analysis to determine the correlation between DKC1 expression and clinical features, revealing its association with common cell cycle pathways and multiple metabolic pathways. Notably, high DKC1 expression was found to indicate poor prognosis in patients with various tumors and to influence drug sensitivity. Moreover, our investigation revealed significant associations between DKC1 expression and the expression of molecules involved in immune regulation and infiltration of lymphocyte subtypes. Ultimately, the increased expression of DKC1 in esophageal cancer tissues was verified using clinical tissue samples. Furthermore, DKC1-mediated promotion of esophageal cancer cell proliferation and migration was confirmed through both in vitro and in vivo experiments. Additionally, it is plausible that DKC1 may play a role in the regulation of cuproptosis.ConclusionIn this study, we conducted a systematic analysis of DKC1 and its regulatory factors and experimentally validated its excellent diagnostic and prognostic abilities in various cancers. Further research indicated that DKC1 may reshape the tumor microenvironment (TME), highlighting the potential of DKC1-based cancer treatment and its usefulness in predicting the response to chemotherapy.

Anti-tumour activity of Panobinostat in oesophageal adenocarcinoma and squamous cell carcinoma cell lines

BackgroundOesophageal cancer remains a challenging disease with high mortality rates and few therapeutic options. In view of these difficulties, epigenetic drugs have emerged as potential alternatives for patient care. The goal of this study was to evaluate the effect and biological consequences of Panobinostat treatment, an HDAC (histone deacetylase) inhibitor already approved for treatment of patients with multiple myeloma, in oesophageal cell lines of normal and malignant origin, with the latter being representative of the two main histological subtypes: adenocarcinoma and squamous cell carcinoma.ResultsPanobinostat treatment inhibited growth and hindered proliferation, colony formation and invasion of oesophageal cancer cells. Considering HDAC tissue expression, HDAC1 was significantly upregulated in normal oesophageal epithelium in comparison with tumour tissue, whereas HDAC3 was overexpressed in oesophageal cancer compared to non-malignant mucosa. No differences between normal and tumour tissue were observed for HDAC2 and HDAC8 expression.ConclusionsPanobinostat exposure effectively impaired malignant features of oesophageal cancer cells. Because HDAC3 was shown to be overexpressed in oesophageal tumour samples, this epigenetic drug may represent an alternative therapeutic option for oesophageal cancer patients.

Metformin suppresses esophageal cancer progression through the radiation‑induced cellular senescence of cancer‑associated fibroblasts.

Senescent cells are known to secrete proteins, including inflammatory cytokines and damage‑associated molecular patterns. This phenomenon is known as the senescence‑associated secretory phenotype (SASP). SASP in cancer stromal fibroblasts is involved in cancer growth and progression. Conversely, metformin, an antidiabetic drug, has been reported to inhibit SASP induction by inhibiting the activation of NF‑κB, a regulator of SASP. To date, at least to the best of our knowledge, there have been no reports regarding cellular senescence in fibroblasts and tumor progression via the SASP‑mediated paracrine pathway. The present study thus aimed to elucidate the induction mechanisms of SASP in radiation‑induced fibroblasts and to determine its effects on cancer progression via the paracrine pathway. Furthermore, the present study aimed to determine whether controlling SASP using metformin suppresses cancer progression. A well‑differentiated esophageal cancer cell line established by the authors' department and fibroblasts isolated and cultured from the non‑cancerous esophageal mucosa of resected esophageal cancer cases were used for the experiments. Fibroblasts were irradiated with 8 Gy radiation, and the changes in the expression of the senescence markers, SA‑β‑gal, p21, p16 and NF‑κB were evaluated using immunofluorescent staining and western blot analysis in the presence or absence of metformin treatment. The culture supernatants of irradiated fibroblasts treated with metformin and those treated without metformin were collected and added to the cancer cells to evaluate their proliferative, invasive and migratory abilities. Vimentin and E‑cadherin expression levels were also evaluated using immunofluorescent staining and western blot analysis. The expression levels of p16, p21 and NF‑κB in irradiated fibroblasts were attenuated by treatment with metformin. Supernatants collected from irradiated fibroblasts exhibited the proliferative activity of esophageal cancer cells, and the promotion of migratory and invasion abilities, which may be due to epithelial‑mesenchymal transition and changes in cell morphology. These reactions were confirmed to be suppressed by the addition of the supernatant of cultured fibroblasts pre‑treated with metformin. On the whole, the present study demonstrates that fibroblasts in the cancer stroma may be involved in tumor progression through cellular senescence.

