Pub Date : 2025-02-18DOI: 10.1016/j.tranon.2025.102328
Jingyi Zhou , Mengkai Yang , Weisong Zhao , He Zhang , Lingling Cao , Qi Li , Gangyang Wang
Background
Chemoresistance poses a significant challenge in the treatment of osteosarcoma (OS). Long non-coding RNAs (lncRNAs) have emerged as crucial regulators of cancer biology. Despite accumulating evidence linking dysregulation of lncRNAs to chemoresistance, the specific regulatory functions and complexities involved in lncRNA-mediated modulation of doxorubicin-based chemotherapy in OS remain understudied.
Methods
We examined expression levels of lncRNA Lnc-PHF3-3 and miR-142-3p in OS tissues and cell lines by lncRNA microarray profiling and qRT-PCR. Gain-of-function and loss-of-function assays were performed to examine the effect of lncRNA Lnc-PHF3-3 and miR-142-3p on chemoresistance of OS cells. Using fluorescence reporter and western blot assays, we also explored the possible mechanisms of Lnc-PHF3-3 in OS cells.
Results
This study aimed to investigate key lncRNAs associated with chemoresistance in OS and identify potential therapeutic targets for patients with chemoresistant OS. To identify chemoresistance-related lncRNAs, microarray analysis was conducted using drug-resistant/drug-sensitive OS cell lines and chemoresistant/chemosensitive OS tissues. Among the identified candidates, a novel lncRNA called Lnc-PHF3-3 was found to be upregulated in doxorubicin-resistant OS cell lines and chemoresistant OS patients. Functional characterization revealed that Lnc-PHF3-3 promoted doxorubicin resistance both in vitro and in vivo. Further investigation revealed that Lnc-PHF3-3 acted as a sponge for microRNA miR-142-3p, and overexpression of miR-142-3p resulted in reduced chemoresistance. Additionally, the high mobility group box 1 (HMGB1) gene was identified as a direct and functional target of miR-142-3p.
Conclusions
We conclude that Lnc-PHF3-3 contributes to doxorubicin resistance in OS by sequestering miR-142-3p and subsequently enhancing HMGB1 expression.
{"title":"Lnc-PHF3-3 aggravates the chemoresistance of osteosarcoma cells to doxorubicin via the miR-142-3p/HMGB1 axis","authors":"Jingyi Zhou , Mengkai Yang , Weisong Zhao , He Zhang , Lingling Cao , Qi Li , Gangyang Wang","doi":"10.1016/j.tranon.2025.102328","DOIUrl":"10.1016/j.tranon.2025.102328","url":null,"abstract":"<div><h3>Background</h3><div>Chemoresistance poses a significant challenge in the treatment of osteosarcoma (OS). Long non-coding RNAs (lncRNAs) have emerged as crucial regulators of cancer biology. Despite accumulating evidence linking dysregulation of lncRNAs to chemoresistance, the specific regulatory functions and complexities involved in lncRNA-mediated modulation of doxorubicin-based chemotherapy in OS remain understudied.</div></div><div><h3>Methods</h3><div>We examined expression levels of lncRNA Lnc-PHF3-3 and miR-142-3p in OS tissues and cell lines by lncRNA microarray profiling and qRT-PCR. Gain-of-function and loss-of-function assays were performed to examine the effect of lncRNA Lnc-PHF3-3 and miR-142-3p on chemoresistance of OS cells. Using fluorescence reporter and western blot assays, we also explored the possible mechanisms of Lnc-PHF3-3 in OS cells.</div></div><div><h3>Results</h3><div>This study aimed to investigate key lncRNAs associated with chemoresistance in OS and identify potential therapeutic targets for patients with chemoresistant OS. To identify chemoresistance-related lncRNAs, microarray analysis was conducted using drug-resistant/drug-sensitive OS cell lines and chemoresistant/chemosensitive OS tissues. Among the identified candidates, a novel lncRNA called Lnc-PHF3-3 was found to be upregulated in doxorubicin-resistant OS cell lines and chemoresistant OS patients. Functional characterization revealed that Lnc-PHF3-3 promoted doxorubicin resistance both in vitro and in vivo. Further investigation revealed that Lnc-PHF3-3 acted as a sponge for microRNA miR-142-3p, and overexpression of miR-142-3p resulted in reduced chemoresistance. Additionally, the high mobility group box 1 (HMGB1) gene was identified as a direct and functional target of miR-142-3p.</div></div><div><h3>Conclusions</h3><div>We conclude that Lnc-PHF3-3 contributes to doxorubicin resistance in OS by sequestering miR-142-3p and subsequently enhancing HMGB1 expression.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"53 ","pages":"Article 102328"},"PeriodicalIF":5.0,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143437882","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-18DOI: 10.1016/j.tranon.2025.102308
Anne-Sophie Becker , Friederike Klauk , Thomas Freitag , Daniel Fabian Strüder , Björn Schneider , Annette Zimpfer , Claudia Maletzki
The clinical outcome of head and neck squamous cell carcinoma (HNSCC) remains poor with high recurrence rates, in part due to resistance to concurrent platinum-based chemotherapy. The anti-apoptotic BCL2 protein is involved in apoptosis resistance and tumor cell invasion/migration. Here, we test whether BCL2 overexpression predicts poor therapeutic response of HNSCC to cisplatin-based chemoradiotherapy and the effects of selective BCL2 inhibition on cisplatin-induced cell changes in vitro.
