Pub Date : 2025-11-21DOI: 10.1016/j.tranon.2025.102613
Hui xie , Xiaonan Hu , Yongde Cai , Sheng Zhu , Zuliang Deng
The role of pyroptosis in pancreatic cancer remains controversial. Using two-sample Mendelian randomization (MR) integrating GWAS data from FinnGen (314,193 controls, 731 cases), pQTL data from Iceland, and the UK Biobank, we systematically investigated causal links between pyroptosis genes and pancreatic cancer. We found that Beta-2-microglobulin (B2M) indirectly increases pancreatic cancer risk by upregulating Neutrophil Elastase (ELANE)—to our knowledge, this is the first study to establish a causal, mediation-based genetic link between B2M and ELANE in the context of pancreatic cancer. Mediation analysis revealed ELANE accounts for 20.572 % [15.32%–25.81 %] of this effect. Sensitivity analyses confirmed robustness without significant pleiotropy, and bioinformatics validation supported our MR findings. Drug sensitivity analysis further identified potential therapeutic agents. The findings support B2M as a diagnostic biomarker for pancreatic cancer, given its significant overexpression in tumors and high diagnostic accuracy (AUC = 0.976, 95 % CI: 0.958–0.993), and highlight the B2M–ELANE axis—identified through a data-driven MR mediation framework—as a promising therapeutic target.
{"title":"B2M regulates ELANE in pyroptosis to affect pancreatic cancer progression","authors":"Hui xie , Xiaonan Hu , Yongde Cai , Sheng Zhu , Zuliang Deng","doi":"10.1016/j.tranon.2025.102613","DOIUrl":"10.1016/j.tranon.2025.102613","url":null,"abstract":"<div><div>The role of pyroptosis in pancreatic cancer remains controversial. Using two-sample Mendelian randomization (MR) integrating GWAS data from FinnGen (314,193 controls, 731 cases), pQTL data from Iceland, and the UK Biobank, we systematically investigated causal links between pyroptosis genes and pancreatic cancer. We found that Beta-2-microglobulin (<em>B2M</em>) indirectly increases pancreatic cancer risk by upregulating Neutrophil Elastase (<em>ELANE</em>)—to our knowledge, this is the first study to establish a causal, mediation-based genetic link between <em>B2M</em> and <em>ELANE</em> in the context of pancreatic cancer. Mediation analysis revealed <em>ELANE</em> accounts for 20.572 % [15.32%–25.81 %] of this effect. Sensitivity analyses confirmed robustness without significant pleiotropy, and bioinformatics validation supported our MR findings. Drug sensitivity analysis further identified potential therapeutic agents. The findings support <em>B2M</em> as a diagnostic biomarker for pancreatic cancer, given its significant overexpression in tumors and high diagnostic accuracy (AUC = 0.976, 95 % CI: 0.958–0.993), and highlight the <em>B2M</em>–<em>ELANE</em> axis—identified through a data-driven MR mediation framework—as a promising therapeutic target.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"63 ","pages":"Article 102613"},"PeriodicalIF":5.0,"publicationDate":"2025-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145579557","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-19DOI: 10.1016/j.tranon.2025.102604
Shixing Li, Xuelei Lou, Zukuan Chang, Jinzhan Liu, Huilin Lu
Background
Esophageal cancer (ESCA) remains difficult to treat with surgery and chemotherapy showing limited impact on patient prognosis. Matrix metalloproteinase 11 (MMP11) has been linked to tumor progression and immune microenvironment modulation. This study explored MMP11′s role in regulating the PD-L1/c-Myc pathway in ESCA.
Methods
MMP11 expression was analyzed in ESCA tissues and cell lines using real-time PCR and western blot. Kaplan-Meier survival curves assessed the relationship between MMP11 expression and patient survival. Functional assays, including wound healing and flow cytometry, were conducted to examine ESCA cell migration and apoptosis.
Results
MMP11 silencing reduced PD-L1 expression and inhibited cell migration, while promoting apoptosis. It also decreased the protein levels of c-Myc pathway-related proteins. Co-culturing MMP11-depleted ESCA cells with PBMCs altered T regulatory cell subsets and increased immunostimulatory cytokine levels. In vivo, MMP11 knockdown suppressed tumor growth, Ki-67 expression, and the PD-L1/c-Myc signaling pathway.
Conclusion
These findings suggest that MMP11 activates the PD-L1/c-Myc pathway, contributing to immune evasion and ESCA progression. Targeting MMP11 could thus serve as a potential therapeutic approach for ESCA immunotherapy.