Phytochemical Composition and Bioactivities of Some Hydrophytes: Antioxidant, Antiparasitic, Antibacterial, and Anticancer Properties and Mechanisms.

Few researches have explored the production of pharmaceuticals from aquatic plants. Therefore, this study explored, for the first time, the phytochemical composition and bioactivities of ten aquatic plants. Aquatic plant shoots from various Nile River canals were collected, dried, and ground for aqueous extract preparation. Phytochemical composition and antioxidant capacity were assessed using DPPH assays. Extracts were tested for antiparasitic, antibacterial, anti-biofilm, and anticancer activities through standard in vitro assays, measuring IC50 values, and evaluating mechanisms of action, including cell viability and high-content screening assays. The results showed that the aquatic plants were rich in pharmaceutical compounds. The antioxidant capacity of these extracts exceeded that of vitamin C. The extracts showed promising antiparasitic activity against pathogens like Opisthorchis viverrini and Plasmodium falciparum, with IC50 values between 0.7 and 2.5 µg/mL. They also demonstrated low MICs against various pathogenic bacteria, causing DNA damage, increased plasma membrane permeability, and 90% biofilm inhibition. In terms of anticancer activity, extracts were effective against a panel of cancer cell lines, with Ludwigia stolonifera exhibiting the highest efficacy. Its IC50 ranged from 0.5 µg/mL for pancreatic, esophageal, and colon cancer cells to 1.5 µg/mL for gastric cancer cells. Overall, IC50 values for all extracts were below 6 µg/mL, showing significant apoptotic activity, increased nuclear intensity, plasma membrane permeability, mitochondrial membrane permeability, and cytochrome c release, and outperforming doxorubicin. This study highlights the potential of aquatic plants as sources for new, safe, and effective drugs with strong antiparasitic, antibacterial, and anticancer properties.

YTHDF1 facilitates esophageal cancer progression via augmenting m6A-dependent TINAGL1 translation

N6-methyladenosine (m6A) is the most abundant internal RNA modification and plays a critical role in carcinogenesis and tumor progression. As a powerful m6A reader, YTHDF1 is implicated in multiple malignancies. However, the functions and underlying mechanisms of YTHDF1 in esophageal cancer (ESCA) are elusive. Here, we revealed that YTHDF1 expression was remarkably up-regulated in ESCA and linked with poor prognosis. Functionally, YTHDF1 promoted ESCA cell proliferation, migration, and metastasis in vitro and in vivo. Mechanistically, we demonstrated that TINAGL1 might be a potential target of YTHDF1. We revealed that YTHDF1 recognized and bound to m6A-modified sites of TINAGL1 mRNA, resulting in enhanced translation of TINAGL1. Furthermore, TINAGL1 knockdown partially rescued tumor-promoting effects of YTHDF1 overexpression. Therefore, we unveil that YTHDF1 facilitates ESCA progression by promoting TINAGL1 translation in an m6A-dependent manner, which offers an attractive therapeutic target for ESCA.

The identification of heterogeneous reactive oxygen subtypes in esophageal squamous cell carcinoma to aid patient prognosis and immunotherapy