BCL2 immunostatus was correlated with survival after chemoradiotherapy in a uniformly treated HNSCC cohort. The combination therapy of ABT-199, a BCL2 inhibitor, and cisplatin was evaluated in vitro using corresponding patient-derived cell lines. Colony formation and the mode of cell death were analyzed in-depth.
Patients with BCL2-positive tumors (44/254) prior to treatment (either radiation, cisplatin monotherapy, or both) had shorter overall and progression-free survival (log-rank; p = 0.048) and a higher rate of tumor relapse (Fisher's exact test; p = 0.0032). BCL2 inhibition alone had no effect on cell functions in our triple panel of cisplatin-sensitive cell lines but enhanced cisplatin-induced effects. Rates of autophagy and cell death, including methuosis, were doubled, while epithelial-mesenchymal transformation was inhibited.
As selective inhibition of BCL2 is available and standard of care in other malignancies, its immunohistochemical assessment could help personalize therapy by identifying a subpopulation to overcome chemoresistance, particularly in locally advanced HNSCC.
{"title":"Inhibition of platin-induced BCL2 increase overcomes chemoresistance in squamous cell carcinoma of the head and neck through resensitization to cell death","authors":"Anne-Sophie Becker , Friederike Klauk , Thomas Freitag , Daniel Fabian Strüder , Björn Schneider , Annette Zimpfer , Claudia Maletzki","doi":"10.1016/j.tranon.2025.102308","DOIUrl":"10.1016/j.tranon.2025.102308","url":null,"abstract":"<div><div>The clinical outcome of head and neck squamous cell carcinoma (HNSCC) remains poor with high recurrence rates, in part due to resistance to concurrent platinum-based chemotherapy. The anti-apoptotic BCL2 protein is involved in apoptosis resistance and tumor cell invasion/migration. Here, we test whether BCL2 overexpression predicts poor therapeutic response of HNSCC to cisplatin-based chemoradiotherapy and the effects of selective BCL2 inhibition on cisplatin-induced cell changes <em>in vitro.</em></div><div>BCL2 immunostatus was correlated with survival after chemoradiotherapy in a uniformly treated HNSCC cohort. The combination therapy of ABT-199, a BCL2 inhibitor, and cisplatin was evaluated <em>in vitro</em> using corresponding patient-derived cell lines. Colony formation and the mode of cell death were analyzed in-depth.</div><div>Patients with BCL2-positive tumors (44/254) prior to treatment (either radiation, cisplatin monotherapy, or both) had shorter overall and progression-free survival (log-rank; <em>p</em> = 0.048) and a higher rate of tumor relapse (Fisher's exact test; <em>p</em> = 0.0032). BCL2 inhibition alone had no effect on cell functions in our triple panel of cisplatin-sensitive cell lines but enhanced cisplatin-induced effects. Rates of autophagy and cell death, including methuosis, were doubled, while epithelial-mesenchymal transformation was inhibited.</div><div>As selective inhibition of BCL2 is available and standard of care in other malignancies, its immunohistochemical assessment could help personalize therapy by identifying a subpopulation to overcome chemoresistance, particularly in locally advanced HNSCC.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"53 ","pages":"Article 102308"},"PeriodicalIF":5.0,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143437883","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-18DOI: 10.1016/j.tranon.2025.102323
Haneen A. Basheer , Nadeem M. Salman , Rami M. Abdullah , Lina Elsalem , Kamyar Afarinkia
Glioma, a highly aggressive form of brain cancer, continues to pose significant therapeutic challenges in the field of medicine. Its invasive nature and resistance to traditional treatments make it particularly difficult to combat. This review examines the potential of metformin, a commonly prescribed antidiabetic medication, as a promising new treatment option for glioma. The potential of metformin to target crucial metabolic pathways in cancer cells presents an encouraging approach to improve therapeutic outcomes. The review explores the complexities of metabolic reprogramming in glioma and metformin's role in inhibiting these metabolic pathways. Preclinical studies demonstrate metformin's efficacy in reducing tumor growth and enhancing the sensitivity of glioma cells to chemotherapy and radiotherapy. Furthermore, clinical studies highlight metformin's potential in improving progression-free survival and overall survival rates in glioma patients. The review also addresses the synergistic effects of combining metformin with other therapeutic agents, such as temozolomide and radiotherapy, to overcome drug resistance and improve treatment efficacy.
Despite the promising findings, the review acknowledges the need for further clinical trials to establish optimal dosing regimens, understand the molecular mechanisms underlying metforminʼs antitumor effects, and identify patient populations that would benefit the most from metformin-based therapies. Additionally, the potential side effects and the long-term impact of metformin on Glioma patients require careful evaluation.