{"title":"MMP11 promotes immune escape in esophageal carcinoma cells via the PD-L1/c-Myc signaling pathway","authors":"Shixing Li, Xuelei Lou, Zukuan Chang, Jinzhan Liu, Huilin Lu","doi":"10.1016/j.tranon.2025.102604","DOIUrl":"10.1016/j.tranon.2025.102604","url":null,"abstract":"<div><h3>Background</h3><div>Esophageal cancer (ESCA) remains difficult to treat with surgery and chemotherapy showing limited impact on patient prognosis. Matrix metalloproteinase 11 (MMP11) has been linked to tumor progression and immune microenvironment modulation. This study explored MMP11′s role in regulating the PD-L1/c-Myc pathway in ESCA.</div></div><div><h3>Methods</h3><div>MMP11 expression was analyzed in ESCA tissues and cell lines using real-time PCR and western blot. Kaplan-Meier survival curves assessed the relationship between MMP11 expression and patient survival. Functional assays, including wound healing and flow cytometry, were conducted to examine ESCA cell migration and apoptosis.</div></div><div><h3>Results</h3><div>MMP11 silencing reduced PD-L1 expression and inhibited cell migration, while promoting apoptosis. It also decreased the protein levels of c-Myc pathway-related proteins. Co-culturing MMP11-depleted ESCA cells with PBMCs altered T regulatory cell subsets and increased immunostimulatory cytokine levels. <em>In vivo</em>, MMP11 knockdown suppressed tumor growth, Ki-67 expression, and the PD-L1/c-Myc signaling pathway.</div></div><div><h3>Conclusion</h3><div>These findings suggest that MMP11 activates the PD-L1/c-Myc pathway, contributing to immune evasion and ESCA progression. Targeting MMP11 could thus serve as a potential therapeutic approach for ESCA immunotherapy.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"63 ","pages":"Article 102604"},"PeriodicalIF":5.0,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145564188","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-18DOI: 10.1016/j.tranon.2025.102602
Xue Han , Han Fu , Zhenshuai Zhang , Jian Wang , Shasha Feng , Li Jiang , Lu Chen , Hui Li , Tianxiao Wang
The current treatments for triple-negative breast cancer (TNBC) rely mainly on chemotherapy. Enhancing the effect of chemotherapy drugs or exploring new targeted drugs is expected to provide more treatment options for patients with TNBC. Our previous studies have shown that the cystathionine-γ-lyase (CSE) plays an important role in the progression of TNBC. So inhibition of CSE may provide a new direction for the treatment of TNBC. This study aimed to explore the relationship between CSE expression and chemotherapy drug sensitivity, as well as the potential therapeutic role of CSE inhibitor Aurintricarboxylic acid (ATA) in TNBC. The results suggest that the expression of CSE is negatively correlated with the sensitivity of chemotherapy drugs and changes in CSE levels affect the sensitivity of chemotherapy drugs in TNBC cells. The CSE inhibitor ATA has significantly enhanced the sensitivity of chemotherapeutic drugs in MDA-MB-231 cells and 4T1 mouse transplanted tumor model. Further mechanism research has found that ATA enhances the sensitivity of chemotherapeutic drugs via SIRT1-STAT3-C-myc-Bcl-2 signaling pathway in TNBC cells. In addtion, ATA also enhances the sensitivity of chemotherapeutic drugs in TNBC cells by regulating the expression of P-glycoprotein (P-gp), glutathione (GSH) and reactive oxygen species (ROS). These findings suggest that ATA may be a promising therapeutic agent for TNBC treatment by enhancing the sensitivity of chemotherapy drugs through multiple mechanisms.