IntroductionEsophageal cancer is increasingly recognized as a significant global malignancy. The main pathological subtype of this cancer is esophageal squamous cell carcinoma (ESCC), which displays a higher degree of malignancy and a poorer prognosis. Reactive oxygen species (ROS) play a critical role in modulating the immune response to tumors, and understanding the regulation of ROS in ESCC could lead to novel and improved therapeutic strategies for ESCC patients. MethodsA consensus matrix derived from genes involved in the ROS pathway revealed two subtypes of ROS. These subtypes were categorized as ROS-active or ROS-suppressive based on their level of ROS activity. The heterogeneity among the different ROS subtypes was then explored from various perspectives, including gene function, immune response, genomic stability, and immunotherapy. In order to assess the prognosis and the potential benefits of immunotherapy, a ROS activity score (RAS) was developed using the identified ROS subtypes. In vitro experiments were performed to confirm the impact of core RAS genes on the proliferative activity of esophageal cancer cell lines. ResultsTwo distinctive subtypes of ROS were identified. The first subtype, referred to as ROS-active, exhibited elevated ROS activity, enhanced involvement in cancer-associated immune pathways, and increased infiltration of effector immune cells. The second subtype, named ROS-suppressive, demonstrated weaker ROS activity but displayed more pronounced dysregulation in the cell cycle and a denser extracellular matrix, indicating malignant characteristics. Genomic stability, particularly in terms of copy number variation (CNV) events, differed between the two ROS subtypes. By developing a RAS model, reliable risk assessment for overall survival (OS) in patients with ESCC was achieved, and the model demonstrated strong predictive capabilities in real-world immunotherapy cohorts. Moreover, the core gene LDLRAD1 within the RAS model was found to enhance proliferative activity in esophageal cancer cell lines. ConclusionBased on the ROS pathway, we successfully identified two distinct subtypes in ESCC: the ROS-active subtype and the ROS-suppressive subtype. These subtypes were utilized to evaluate prognosis and the sensitivity to immunotherapy.

Synthesis and evaluation of new tetrapyrrole derivatives with photodynamic anti-tumor effects

As a promising anti-tumor method, photodynamic therapy (PDT) has garnered increased interest over the past decades. Since the efficacy of PDT relies on the properties of photosensitizers, tremendous efforts have been exerted in the quest for novel photoactive agents with long wavelength absorbance and high phototoxicity. In this investigation, a series of five tetrapyrrole derivatives were newly synthesized and evaluated. They all manifested sharp UV–vis absorption peak at ∼680 nm, high molar extinction coefficient (>74200 L mol−1 cm−1), impressive reactive oxygen species generation abilities and obvious photo-damage on cancer in vitro and in vivo. Among them, I4 displayed the most excellent singlet oxygen generation slope (K = 0.0531 s−1, ΦΔ = 0.87), the strongest anti-proliferation effects towards human esophageal cancer cell line Eca-109 in vitro, and more remarkable tumor inhibition rates (90.2 %) than m-THPC in vivo. Subcellular localization experiments demonstrated that I4 could distribute in mitochondria, endoplasmic reticulum and lysosomes. Hence, compound I4 could be viewed as a potential photosensitizer drug for further studies in PDT.

XRCC2 knockdown effectively sensitizes esophageal cancer to albumin-paclitaxel in vitro and in vivo.

Esophageal cancer (EC), a prevalent malignancy, has a high incidence and mortality. X-ray repair cross complementing 2 (XRCC2) functions on DNA damage and repair that works the progression of various cancers. Nevertheless, the role and mechanism of XRCC2 remain unknown in EC. The XRCC2 expression was examined by reverse transcription quantitative polymerase chain reaction and western blot. The function of XRCC2 in EC were investigated through cell counting kit-8, colony formation, transwell, flow cytometry, chromatin immunoprecipitation, luciferase, and western blot experiments. Besides, the role of XRCC2 in EC was assessed by western blot and immunohistochemistry experiments after nude mice were injected with EC109 cells and treated with nab-paclitaxel. The XRCC2 expression was upregulated in EC. Knockdown of XRCC2 diminished cell viability, and the number of colonies, migration cells and invasion cells of KYSE150 and EC109 cells. Silencing of XRCC2 diminished the cell viability of both two cells with a lower IC50, whereas boosted the apoptosis rate of both cells with the treatment of albumin-paclitaxel. All these outcomes were reverse with the upregulation of XRCC2 in both two cells. Mechanically, XRCC2 was transcriptionally regulated by specificity protein 1 (SP1), and silencing of SP1 inhibited the cell growth of EC. In vivo, transfection of shXRCC2 with or without albumin-paclitaxel treatment both decreased the tumor size and weight, as well as the expression of XRCC2 and Ki-67 in xenografted mice. XRCC2 transcriptionally regulated by SP2 promoted proliferation, migration, invasion, and chemoresistance of EC cells.