In conclusion, this review underscores the potential of metformin as a repurposed drug in glioma treatment, emphasizing its multifaceted role in targeting metabolic dysregulation. Metformin holds promise as part of a combination therapy approach to improve the therapeutic landscape of glioma and offers hope for better patient outcomes.
{"title":"Metformin and glioma: Targeting metabolic dysregulation for enhanced therapeutic outcomes","authors":"Haneen A. Basheer , Nadeem M. Salman , Rami M. Abdullah , Lina Elsalem , Kamyar Afarinkia","doi":"10.1016/j.tranon.2025.102323","DOIUrl":"10.1016/j.tranon.2025.102323","url":null,"abstract":"<div><div>Glioma, a highly aggressive form of brain cancer, continues to pose significant therapeutic challenges in the field of medicine. Its invasive nature and resistance to traditional treatments make it particularly difficult to combat. This review examines the potential of metformin, a commonly prescribed antidiabetic medication, as a promising new treatment option for glioma. The potential of metformin to target crucial metabolic pathways in cancer cells presents an encouraging approach to improve therapeutic outcomes. The review explores the complexities of metabolic reprogramming in glioma and metformin's role in inhibiting these metabolic pathways. Preclinical studies demonstrate metformin's efficacy in reducing tumor growth and enhancing the sensitivity of glioma cells to chemotherapy and radiotherapy. Furthermore, clinical studies highlight metformin's potential in improving progression-free survival and overall survival rates in glioma patients. The review also addresses the synergistic effects of combining metformin with other therapeutic agents, such as temozolomide and radiotherapy, to overcome drug resistance and improve treatment efficacy.</div><div>Despite the promising findings, the review acknowledges the need for further clinical trials to establish optimal dosing regimens, understand the molecular mechanisms underlying metforminʼs antitumor effects, and identify patient populations that would benefit the most from metformin-based therapies. Additionally, the potential side effects and the long-term impact of metformin on Glioma patients require careful evaluation.</div><div>In conclusion, this review underscores the potential of metformin as a repurposed drug in glioma treatment, emphasizing its multifaceted role in targeting metabolic dysregulation. Metformin holds promise as part of a combination therapy approach to improve the therapeutic landscape of glioma and offers hope for better patient outcomes.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"53 ","pages":"Article 102323"},"PeriodicalIF":5.0,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143429960","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-17DOI: 10.1016/j.tranon.2025.102302
Fiona O'Connell , Eimear Mylod , Noel E. Donlon , Maria Davern , Christine Butler , Niamh O'Connor , Meghana S. Menon , Claire L. Donohoe , Narayanasamy Ravi , Derek G. Doherty , Margaret R. Dunne , John V. Reynolds , Helen M. Roche , Jacintha O'Sullivan
Oesophageal adenocarcinoma (OAC) is a poor prognosis cancer with limited responses to standard of care treatments including chemotherapy and chemoradiotherapy. OAC has one of the strongest associations with obesity, its anatomical location surrounded by visceral adipose tissue has been postulated to intensify this association. Adipose tissue is a regulatory organ with many unknown downstream functions, including its direct response to chemotherapy and radiotherapy. To elucidate the role of visceral adipose tissue in this disease state, metabolic and secreted pro-inflammatory cytokines analysis was conducted on human ex-vivo adipose tissue explants following exposure to FLOT-chemotherapy and CROSS-chemoradiotherapy. To assess how these complex treated microenvironments impact cancer cell metabolism, dendritic cell, and macrophage phenotype, mitochondrial bioenergetics and surface markers expression were examined using seahorse technology and flow cytometry respectively. This study observed that chemotherapy and chemoradiotherapy differentially alter adipose tissue metabolism and secretome, with chemoradiotherapy increasing pro-inflammatory associated mediators (p<0.05). The chemoradiotherapy-treated adipose secretome increased cancer cell spare respiratory capacity and dendritic cell adhesion markers (p<0.05). In contrast, the chemotherapy-treated adipose microenvironment enhanced mitochondrial dysfunction in cancer cells, increasing their reliance on glycolysis and enhancing pro-inflammatory marker expression on LPS-primed macrophages (p<0.05). This study for the first time demonstrates how adipose tissue, and its microenvironment can be significantly impacted by chemotherapy and chemoradiotherapy. These alterations in the adipose secretome in response to therapeutic regimens elicited distinct effects on immune cell phenotype and cancer cells metabolism, raising the question, does the wider tumour microenvironment including the adipose milieu mitigate the efficacy of current treatments.