{"title":"Aurintricarboxylic acid, an inhibitor of cystathionine γ-lyase, enhances the sensitivity of chemotherapy drugs in TNBC","authors":"Xue Han , Han Fu , Zhenshuai Zhang , Jian Wang , Shasha Feng , Li Jiang , Lu Chen , Hui Li , Tianxiao Wang","doi":"10.1016/j.tranon.2025.102602","DOIUrl":"10.1016/j.tranon.2025.102602","url":null,"abstract":"<div><div>The current treatments for triple-negative breast cancer (TNBC) rely mainly on chemotherapy. Enhancing the effect of chemotherapy drugs or exploring new targeted drugs is expected to provide more treatment options for patients with TNBC. Our previous studies have shown that the cystathionine-γ-lyase (CSE) plays an important role in the progression of TNBC. So inhibition of CSE may provide a new direction for the treatment of TNBC. This study aimed to explore the relationship between CSE expression and chemotherapy drug sensitivity, as well as the potential therapeutic role of CSE inhibitor Aurintricarboxylic acid (ATA) in TNBC. The results suggest that the expression of CSE is negatively correlated with the sensitivity of chemotherapy drugs and changes in CSE levels affect the sensitivity of chemotherapy drugs in TNBC cells. The CSE inhibitor ATA has significantly enhanced the sensitivity of chemotherapeutic drugs in MDA-MB-231 cells and 4T1 mouse transplanted tumor model. Further mechanism research has found that ATA enhances the sensitivity of chemotherapeutic drugs via SIRT1-STAT3-C-myc-Bcl-2 signaling pathway in TNBC cells. In addtion, ATA also enhances the sensitivity of chemotherapeutic drugs in TNBC cells by regulating the expression of P-glycoprotein (P-gp), glutathione (GSH) and reactive oxygen species (ROS). These findings suggest that ATA may be a promising therapeutic agent for TNBC treatment by enhancing the sensitivity of chemotherapy drugs through multiple mechanisms.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"63 ","pages":"Article 102602"},"PeriodicalIF":5.0,"publicationDate":"2025-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145557766","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-17DOI: 10.1016/j.tranon.2025.102605
Jinbao Yin , Binbin Li , Hui Xiong , Jiepeng Gan , Lan Liang
Background
Myeloid-derived suppressor cells (MDSCs) function as critical immunosuppressive constituents within the breast cancer tumor microenvironment (TME). However, their molecular variability and clinical translation potential remain inadequately characterized.
Methods
By combining single-cell RNA sequencing (scRNA-seq) with bulk multi-omics datasets, we screened and confirmed MDSCs signature genes specific to breast cancer. A prognostic risk scoring model was constructed using machine learning approaches and tested across multiple independent patient cohorts. The model’s predictive capacity for chemotherapy sensitivity, immunotherapy responsiveness, and TME features was systematically assessed.
Results
After integrating the single-cell datasets GSE161529 and GSE176078, we identified 12,767 MDSCs along with their 209 characteristic genes. To ensure the reliability of our results, we employed various analytical methods and utilized diverse data for validation. From this signature, a 5-gene risk score model comprising BCL2A1, GDI2, GRINA, RNASE1, and SERPINA1 was constructed, demonstrating robust prognostic stratification with a 1- to 10-year overall survival (OS) AUC exceeding 0.6 and independent predictive value. High-risk patients exhibited characteristic features of an immunosuppressive tumor microenvironment (TME), including increased M2 macrophages and regulatory T cells, alongside diminished cytotoxic T lymphocyte activity. These patients also showed poor responses to both chemotherapy and immunotherapy.
Conclusion
This investigation marks the initial systematic characterization of a new MDSCs gene signature in breast cancer, alongside the establishment of an MDSCs-associated marker scoring framework with multi-aspect clinical translation capability, thereby linking MDSCs fundamental biology to precision oncology in this cancer type.
{"title":"Development of a single-cell derived MDSCs signature score for prognostic risk stratification and therapeutic decision guidance in breast cancer","authors":"Jinbao Yin , Binbin Li , Hui Xiong , Jiepeng Gan , Lan Liang","doi":"10.1016/j.tranon.2025.102605","DOIUrl":"10.1016/j.tranon.2025.102605","url":null,"abstract":"<div><h3>Background</h3><div>Myeloid-derived suppressor cells (MDSCs) function as critical immunosuppressive constituents within the breast cancer tumor microenvironment (TME). However, their molecular variability and clinical translation potential remain inadequately characterized.</div></div><div><h3>Methods</h3><div>By combining single-cell RNA sequencing (scRNA-seq) with bulk multi-omics datasets, we screened and confirmed MDSCs signature genes specific to breast cancer. A prognostic risk scoring model was constructed using machine learning approaches and tested across multiple independent patient cohorts. The model’s predictive capacity for chemotherapy sensitivity, immunotherapy responsiveness, and TME features was systematically assessed.