Unveiling esophageal cancer treatment mechanisms: network pharmacology and molecular docking of Physcion.

This study investigates the effects of Physcion on esophageal cancer and its possible mechanisms of action. Potential Physcion targets were identified using databases. Transcriptomic data from 17 esophageal cancer and adjacent tissues were analyzed to find differentially expressed genes, intersecting with potential targets to select 16 key genes. Their expression and distribution were evaluated in patient sequencing data. Diagnostic potential was assessed through differential gene expression and ROC curves. Pathway enrichment analysis was performed using KEGG, and molecular docking simulations were conducted to assess Physcion's binding affinity to key genes. In vitro assays complemented these findings. A total of 161 drug targets were identified, narrowing down to 16 pivotal genes. Expression patterns were examined across cell populations, and enrichment analysis showed significant PI3K/AKT pathway involvement. Molecular docking indicated strong binding of Physcion to HSP90AA1 and MMP2. In vitro assays confirmed Physcion's dose- and time-dependent impact on esophageal cancer cells, with significant DAPI staining effects. Physcion shows promise as a therapeutic agent for esophageal cancer. The study supports its potential for clinical development and future research in esophageal cancer treatment.

Exploring the interplay between iron metabolism imbalance and esophageal cancer

Abstract Iron metabolism plays a crucial role in various physiological processes, and its dysregulation has been implicated in many cancers. Epidemiological studies have confirmed a significant correlation between iron overload and an increased risk of oesophageal cancer. The purpose of this review is to investigate the relationship between iron metabolism imbalance and oesophageal cancer and to explore the potential application of iron metabolism regulatory mechanisms in the treatment of oesophageal cancer. This paper details the physiological mechanisms that regulate cellular iron homeostasis, including absorption, storage, utilization, and excretion and focuses on changes in iron homeostasis in oesophageal cancer cells. In addition, the paper discusses the multifaceted roles of iron in tumourigenesis, progression and metastasis, as well as the impact of iron metabolism in the tumour microenvironment. Finally, this paper discusses the potential impact of ferroptosis on cancer cell survival, highlights the importance of iron metabolism in oesophageal cancer, and provides new ideas for the prevention, diagnosis and treatment of oesophageal cancer. Future research should further elucidate the specific role of iron metabolism in esophageal cancer pathogenesis and explore new therapeutic approaches using these mechanisms for more effective treatment strategies.

Neoadjuvant immunochemotherapy improves clinical outcomes of patients with esophageal cancer by mediating anti-tumor immunity of CD8+ T (Tc1) and CD16+ NK cells.

Esophageal cancer (ESCA) is one of the most common tumors in the world, and treatment using neoadjuvant therapy (NT) based on radiotherapy and/or chemotherapy has still unsatisfactory results. Neoadjuvant immunochemotherapy (NICT) has also become an effective treatment strategy nowadays. However, its impact on the tumor microenvironment (TME) and regulatory mechanisms on T cells and NK cells needs to be further elucidated. A total of 279 cases of ESCA who underwent surgery alone [non-neoadjuvant therapy (NONE)], neoadjuvant chemotherapy (NCT), and NICT were collected, and their therapeutic effect and survival period were compared. Further, RNA sequencing combined with biological information was used to analyze the expression of immune-related genes. Immunohistochemistry, immunofluorescence, and quantitative real-time PCR (qRT-PCR) were used to verify the activation and infiltration status of CD8+ T and CD16+ NK cells, as well as the function and regulatory pathway of killing tumor cells. Patients with ESCA in the NICT group showed better clinical response, median survival, and 2-year survival rates (p < 0.05) compared with the NCT group. Our RNA sequencing data revealed that NICT could promote the expression of immune-related genes. The infiltration and activation of immune cells centered with CD8+ T cells were significantly enhanced. CD8+ T cells activated by PD-1 inhibitors secreted more IFN-γ and cytotoxic effector factor cells through the transcription factor of EOMES and TBX21. At the same time, activated CD8+ T cells mediated the CD16+ NK cell activation and secreted more IFN-γ to kill ESCA cells. In addition, the immunofluorescence co-staining results showed that more CD276+ tumor cells and CD16+ NK cells were existed in pre-NCT and pre-NICT group. However, CD276+ tumor cells were reduced significantly in the post-NICT group, while they still appeared in the post-NCT group, which means that CD16+ NK cells can recognize and kill CD276+ tumor cells after immune checkpoint blocker (ICB) treatment. NICT can improve the therapeutic effect and survival period of resectable ESCA patients. NICT could promote the expression of immune-related genes and activate CD8+ T and CD16+ NK cells to secrete more IFN-γ to kill ESCA cells. It provides a theoretical basis and clinical evidence for its potential as an NT strategy in ESCA.