{"title":"Adipose tissue from oesophageal adenocarcinoma patients is differentially affected by chemotherapy and chemoradiotherapy regimens altering immune cell phenotype and cancer cell metabolism","authors":"Fiona O'Connell , Eimear Mylod , Noel E. Donlon , Maria Davern , Christine Butler , Niamh O'Connor , Meghana S. Menon , Claire L. Donohoe , Narayanasamy Ravi , Derek G. Doherty , Margaret R. Dunne , John V. Reynolds , Helen M. Roche , Jacintha O'Sullivan","doi":"10.1016/j.tranon.2025.102302","DOIUrl":"10.1016/j.tranon.2025.102302","url":null,"abstract":"<div><div>Oesophageal adenocarcinoma (OAC) is a poor prognosis cancer with limited responses to standard of care treatments including chemotherapy and chemoradiotherapy. OAC has one of the strongest associations with obesity, its anatomical location surrounded by visceral adipose tissue has been postulated to intensify this association. Adipose tissue is a regulatory organ with many unknown downstream functions, including its direct response to chemotherapy and radiotherapy. To elucidate the role of visceral adipose tissue in this disease state, metabolic and secreted pro-inflammatory cytokines analysis was conducted on human <em>ex-vivo</em> adipose tissue explants following exposure to FLOT-chemotherapy and CROSS-chemoradiotherapy. To assess how these complex treated microenvironments impact cancer cell metabolism, dendritic cell, and macrophage phenotype, mitochondrial bioenergetics and surface markers expression were examined using seahorse technology and flow cytometry respectively. This study observed that chemotherapy and chemoradiotherapy differentially alter adipose tissue metabolism and secretome, with chemoradiotherapy increasing pro-inflammatory associated mediators (<em>p</em> <em><</em> <em>0.05</em>). The chemoradiotherapy-treated adipose secretome increased cancer cell spare respiratory capacity and dendritic cell adhesion markers (<em>p</em> <em><</em> <em>0.05</em>). In contrast, the chemotherapy-treated adipose microenvironment enhanced mitochondrial dysfunction in cancer cells, increasing their reliance on glycolysis and enhancing pro-inflammatory marker expression on LPS-primed macrophages (<em>p</em> <em><</em> <em>0.05</em>). This study for the first time demonstrates how adipose tissue, and its microenvironment can be significantly impacted by chemotherapy and chemoradiotherapy. These alterations in the adipose secretome in response to therapeutic regimens elicited distinct effects on immune cell phenotype and cancer cells metabolism, raising the question, does the wider tumour microenvironment including the adipose milieu mitigate the efficacy of current treatments.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"53 ","pages":"Article 102302"},"PeriodicalIF":5.0,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143429961","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-11DOI: 10.1016/j.tranon.2025.102319
Pengfei Chen , Kun Li , Jinwei Chen , He Hei , Jiaxin Geng , Nannan Huang , Mengyu Lei , Huijie Jia , Jianzhuang Ren , Chenwang Jin
Hepatocellular carcinoma (HCC) poses a significant clinical challenge due to high mortality and limited treatment options. Radiofrequency ablation (RFA) is commonly used but can be limited by tumor recurrence. This study explores the potential of combining RFA with an attenuated Salmonella strain carrying siRNA-PD-L1 and endostatin to enhance HCC treatment. In this study, an H22 subcutaneous tumor mouse model was used, with animals divided into five groups for treatment with a blank control, a blank Salmonella plasmid, RFA alone, siRNA-PD-L1-endostatin, or a combination of RFA and siRNA-PD-L1-endostatin. The combination therapy significantly reduced tumor growth, angiogenesis, and PD-L1/VEGF expression in tumor tissues post-RFA. Additionally, it induced tumor cell apoptosis, inhibited proliferation and migration, and increased the infiltration of T lymphocytes, granzyme B+T cells, and CD86+macrophages within tumors. There was also a notable rise in T and NK cell populations in the spleen. In conclusion, combining RFA with siRNA-PD-L1-endostatin delivered by attenuated Salmonella synergistically enhances anti-tumor effects, boosts the anti-tumor immune response, and improves RFA efficacy for HCC.
{"title":"Enhanced effect of radiofrequency ablation on HCC by siRNA-PD-L1-endostatin Co-expression plasmid delivered","authors":"Pengfei Chen , Kun Li , Jinwei Chen , He Hei , Jiaxin Geng , Nannan Huang , Mengyu Lei , Huijie Jia , Jianzhuang Ren , Chenwang Jin","doi":"10.1016/j.tranon.2025.102319","DOIUrl":"10.1016/j.tranon.2025.102319","url":null,"abstract":"<div><div>Hepatocellular carcinoma (HCC) poses a significant clinical challenge due to high mortality and limited treatment options. Radiofrequency ablation (RFA) is commonly used but can be limited by tumor recurrence. This study explores the potential of combining RFA with an attenuated Salmonella strain carrying siRNA-PD-L1 and endostatin to enhance HCC treatment. In this study, an H22 subcutaneous tumor mouse model was used, with animals divided into five groups for treatment with a blank control, a blank Salmonella plasmid, RFA alone, siRNA-PD-L1-endostatin, or a combination of RFA and siRNA-PD-L1-endostatin. The combination therapy significantly reduced tumor growth, angiogenesis, and PD-L1/VEGF expression in tumor tissues post-RFA. Additionally, it induced tumor cell apoptosis, inhibited proliferation and migration, and increased the infiltration of T lymphocytes, granzyme <em>B</em><sup>+</sup> <em>T</em> cells, and CD86<sup>+</sup>macrophages within tumors. There was also a notable rise in T and NK cell populations in the spleen. In conclusion, combining RFA with siRNA-PD-L1-endostatin delivered by attenuated Salmonella synergistically enhances anti-tumor effects, boosts the anti-tumor immune response, and improves RFA efficacy for HCC.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"53 ","pages":"Article 102319"},"PeriodicalIF":5.0,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143378889","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-10DOI: 10.1016/j.tranon.2025.102316