</div></div><div><h3>Results</h3><div>After integrating the single-cell datasets GSE161529 and GSE176078, we identified 12,767 MDSCs along with their 209 characteristic genes. To ensure the reliability of our results, we employed various analytical methods and utilized diverse data for validation. From this signature, a 5-gene risk score model comprising BCL2A1, GDI2, GRINA, RNASE1, and SERPINA1 was constructed, demonstrating robust prognostic stratification with a 1- to 10-year overall survival (OS) AUC exceeding 0.6 and independent predictive value. High-risk patients exhibited characteristic features of an immunosuppressive tumor microenvironment (TME), including increased M2 macrophages and regulatory T cells, alongside diminished cytotoxic T lymphocyte activity. These patients also showed poor responses to both chemotherapy and immunotherapy.</div></div><div><h3>Conclusion</h3><div>This investigation marks the initial systematic characterization of a new MDSCs gene signature in breast cancer, alongside the establishment of an MDSCs-associated marker scoring framework with multi-aspect clinical translation capability, thereby linking MDSCs fundamental biology to precision oncology in this cancer type.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"63 ","pages":"Article 102605"},"PeriodicalIF":5.0,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145551131","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-15DOI: 10.1016/j.tranon.2025.102601
Li Xu , Hui Zhang , Kai Wang , Xuejie Gao , Wenxuan Bu , Dandan Yu , Ke Hu , Qikai Zhang , Guanli Wang , Xiaosong Wu , Xinyan Jia , Yu Peng , Dongliang Song , Hongfei Yi , Haiyan Cai , Jumei Shi , Qilin Feng
Multiple myeloma (MM) is a challenging hematologic malignancy with increasing incidence. Cuproptosis, a copper-dependent form of cell death associated with mitochondrial metabolism and protein lipoylation, remains unexplored in MM. This study aims to investigate this connection using transcriptome profiling and clinical data from the Gene Expression Omnibus database. Analysis of copper death-related genes (CRGs) revealed significant expression differences in 6 out of 12 CRGs, with GLS, ATP7B, PDHA1, MTF1, CDKN2A and DLAT showing notable correlations with survival of MM patients. Unsupervised clustering identified two cuproptosis molecular subtypes in MM patients, which exhibited significant associations with clinical features, prognosis, and immune cell infiltration. These subtypes identified 186 potential MM target genes, enriched in protein binding and intracellular/extracellular structure regulations. Five key biomarkers (CKS2, HGF, HSP90B1, PRIM1, and VCAM1) effectively stratified patients into high- and low-risk groups, strongly correlated with age, ISS stage, serum LDH content, and survival. Functional enrichment analysis revealed differential genes were involved in regulating cell membrane structure, protein binding, and metabolic pathways. High- and low-risk groups displayed distinct immune cell infiltration patterns and immune checkpoint expressions. In vitro experiments, the combination of elesclomol (a copper ion carrier) and bortezomib (Bortezomib) demonstrated a synergistic anti-myeloma effect through excessive intracellular reactive oxygen species generation. This study provides valuable insights into the role of CRGs in MM, potentially aiding in prognosis prediction and the development of effective, personalized therapeutic strategies.
{"title":"Identification of cuproptosis-related subtypes, construction of a prognosis model, and tumor microenvironment landscape in multiple myeloma","authors":"Li Xu , Hui Zhang , Kai Wang , Xuejie Gao , Wenxuan Bu , Dandan Yu , Ke Hu , Qikai Zhang , Guanli Wang , Xiaosong Wu , Xinyan Jia , Yu Peng , Dongliang Song , Hongfei Yi , Haiyan Cai , Jumei Shi , Qilin Feng","doi":"10.1016/j.tranon.2025.102601","DOIUrl":"10.1016/j.tranon.2025.102601","url":null,"abstract":"<div><div>Multiple myeloma (MM) is a challenging hematologic malignancy with increasing incidence. Cuproptosis, a copper-dependent form of cell death associated with mitochondrial metabolism and protein lipoylation, remains unexplored in MM. This study aims to investigate this connection using transcriptome profiling and clinical data from the Gene Expression Omnibus database. Analysis of copper death-related genes (CRGs) revealed significant expression differences in 6 out of 12 CRGs, with GLS, ATP7B, PDHA1, MTF1, CDKN2A and DLAT showing notable correlations with survival of MM patients. Unsupervised clustering identified two cuproptosis molecular subtypes in MM patients, which exhibited significant associations with clinical features, prognosis, and immune cell infiltration. These subtypes identified 186 potential MM target genes, enriched in protein binding and intracellular/extracellular structure regulations. Five key biomarkers (CKS2, HGF, HSP90B1, PRIM1, and VCAM1) effectively stratified patients into high- and low-risk groups, strongly correlated with age, ISS stage, serum LDH content, and survival. Functional enrichment analysis revealed differential genes were involved in regulating cell membrane structure, protein binding, and metabolic pathways. High- and low-risk groups displayed distinct immune cell infiltration patterns and immune checkpoint expressions. In vitro experiments, the combination of elesclomol (a copper ion carrier) and bortezomib (Bortezomib) demonstrated a synergistic anti-myeloma effect through excessive intracellular reactive oxygen species generation. This study provides valuable insights into the role of CRGs in MM, potentially aiding in prognosis prediction and the development of effective, personalized therapeutic strategies.