Recombinant human protein TCFL5-activated NRSN2-AS1 promotes esophageal cancer progression via the microRNA-874-5p/RELT regulatory axis

The incidence of esophageal cancer continues to increase worldwide. Current therapeutic approaches have limited efficacy, so in order to search for better markers of the disease, it is necessary to further elucidate its molecular pathogenesis. Regulation of gene expression by long non-coding Rnas plays a role in many diseases, however the role in esophageal cancer is unclear. The aim of this study was to elucidate the role and regulatory mechanism of long non-coding RNA NRSN2-AS1 in the progression of esophageal cancer. By real-time quantitative PCR, immunohistochemistry, RNA interference, western blotting, and double luciferase reporter gene analysis, we found that NRSN2-AS1 was up-regulated in esophageal cancer tissues and cell lines, and was closely related to disease stage and prognosis. Functional studies have shown that the silencing of NRSN2-AS1 inhibits the proliferation of esophageal cancer cells, induces apoptosis, and prevents cell migration and invasion. In mouse models, NRSN2-AS1 also promoted tumor growth. The transcription factor TCFL5 upregulates the transcription of NRSN2-AS1, which acts as a sponge for microRNA(miR)-874–5p, thereby upregulating the expression of the oncogene RELT. Activation of the NRSN2-AS1/miR-874-5p/RELT regulatory axis was validated in vivo.

Angiopoietin-Like Protein 2 Expression in Tumor Cells Supports Tumor-Associated Macrophage-Induced Tumor Progression in Esophageal Cancer.

Tumor-associated macrophages(TAM),a major component of the tumor microenvironment, play key roles in tumor formation and progression; however, mechanisms underlying TAM-induced tumor progression are complex and not well known. We previously reported that tumor cell-derived angiopoietin-like protein 2 (ANGPTL2) functions as a tumor promoter in some cancer contexts. We examined ANGPTL2 expression in paraffin-embedded tumor samples from resected specimens of 221 patients with esophageal cancer. Patients were subdivided into four groups based on immunohistochemistry scores described above: ANGPTL2-low/TAM-low, ANGPTL2-low/TAM-high, ANGPTL2-high/TAM-low, and ANGPTL2-high/TAM-high groups. Gene expression datasets of esophageal cancer cell lines were obtained from the cancer cell line encyclopedia public database. In this study, we demonstrate that TAM infiltration is associated with poor prognosis in patients with esophageal cancer whose tumor cells show relatively higher ANGPTL2 expression levels; however, TAM infiltration did not affect prognosis in patients with ANGPTL2-low-expressing esophageal cancer, suggesting that ANGPTL2 expression in esophageal cancer cells is required for TAM-induced tumor progression. Our analysis of public datasets indicates a potential positive correlation of ANGPTL2 expression levels with that of transforming growth factor (TGF)-β, a TAM-activating factor, in esophageal cancer cell lines. We conclude that ANGPTL2 signaling in tumor cells supports TAM-induced tumor progression and contributes to poor prognosis in patients with esophageal cancer. These findings overall provide novel insight into pro-tumor ANGPTL2 functions and illustrate the essential role of cancer cell/TAM crosstalk in cancer progression.