Heng Zheng, Yong Pan
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in the digestive tract, with c-kit and PDGFRA mutations being the primary causes. However, GIST pathogenesis is not still fully understood. Differential expression analysis, Univariate Cox regression and Kaplan-Meier curves were utilized to screen for up-regulated and prognostically relevant genes. The expression distribution was compared across various demographics and clinical groups. The relationship between gene expression and cytokine pathway activation was assessed via CytoSig. Immune cell infiltration was analyzed using TIMER2.0. Four paired GIST and adjacent normal tissues were collected to validate the expression trend. CCK8 assays and scratch wound healing assays were conducted in GIST-T1 and GIST-882 cells. Results indicated that LARP7 was up-regulated in GISTs at both mRNA and protein levels. This elevated expression was associated with poor prognosis, particularly in GISTs located in the small intestine and those with larger tumor sizes. LARP7 was implicated in the expression of IFN-induced genes and the negative regulation of viral processes. Predictions of cytokine pathways supported these findings, and immune cell infiltration analysis revealed a higher presence of CD8+ T cells in GISTs with high LARP7 expression. The lncRNA (H19 or LINC00665)-miRNA(hsa-miR-138–5p) axis targeted LARP7. Furthermore, LARP7 was elevated in imatinib-resistant GISTs, with some other drugs predicted to aid in therapy. LARP7 knockdown resulted in reduced proliferation and migration of GIST-T1 and GIST-882 cells. Overall, high expression of LARP7 correlates with poor prognosis in GISTs, highlighting its potential as a therapeutic target.
{"title":"Transcriptome-proteome integration analysis identifies elevated expression of LARP7 promoting the tumorigenesis and development of gastrointestinal stromal tumors","authors":"Heng Zheng, Yong Pan","doi":"10.1016/j.tranon.2025.102316","DOIUrl":"10.1016/j.tranon.2025.102316","url":null,"abstract":"<div><div>Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in the digestive tract, with c-kit and PDGFRA mutations being the primary causes. However, GIST pathogenesis is not still fully understood. Differential expression analysis, Univariate Cox regression and Kaplan-Meier curves were utilized to screen for up-regulated and prognostically relevant genes. The expression distribution was compared across various demographics and clinical groups. The relationship between gene expression and cytokine pathway activation was assessed via CytoSig. Immune cell infiltration was analyzed using TIMER2.0. Four paired GIST and adjacent normal tissues were collected to validate the expression trend. CCK8 assays and scratch wound healing assays were conducted in GIST-T1 and GIST-882 cells. Results indicated that LARP7 was up-regulated in GISTs at both mRNA and protein levels. This elevated expression was associated with poor prognosis, particularly in GISTs located in the small intestine and those with larger tumor sizes. LARP7 was implicated in the expression of IFN-induced genes and the negative regulation of viral processes. Predictions of cytokine pathways supported these findings, and immune cell infiltration analysis revealed a higher presence of CD8+ <em>T</em> cells in GISTs with high LARP7 expression. The lncRNA (H19 or LINC00665)-miRNA(hsa-miR-138–5p) axis targeted LARP7. Furthermore, LARP7 was elevated in imatinib-resistant GISTs, with some other drugs predicted to aid in therapy. LARP7 knockdown resulted in reduced proliferation and migration of GIST-T1 and GIST-882 cells. Overall, high expression of LARP7 correlates with poor prognosis in GISTs, highlighting its potential as a therapeutic target.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"53 ","pages":"Article 102316"},"PeriodicalIF":5.0,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143376583","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-10DOI: 10.1016/j.tranon.2025.102298
Fei Zhang , RuiFang Liu , ZhenLing Xu , WenJie Chen , XiYa Lu , Yang Wang
<div><h3>Background</h3><div>premature ovarian failure (POF) is a significant condition characterized by the early loss of ovarian function, often leading to infertility and other health complications. Traditional Chinese Medicine (TCM) formulations, such as Chaihu Shugan San and Zuogui Yin, have been used to address various gynecological disorders. This study aims to evaluate the therapeutic effects of Chaihu Shugan San, Zuogui Yin, and their combination on POI in a rat model and to elucidate the underlying mechanisms involving the PI3K/Akt/mTOR signaling pathway.</div></div><div><h3>Methods</h3><div>In this study, a premature ovarian failure (POF) rat model was established using chronic unpredictable mild stress (CUMS) combined with cyclophosphamide injections. Rats were treated with Chaihu Shugan San, Zuogui Yin, or their combination. Key outcomes, including ovarian granulosa cell proliferation, follicular integrity, and hormonal levels (FSH and E2), were assessed. Histopathological changes in ovarian tissue were evaluated using hematoxylin and eosin (H&E) staining, while apoptosis was detected through immunohistochemistry and Western blot analysis of proteins such as Bcl-2, Bax, Caspase3, and Caspase9. The activity of the PI3K/Akt/mTOR signaling pathway was quantified using Western blot, and statistical significance was determined (<em>P</em> < 0.05).