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"63 ","pages":"Article 102601"},"PeriodicalIF":5.0,"publicationDate":"2025-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145528922","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Biomarkers for evaluating response to neoadjuvant chemotherapy (NACT) in ER+/HER2− breast cancer remain limited. This study explores the impact of NACT on tumor proliferation dynamics and its association with relapse-free interval (RFI) among 175 patients with early ER+/HER2− breast tumors. Proliferation was assessed at baseline, after completing two NACT cycles, and in the residual tumor using Ki67 immunohistochemistry (IHC) and two gene expression assays (GEAs): SSP-Ki67 and AURKA score. Slight to moderate agreement was observed between IHC and GEAs, with IHC-Ki67 consistently classifying more tumors as highly proliferative compared to SSP-Ki67 at both baseline and surgery. Proliferation status at baseline was not prognostic for RFI using either IHC-Ki67 or SSP-Ki67 in our cohort. However, patients with persistently high proliferation after two NACT cycles or in the residual tumor following NACT were at increased risk of relapse, with SSP-Ki67 outperforming IHC-Ki67 in identifying patients with a poorer prognosis. Our results demonstrate that tumor proliferation status measured after brief exposure to NACT or in the residual tumor post-NACT holds prognostic value and may inform the tailoring of post-neoadjuvant treatment strategies in patients with early luminal breast cancer, and that relying on IHC-Ki67 to evaluate treatment response may potentially lead to overtreatment.
{"title":"Dynamic assessment of proliferation to guide response-adapted therapy in the setting of neoadjuvant chemotherapy in ER+/HER2- breast cancer","authors":"Hani Saghir , Srinivas Veerla , Niklas Loman , Siker Kimbung","doi":"10.1016/j.tranon.2025.102597","DOIUrl":"10.1016/j.tranon.2025.102597","url":null,"abstract":"<div><div>Biomarkers for evaluating response to neoadjuvant chemotherapy (NACT) in ER+/HER2− breast cancer remain limited. This study explores the impact of NACT on tumor proliferation dynamics and its association with relapse-free interval (RFI) among 175 patients with early ER+/HER2− breast tumors. Proliferation was assessed at baseline, after completing two NACT cycles, and in the residual tumor using Ki67 immunohistochemistry (IHC) and two gene expression assays (GEAs): SSP-Ki67 and AURKA score. Slight to moderate agreement was observed between IHC and GEAs, with IHC-Ki67 consistently classifying more tumors as highly proliferative compared to SSP-Ki67 at both baseline and surgery. Proliferation status at baseline was not prognostic for RFI using either IHC-Ki67 or SSP-Ki67 in our cohort. However, patients with persistently high proliferation after two NACT cycles or in the residual tumor following NACT were at increased risk of relapse, with SSP-Ki67 outperforming IHC-Ki67 in identifying patients with a poorer prognosis. Our results demonstrate that tumor proliferation status measured after brief exposure to NACT or in the residual tumor post-NACT holds prognostic value and may inform the tailoring of post-neoadjuvant treatment strategies in patients with early luminal breast cancer, and that relying on IHC-Ki67 to evaluate treatment response may potentially lead to overtreatment.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"63 ","pages":"Article 102597"},"PeriodicalIF":5.0,"publicationDate":"2025-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145529020","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-11DOI: 10.1016/j.tranon.2025.102600
Tong Yuan , Junjie Liu , Ronghua Zhu , Jiang Li , Zhiyong Huang , Huifang Liang , Haisu Tao , Erlei Zhang
Background
Intelectin 1 (ITLN1) is a recently discovered secretory adipokine with pivotal functions in the innate immune system, inflammation, and the facilitation of glucose uptake. Nonetheless, its exact functions in hepatocellular carcinoma (HCC) remain not fully elucidated.
Methods
In this study, ITLN1 was identified as a clinically significant secretory adipokine linked to HCC, validated through qRT-PCR, western blot, immunohistochemistry, and TCGA data. Its role in HCC was explored using CCK-8, clone formation, EdU, migration, and cell cycle assays, alongside xenograft tumor experiments. RNA sequencing, luciferase reporter assays, and ChIP assays confirmed ITLN1′s molecular mechanisms in inhibiting HCC proliferation.