Unveiling the anti-tumor and anti-fibrotic potentials of Kanglaite in esophageal cancer through PVT1/TGF-β/Smad axis inhibition

Esophageal cancer (EC) poses a significant challenge among tract tumors worldwide due to its complex molecular composition, which remains largely unexplored. Kanglaite (KLT), a medicine known for its anti-tumor properties, is emerging as a potential ally in the culinary world. Plasmacytoma Variant translocation 1 (PVT1) plays a significant role in the complex nature of esophageal cancer, showing high expression levels in tumor tissues. During our investigation, we discovered a higher presence of PVT1 in cancer tissues, which led us to explore its functions further. Through manipulating techniques, we found that inhibiting PVT1 not only hinders the growth of esophageal cancer cells but also reduces fibrosis. This is similar to enhancing the texture and flavor of a dish. Our study reveals the interactions at play, highlighting how PVT1 orchestrates the TGF β/Smad pathway – a component in the development of esophageal cancer. Introducing KLT, an expert poised to revolutinize the approach to cancer treatment. Our research demonstrates KLT’s effectiveness in regulating the PVT1/TGF-β/Smad axis, uncovering its fibrotic properties, and its ability to hinder the progression of esophageal cancer. With these discoveries, KLT emerges as a promising option for the treatment of esophageal cancer.

Capivasertib reverses chemotherapy-induced esophageal cancer resistance via inhibiting Akt-associated Mcl-1 upregulation

The development of resistance to chemotherapy in esophageal cancer represents a significant challenge in cancer treatment. Therefore, our study aimed to identify effective therapeutic strategies by examining the molecules involved in this chemoresistance. We consistently observed an increase in the expression of Mcl-1 in cells exposed to both short and long-term treatment with cisplatin, a drug commonly used in esophageal cancer therapy. Functional analysis showed that Mcl-1 regulates esophageal cancer cell response to cisplatin treatment. Notably, this upregulation of Mcl-1 was not dependent on eukaryotic initiation factor 4E (eIF4E). Instead, it was associated with increased stability due to the activation of Akt. Capivasertib, a potent pan-Akt kinase drug, significantly decreased Mcl-1 level via inhibiting Akt signaling pathway in chemo-resistant cells. In addition, capivasertib not only decreased the viability of chemo-resistant esophageal cancer cells but also synergistically enhanced the effects of cisplatin. In multiple mouse models, representing both chemo-resistant and chemo-sensitive esophageal cancer, capivasertib administered at non-toxic doses demonstrated remarkable efficacy. It significantly extended the overall survival of the mice. Our research underscores the pivotal role of Akt-associated Mcl-1 upregulation in the development of chemo-resistance in esophageal cancer cells. Furthermore, it highlights the potential of capivasertib to reverse this resistance mechanism.

Porphyromonas gingivalis infection facilitates immune escape of esophageal cancer by enhancing YTHDF2-mediated Fas degradation

To investigate the effect of Porphyromonas gingivalis (Pg) infection on immune escape of oesophageal cancer cells and the role of YTHDF2 and Fas in this regulatory mechanism. We examined YTHDF2 and Fas protein expressions in esophageal squamous cell carcinoma (ESCC) tissues with and without Pg infection using immunohistochemistry and in Pg-infected KYSE150 cells using Western blotting. The interaction between YTHDF2 and Fas was investigated by co-immunoprecipitation (Co-IP). Pg-infected KYSE150 cells with lentivirus-mediated YTHDF2 knockdown were examined for changes in expression levels of YTHDF2, cathepsin B (CTSB), Fas and FasL proteins, and the effect of E64 (a cathepsin inhibitor) on these proteins were observed. After Pg infection and E64 treatment, KYSE150 cells were co-cultured with human peripheral blood mononuclear cells (PBMCs), and the expressions of T cell-related effector molecules were detected by flow cytometry. ESCC tissues and cells with Pg infection showed significantly increased YTHDF2 expression and lowered Fas expression. The results of Co-IP demonstrated a direct interaction between YTHDF2 and Fas. In Pg-infected KYSE150 cells with YTHDF2 knockdown, the expression of CTSB was significantly reduced while Fas and FasL expressions were significantly increased. E64 treatment of KYSE150 cells significantly decreased the expression of CTSB without affecting YTHDF2 expression and obviously increased Fas and FasL expressions. Flow cytometry showed that in Pg-infected KYSE150 cells co-cultured with PBMCs, the expressions of Granzyme B and Ki67 were significantly decreased while PD-1 expression was significantly enhanced. Pg infection YTHDF2-dependently regulates the expression of Fas to facilitate immune escape of esophageal cancer and thus promoting cancer progression, suggesting the key role of YTHDF2 in regulating immune escape of esophageal cancer.