</div></div><div><h3>Results</h3><div>The results showed that all three treatments significantly improved ovarian function in the POF rat model. Compared to the model group, Chaihu Shugan San, Zuogui Yin, and their combination increased granulosa cell proliferation (<em>P</em> < 0.01), reduced follicular atresia (<em>P</em> < 0.05), and normalized hormone levels (FSH: reduced by 36.5 %; E2: increased by 42.8 %, <em>P</em> < 0.05). Histopathological analysis confirmed preserved follicular structure and reduced apoptosis in treated groups. Western blot results revealed enhanced PI3K/Akt/mTOR pathway activity, with upregulated Bcl-2 expression (<em>P</em> < 0.01), downregulated Bax expression (<em>P</em> < 0.01), and decreased Caspase3 and Caspase9 levels (<em>P</em> < 0.05). Additionally, CyclinD2 and P70S6 K expression were significantly increased in treated groups, suggesting enhanced cell cycle progression and protein synthesis.</div></div><div><h3>Conclusion</h3><div>Chaihu Shugan San, Zuogui Yin, and their combination exhibit potential efficacy as treatments for POF in rats by enhancing granulosa cell proliferation, preserving follicular integrity, and inhibiting apoptosis. These therapeutic effects are mediated through the activation of the PI3K/Akt/mTOR signaling pathway and regulation of apoptosis-related proteins. This study highlights the importance of further exploring apoptosis-related pathways to understand the therapeutic mechanisms of these TCM formulations, providing a foundation for new clinical strategies to manage POF and related reproductive health issue
{"title":"Chaihu Shugan San and Zuogui Yin synergistically improve premature ovarian failure in a rat model via the PI3K/Akt/mTOR pathway","authors":"Fei Zhang , RuiFang Liu , ZhenLing Xu , WenJie Chen , XiYa Lu , Yang Wang","doi":"10.1016/j.tranon.2025.102298","DOIUrl":"10.1016/j.tranon.2025.102298","url":null,"abstract":"<div><h3>Background</h3><div>premature ovarian failure (POF) is a significant condition characterized by the early loss of ovarian function, often leading to infertility and other health complications. Traditional Chinese Medicine (TCM) formulations, such as Chaihu Shugan San and Zuogui Yin, have been used to address various gynecological disorders. This study aims to evaluate the therapeutic effects of Chaihu Shugan San, Zuogui Yin, and their combination on POI in a rat model and to elucidate the underlying mechanisms involving the PI3K/Akt/mTOR signaling pathway.</div></div><div><h3>Methods</h3><div>In this study, a premature ovarian failure (POF) rat model was established using chronic unpredictable mild stress (CUMS) combined with cyclophosphamide injections. Rats were treated with Chaihu Shugan San, Zuogui Yin, or their combination. Key outcomes, including ovarian granulosa cell proliferation, follicular integrity, and hormonal levels (FSH and E2), were assessed. Histopathological changes in ovarian tissue were evaluated using hematoxylin and eosin (H&E) staining, while apoptosis was detected through immunohistochemistry and Western blot analysis of proteins such as Bcl-2, Bax, Caspase3, and Caspase9. The activity of the PI3K/Akt/mTOR signaling pathway was quantified using Western blot, and statistical significance was determined (<em>P</em> < 0.05).</div></div><div><h3>Results</h3><div>The results showed that all three treatments significantly improved ovarian function in the POF rat model. Compared to the model group, Chaihu Shugan San, Zuogui Yin, and their combination increased granulosa cell proliferation (<em>P</em> < 0.01), reduced follicular atresia (<em>P</em> < 0.05), and normalized hormone levels (FSH: reduced by 36.5 %; E2: increased by 42.8 %, <em>P</em> < 0.05). Histopathological analysis confirmed preserved follicular structure and reduced apoptosis in treated groups. Western blot results revealed enhanced PI3K/Akt/mTOR pathway activity, with upregulated Bcl-2 expression (<em>P</em> < 0.01), downregulated Bax expression (<em>P</em> < 0.01), and decreased Caspase3 and Caspase9 levels (<em>P</em> < 0.05). Additionally, CyclinD2 and P70S6 K expression were significantly increased in treated groups, suggesting enhanced cell cycle progression and protein synthesis.</div></div><div><h3>Conclusion</h3><div>Chaihu Shugan San, Zuogui Yin, and their combination exhibit potential efficacy as treatments for POF in rats by enhancing granulosa cell proliferation, preserving follicular integrity, and inhibiting apoptosis. These therapeutic effects are mediated through the activation of the PI3K/Akt/mTOR signaling pathway and regulation of apoptosis-related proteins. This study highlights the importance of further exploring apoptosis-related pathways to understand the therapeutic mechanisms of these TCM formulations, providing a foundation for new clinical strategies to manage POF and related reproductive health issue","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"53 ","pages":"Article 102298"},"PeriodicalIF":5.0,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143376581","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-09DOI: 10.1016/j.tranon.2025.102310
Junfeng Xu , Na Li , Hui Xie , Changwei Duan , Xingchen Liao , Ruoran Li , Heng Zhang , Yuanming Pan , Xianzong Ma , Shuwen Du , Jianqiu Sheng , Xin Wang , Lang Yang , Peng Jin
Background
Colony-stimulating factor 3 (CSF3) is a cytokine that promotes inflammation by stimulating the maturation, proliferation, and trafficking of myeloid progenitor cells. However, the functional importance of CSF3 in colorectal cancer (CRC) remains unclear.