Results
Our study revealed that ITLN1 expression was significantly downregulated in HCC tissues compared to adjacent non-tumor tissues, and its reduced expression was associated with poor overall survival. Functionally, ITLN1 attenuated HCC proliferation in a cell cycle arrest manner via activation of ERK1/2 signaling. We also identified transcription factor interferon regulatory factor 1 (IRF1) as a regulator of ITLN1 through bioinformatics analysis and affirmed the binding site on the ITLN1 promoter. Furthermore, interferon-gamma (IFNγ), a classic upstream cytokine of IRF1, could promote ITLN1 expression through IRF1. Subsequently, the IFNγ-IRF1-ITLN1 axis was identified and found to inhibit HCC cell proliferation and cell cycle progression.
Conclusions
In summary, our study found that ITLN1, regulated by IFNγ-IRF1 axis, suppresses HCC proliferation by constitutively activating ERK1/2 signaling and holds promise as a prospective prognostic indicator and a plausible therapeutic target for HCC.
{"title":"ITLN1, orchestrated by the IFNγ-IRF1 axis, suppresses hepatocellular carcinoma proliferation via ERK1/2 activation","authors":"Tong Yuan , Junjie Liu , Ronghua Zhu , Jiang Li , Zhiyong Huang , Huifang Liang , Haisu Tao , Erlei Zhang","doi":"10.1016/j.tranon.2025.102600","DOIUrl":"10.1016/j.tranon.2025.102600","url":null,"abstract":"<div><h3>Background</h3><div>Intelectin 1 (ITLN1) is a recently discovered secretory adipokine with pivotal functions in the innate immune system, inflammation, and the facilitation of glucose uptake. Nonetheless, its exact functions in hepatocellular carcinoma (HCC) remain not fully elucidated.</div></div><div><h3>Methods</h3><div>In this study, ITLN1 was identified as a clinically significant secretory adipokine linked to HCC, validated through qRT-PCR, western blot, immunohistochemistry, and TCGA data. Its role in HCC was explored using CCK-8, clone formation, EdU, migration, and cell cycle assays, alongside xenograft tumor experiments. RNA sequencing, luciferase reporter assays, and ChIP assays confirmed ITLN1′s molecular mechanisms in inhibiting HCC proliferation.</div></div><div><h3>Results</h3><div>Our study revealed that ITLN1 expression was significantly downregulated in HCC tissues compared to adjacent non-tumor tissues, and its reduced expression was associated with poor overall survival. Functionally, ITLN1 attenuated HCC proliferation in a cell cycle arrest manner via activation of ERK1/2 signaling. We also identified transcription factor interferon regulatory factor 1 (IRF1) as a regulator of ITLN1 through bioinformatics analysis and affirmed the binding site on the ITLN1 promoter. Furthermore, interferon-gamma (IFNγ), a classic upstream cytokine of IRF1, could promote ITLN1 expression through IRF1. Subsequently, the IFNγ-IRF1-ITLN1 axis was identified and found to inhibit HCC cell proliferation and cell cycle progression.</div></div><div><h3>Conclusions</h3><div>In summary, our study found that ITLN1, regulated by IFNγ-IRF1 axis, suppresses HCC proliferation by constitutively activating ERK1/2 signaling and holds promise as a prospective prognostic indicator and a plausible therapeutic target for HCC.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"63 ","pages":"Article 102600"},"PeriodicalIF":5.0,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145496943","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-10DOI: 10.1016/j.tranon.2025.102596
Benjamin Hay , Aurélien Brun , Anne Fougerat , Vera Mazurak , Olivier Le Bacquer , Jérémie Talvas , Frédéric Capel
Cachexia is a multifactorial syndrome that occurs in many cancers, particularly in their advanced stages, decreasing the quality of life and lifespan of patients. One of the hallmarks of cancer-associated cachexia is skeletal muscle wasting. Multiple causes include inflammation, metabolic deregulation, energy utilization, endoplasmic reticulum and oxidative stress. Loss of skeletal muscle is characterised by an imbalance in protein homeostasis, with decreased anabolism (regulated by the Akt/GSK3/eIF2α and Akt/mTORC1 pathways) and increased catabolism (regulated by autophagy and the ubiquitin-proteasome system), as well as an impairment in myogenesis. Accumulating evidence suggests that dietary intervention of β-hydroxybutyrate, the major ketone body produced by ketogenesis, and n-3 polyunsaturated fatty acids may mitigate skeletal muscle wasting. Polyunsaturated fatty acids and β-hydroxybutyrate are able to favourably modulate inflammation, insulin resistance, unfolded protein response and stresses (such as metabolic stress and oxidative stress). A well-adapted nutritional strategy may include a “classic” diet supplemented with β-hydroxybutyrate and polyunsaturated fatty acids to maintain skeletal muscle integrity and reduce wasting.