IQGAP1 overexpression attenuates chemosensitivity through YAP-mediated ferroptosis inhibition in esophageal squamous cell cancer cells

Chemoresistance is one of the major hindrances to many cancer therapies, including esophageal squamous cell carcinoma (ESCC). Ferroptosis, a new programmed cell death, plays an essential role in chemoresistance. IQ-domain GTPase activating protein 1 (IQGAP1) is a scaffold protein and functions as an oncogene in various human malignancies. However, the underlying effect and molecular mechanisms of IQGAP1 on paclitaxel (PTX) resistance and ferroptosis in ESCC remain to be elucidated. In this study, we found that IQGAP1 was highly expressed in ESCC tissues and could as a potential biomarker for diagnosis and predicting the prognosis of ESCC. Functional studies revealed that IQGAP1 overexpression reduced the sensitivity of ESCC cells to PTX by enhancing ESCC cell viability and proliferation and inhibiting cell death, and protected ESCC cells from ferroptosis, whereas IQGAP1 knockdown exhibited contrary effects. Importantly, reductions of chemosensitivity and ferroptosis caused by IQGAP1 overexpression were reversed with ferroptosis inducer RSL3, while the increases of chemosensitivity and ferroptosis caused by IQGAP1 knockdown were reversed with ferroptosis inhibitor ferrostatin-1 (Fer-1) in ESCC cells, indicating that IQGAP1 played a key role in resistance to PTX through regulating ferroptosis. Mechanistically, we demonstrated that IQGAP1 overexpression upregulated the expression of Yes-associated protein (YAP), the central mediator of the Hippo pathway. YAP inhibitor Verteporfin (VP) could reverse the effects of IQGAP1 overexpression on ESCC chemoresistance and ferroptosis. Taken together, our findings suggest that IQGAP1 promotes chemoresistance by blocking ferroptosis through targeting YAP. IQGAP1 may be a novel therapeutic target for overcoming chemoresistance in ESCC.

Copper complex@Paclitaxel: A new dual-functional fluorescent-responsive composite material and treatment on esophageal cancer cells

Esophageal cancer (EC) is a common and fatal malignant tumor of the digestive tract, characterized by high morbidity and mortality. Despite advances in surgery, radiotherapy, and anti-cancer drugs, the five-year survival rate remains low. Therefore, exploring effective therapeutic agents to inhibit the proliferation and invasion of EC is crucial. In this study, a novel coordination polymer CP1 was synthesized by reacting the bifunctional ligand 2,5-bis(1H-1,2,4-triazol-1-yl)terephthalic acid (H2dttpa) containing carboxylic acid and triazolyl groups with Cu(NO3)2·3H2O in a mixed solvent of water and N,N-dimethylformamide. Structural analysis revealed that CP1 adopts a two-dimensional layered network with a trinodal (3,4,4)-connected topology. Furthermore, CP1 exhibits excellent fluorescent properties due to charge transfer from the ligand to the metal, making it suitable for selective and sensitive fluorescence sensing of Fe3+ with a quenching efficiency of up to 90.5 %. This indicates the potential application of CP1 as a fluorescent sensor for Fe3+ detection. Moreover, paclitaxel was selected as a model drug to form a prodrug (CP1@Paclitaxel) with hydrogen bonding enhancing the interaction between the prodrug and CP1. The photothermal properties of CP1@Paclitaxel were investigated, showing an increase of 13 °C and 25 °C, respectively, in a concentration-dependent manner. The therapeutic activity of the newly synthesized system against EC cancer was evaluated, and its specific mechanism of action was investigated. This design provides a novel approach to address drug delivery issues in EC and offers a flexible strategy for expanding the biomedical applications of metal–organic frameworks (MOFs).