Methods
CSF3 expression levels in CRC cells and tissues were detected by quantitative real-time PCR (qRT-PCR), western blot and immunohistochemistry (IHC). In vitro and in vivo assays were performed to investigate the oncogenic function of CSF3 in the tumor associated malignant phenotypes and the tumorigenic capability of CRC cells. Immunocoprecipitation was performed to verify the regulatory effects of CSF3 on IκBα ubiquitination.
Results
We found that CSF3 was overexpressed in CRC tissues compared to adjacent normal tissues, which correlated with poor patient survival. In vitro, silencing CSF3 significantly impaired cell proliferation, colony formation, and migration, while enhancing apoptosis. In vivo, silencing CSF3 resulted in reduced tumor growth, weight, and volume, indicating its potential as a therapeutic target. Mechanistically, CSF3 was found to mediate CRC development by activating the NF-κB signaling pathway, as evidenced by the decreased phosphorylation of p65 and reduced IκBα ubiquitination in CSF3-silenced cells. Furthermore, CSF3 silencing modulated immune infiltration in CRC, promoting an anti-tumor immune response and altering the tumor microenvironment.
Conclusion
CSF3 modulated the NF-κB signaling pathway through a distinct mechanism involving p65 phosphorylation and the activation of NF-κB by enhancing IκBα ubiquitination, thereby effectively promoting CRC development, and CSF3 may serve as a potential therapeutic target for repressing CRC advance and metastasis.
{"title":"CSF3 promotes colorectal cancer progression by activating p65/NF-κB signaling pathway and inducing an immunosuppressive microenvironment","authors":"Junfeng Xu , Na Li , Hui Xie , Changwei Duan , Xingchen Liao , Ruoran Li , Heng Zhang , Yuanming Pan , Xianzong Ma , Shuwen Du , Jianqiu Sheng , Xin Wang , Lang Yang , Peng Jin","doi":"10.1016/j.tranon.2025.102310","DOIUrl":"10.1016/j.tranon.2025.102310","url":null,"abstract":"<div><h3>Background</h3><div>Colony-stimulating factor 3 (CSF3) is a cytokine that promotes inflammation by stimulating the maturation, proliferation, and trafficking of myeloid progenitor cells. However, the functional importance of CSF3 in colorectal cancer (CRC) remains unclear.</div></div><div><h3>Methods</h3><div>CSF3 expression levels in CRC cells and tissues were detected by quantitative real-time PCR (qRT-PCR), western blot and immunohistochemistry (IHC). <em>In vitro</em> and <em>in vivo</em> assays were performed to investigate the oncogenic function of CSF3 in the tumor associated malignant phenotypes and the tumorigenic capability of CRC cells. Immunocoprecipitation was performed to verify the regulatory effects of CSF3 on IκBα ubiquitination.</div></div><div><h3>Results</h3><div>We found that CSF3 was overexpressed in CRC tissues compared to adjacent normal tissues, which correlated with poor patient survival. <em>In vitro</em>, silencing CSF3 significantly impaired cell proliferation, colony formation, and migration, while enhancing apoptosis. <em>In vivo</em>, silencing CSF3 resulted in reduced tumor growth, weight, and volume, indicating its potential as a therapeutic target. Mechanistically, CSF3 was found to mediate CRC development by activating the NF-κB signaling pathway, as evidenced by the decreased phosphorylation of p65 and reduced IκBα ubiquitination in CSF3-silenced cells. Furthermore, CSF3 silencing modulated immune infiltration in CRC, promoting an anti-tumor immune response and altering the tumor microenvironment.</div></div><div><h3>Conclusion</h3><div>CSF3 modulated the NF-κB signaling pathway through a distinct mechanism involving p65 phosphorylation and the activation of NF-κB by enhancing IκBα ubiquitination, thereby effectively promoting CRC development, and CSF3 may serve as a potential therapeutic target for repressing CRC advance and metastasis.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"53 ","pages":"Article 102310"},"PeriodicalIF":5.0,"publicationDate":"2025-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143372266","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-09DOI: 10.1016/j.tranon.2025.102279
Ruiqing Ma , Guojun Li , Yingjiang Ye , Lei Liang , Chong Wang , Haipeng Zhou , Pu Zhang , Lubiao An , Guanjun Shi , Qian Chen , Hongbin Xu , Zhidong Gao
Introduction
Pseudomyxoma Peritonei (PMP) is an extremely rare disease characterized by progressive accumulation of mucinous ascites and implants in the peritoneum. We investigated the prognostic value for response to cytoreductive surgery (CRS) or hyperthermic intraperitoneal chemotherapy (HIPEC) and dissected potential beneficial targeted therapy utilizing genomic characteristics.