{"title":"Nutritional strategies against skeletal muscle wasting in cancer-associated cachexia: the role of β-hydroxybutyrate and polyunsaturated fatty acids","authors":"Benjamin Hay , Aurélien Brun , Anne Fougerat , Vera Mazurak , Olivier Le Bacquer , Jérémie Talvas , Frédéric Capel","doi":"10.1016/j.tranon.2025.102596","DOIUrl":"10.1016/j.tranon.2025.102596","url":null,"abstract":"<div><div>Cachexia is a multifactorial syndrome that occurs in many cancers, particularly in their advanced stages, decreasing the quality of life and lifespan of patients. One of the hallmarks of cancer-associated cachexia is skeletal muscle wasting. Multiple causes include inflammation, metabolic deregulation, energy utilization, endoplasmic reticulum and oxidative stress. Loss of skeletal muscle is characterised by an imbalance in protein homeostasis, with decreased anabolism (regulated by the Akt/GSK3/eIF2α and Akt/mTORC1 pathways) and increased catabolism (regulated by autophagy and the ubiquitin-proteasome system), as well as an impairment in myogenesis. Accumulating evidence suggests that dietary intervention of β-hydroxybutyrate, the major ketone body produced by ketogenesis, and n-3 polyunsaturated fatty acids may mitigate skeletal muscle wasting. Polyunsaturated fatty acids and β-hydroxybutyrate are able to favourably modulate inflammation, insulin resistance, unfolded protein response and stresses (such as metabolic stress and oxidative stress). A well-adapted nutritional strategy may include a “classic” diet supplemented with β-hydroxybutyrate and polyunsaturated fatty acids to maintain skeletal muscle integrity and reduce wasting.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"63 ","pages":"Article 102596"},"PeriodicalIF":5.0,"publicationDate":"2025-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145496962","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-10DOI: 10.1016/j.tranon.2025.102583
Hai Zhou, Xin Huang, Xianzhong Liu
Objective
MTA1 (Metastasis-associated protein 1) is implicated in various malignancies, but its role in gastric cancer (GC) stemness and chemoresistance remains unclear. This study explores the effect of MTA1 on these processes and its underlying mechanisms.
Methods
MTA1 expression was assessed in GC tissues, paracancerous tissues, and cell lines. Lentiviral vectors were used to overexpress or silence MTA1 in AGS cells. Functional assays included MTT for drug sensitivity, flow cytometry for apoptosis, sphere formation to assess stemness, and Western blot for SOX-2, OCT-4, Bax, and Bcl2 expression. In addition, TCGA gastric cancer datasets were analyzed to evaluate the association of MTA1 expression with patient prognosis and predicted cisplatin sensitivity.
Results
MTA1 was significantly upregulated in GC tissues and cells. Its overexpression increased resistance to doxorubicin and cisplatin (↑IC50), inhibited apoptosis, and enhanced stemness via upregulation of SOX-2 and OCT-4. Conversely, MTA1 knockdown sensitized cells to chemotherapy, promoted apoptosis, and reduced stem-like properties. Public dataset analysis confirmed that MTA1 is upregulated in gastric cancer, associated with poor survival, and shows a trend toward reduced cisplatin sensitivity.
Conclusion
MTA1 enhances chemoresistance and stemness in gastric cancer cells by modulating apoptosis and stemness-related proteins. It may serve as a novel therapeutic target for personalized GC treatment.
{"title":"MTA1 upregulation enhances stemness and chemoresistance of gastric cancer cells","authors":"Hai Zhou, Xin Huang, Xianzhong Liu","doi":"10.1016/j.tranon.2025.102583","DOIUrl":"10.1016/j.tranon.2025.102583","url":null,"abstract":"<div><h3>Objective</h3><div>MTA1 (Metastasis-associated protein 1) is implicated in various malignancies, but its role in gastric cancer (GC) stemness and chemoresistance remains unclear. This study explores the effect of MTA1 on these processes and its underlying mechanisms.</div></div><div><h3>Methods</h3><div>MTA1 expression was assessed in GC tissues, paracancerous tissues, and cell lines. Lentiviral vectors were used to overexpress or silence MTA1 in AGS cells. Functional assays included MTT for drug sensitivity, flow cytometry for apoptosis, sphere formation to assess stemness, and Western blot for SOX-2, OCT-4, Bax, and Bcl2 expression. In addition, TCGA gastric cancer datasets were analyzed to evaluate the association of MTA1 expression with patient prognosis and predicted cisplatin sensitivity.</div></div><div><h3>Results</h3><div>MTA1 was significantly upregulated in GC tissues and cells. Its overexpression increased resistance to doxorubicin and cisplatin (↑IC50), inhibited apoptosis, and enhanced stemness via upregulation of SOX-2 and OCT-4. Conversely, MTA1 knockdown sensitized cells to chemotherapy, promoted apoptosis, and reduced stem-like properties. Public dataset analysis confirmed that MTA1 is upregulated in gastric cancer, associated with poor survival, and shows a trend toward reduced cisplatin sensitivity.</div></div><div><h3>Conclusion</h3><div>MTA1 enhances chemoresistance and stemness in gastric cancer cells by modulating apoptosis and stemness-related proteins. It may serve as a novel therapeutic target for personalized GC treatment.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"63 ","pages":"Article 102583"},"PeriodicalIF":5.0,"publicationDate":"2025-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145496929","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-10DOI: 10.1016/j.tranon.2025.102590
Shicheng Liu , Qingtao Zhao , Dahu Ren , Lingxin Kong , Hongzhen Zhao , Guochen Duan
Lung adenocarcinoma (LUAD) remains a leading cause of cancer-related mortality, with chemotherapy resistance and tumor heterogeneity posing significant challenges. The Chromobox (CBX) protein family, crucial epigenetic regulators in tumor progression, has not been systematically characterized in LUAD. This study aimed to develop a CBX-based molecular classification system for LUAD and explore the mechanistic role of the CDX2-CBX3 regulatory axis in tumor progression. Through multiomics analysis of TCGA-LUAD data, four distinct CBX subtypes were identified, each associated with variations in survival, clinical stage, DNA repair pathway activation, and immune cell infiltration. Mechanistic investigations (ChIP-qPCR, luciferase assays, and gain/loss-of-function experiments) confirmed that CDX2 directly upregulates CBX3 transcription via conserved promoter binding. CDX2 overexpression enhanced migration, invasion, and xenograft growth, whereas CBX3 knockdown suppressed these phenotypic changes. In conclusion, this study defines clinically relevant CBX molecular subtypes in LUAD and reveals the CDX2-CBX3 transcriptional cascade as a novel driver of tumor progression, offering potential targets for precision therapy.
{"title":"Clinical significance and molecular mechanism of CDX2-CBX3 regulatory axis in lung adenocarcinoma progression","authors":"Shicheng Liu , Qingtao Zhao , Dahu Ren , Lingxin Kong , Hongzhen Zhao , Guochen Duan","doi":"10.1016/j.tranon.2025.102590","DOIUrl":"10.1016/j.tranon.2025.102590","url":null,"abstract":"<div><div>Lung adenocarcinoma (LUAD) remains a leading cause of cancer-related mortality, with chemotherapy resistance and tumor heterogeneity posing significant challenges. The Chromobox (CBX) protein family, crucial epigenetic regulators in tumor progression, has not been systematically characterized in LUAD. This study aimed to develop a CBX-based molecular classification system for LUAD and explore the mechanistic role of the CDX2-CBX3 regulatory axis in tumor progression. Through multiomics analysis of TCGA-LUAD data, four distinct CBX subtypes were identified, each associated with variations in survival, clinical stage, DNA repair pathway activation, and immune cell infiltration. Mechanistic investigations (ChIP-qPCR, luciferase assays, and gain/loss-of-function experiments) confirmed that CDX2 directly upregulates CBX3 transcription <em>via</em> conserved promoter binding. CDX2 overexpression enhanced migration, invasion, and xenograft growth, whereas CBX3 knockdown suppressed these phenotypic changes. In conclusion, this study defines clinically relevant CBX molecular subtypes in LUAD and reveals the CDX2-CBX3 transcriptional cascade as a novel driver of tumor progression, offering potential targets for precision therapy.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"63 ","pages":"Article 102590"},"PeriodicalIF":5.0,"publicationDate":"2025-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145496897","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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