Methods
Whole-exome sequencing (WES) was performed on tissue specimens and matched white blood cells from 81 patients with PMP. The study investigated mutational signatures, profiling, and their correlation with progression-free survival (PFS) and overall survival (OS).
Results
Signature 3 (HRD) and signature 15 (dMMR) were dominant. NMF cluster 1, characterized by signature 4, exhibited a worse prognosis. The p53 and TGF-β signaling pathways may contribute as risk factors for worse OS and PFS, respectively. MUC16-mutated patients had worse PFS (P = 0.016) and OS (P = 0.004) compared to wild-type patients. Patients with tumor mutational burden (TMB) > 1(P = 0.026) or alterations in TP53 (P = 0.006) or SMAD4 (P = 0.013) had significantly worse OS compared to those with a TMB < 1 or normal genes. Patients with homologous recombination deficiency (HRD) positivity (P = 0.003) or alterations in TGFBR2 (P = 0.037) experienced worse PFS compared to their respective control groups. Furthermore, NMF cluster1 (P = 0.020), TP53 (P = 0.004), and MUC16 (P = 0.013) were identified as independent prognostic factors for OS, while HRD status (P = 0.003) was independent predictors for PFS in PMP.
Conclusions
The study reveals that genomic profiling can serve as a robust tool for identifying prognostic markers in PMP. The identified genomic mutations and signaling pathway offer new avenues for targeted therapies.
{"title":"Prognosis conferred by molecular features of appendix-derived Pseudomyxoma Peritonei","authors":"Ruiqing Ma , Guojun Li , Yingjiang Ye , Lei Liang , Chong Wang , Haipeng Zhou , Pu Zhang , Lubiao An , Guanjun Shi , Qian Chen , Hongbin Xu , Zhidong Gao","doi":"10.1016/j.tranon.2025.102279","DOIUrl":"10.1016/j.tranon.2025.102279","url":null,"abstract":"<div><h3>Introduction</h3><div>Pseudomyxoma Peritonei (PMP) is an extremely rare disease characterized by progressive accumulation of mucinous ascites and implants in the peritoneum. We investigated the prognostic value for response to cytoreductive surgery (CRS) or hyperthermic intraperitoneal chemotherapy (HIPEC) and dissected potential beneficial targeted therapy utilizing genomic characteristics.</div></div><div><h3>Methods</h3><div>Whole-exome sequencing (WES) was performed on tissue specimens and matched white blood cells from 81 patients with PMP. The study investigated mutational signatures, profiling, and their correlation with progression-free survival (PFS) and overall survival (OS).</div></div><div><h3>Results</h3><div>Signature 3 (HRD) and signature 15 (dMMR) were dominant. NMF cluster 1, characterized by signature 4, exhibited a worse prognosis. The p53 and TGF-β signaling pathways may contribute as risk factors for worse OS and PFS, respectively. <em>MUC16</em>-mutated patients had worse PFS (<em>P</em> = 0.016) and OS (<em>P</em> = 0.004) compared to wild-type patients. Patients with tumor mutational burden (TMB) > 1(<em>P</em> = 0.026) or alterations in <em>TP53</em> (<em>P</em> = 0.006) or <em>SMAD4</em> (<em>P</em> = 0.013) had significantly worse OS compared to those with a TMB < 1 or normal genes. Patients with homologous recombination deficiency (HRD) positivity (<em>P</em> = 0.003) or alterations in <em>TGFBR2</em> (<em>P</em> = 0.037) experienced worse PFS compared to their respective control groups. Furthermore, NMF cluster1 (<em>P</em> = 0.020), <em>TP53</em> (<em>P</em> = 0.004), and <em>MUC16</em> (<em>P</em> = 0.013) were identified as independent prognostic factors for OS, while HRD status (<em>P</em> = 0.003) was independent predictors for PFS in PMP.</div></div><div><h3>Conclusions</h3><div>The study reveals that genomic profiling can serve as a robust tool for identifying prognostic markers in PMP. The identified genomic mutations and signaling pathway offer new avenues for targeted therapies.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"53 ","pages":"Article 102279"},"PeriodicalIF":5.0,"publicationDate":"2025-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143376582","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-07DOI: 10.1016/j.tranon.2025.102300
Haoyao Jiang , Xiangfeng Jin , Haiyong Gu , Bin Li , Zhigang Li , Yifeng Sun
Esophageal squamous cell carcinoma (ESCC) is highly malignant worldwide. Despite significant advances in the treatment of ESCC, the prognosis remains unfavourable, necessitating research into its mechanisms and treatments. Spindle component 25 (SPC25) can ensure the fidelity of mitotic progression and the accurate segregation of chromosomes, thus plays an important role in the development of malignant tumors, but its role in ESCC is yet to be determined. In this study, the expression of SPC25 was assessed by IHC in 88 primary ESCC samples, with its expression being correlated with advanced clinical features. The function of SPC25 in the proliferation, migration and tumorigenicity of ESCC cells was verified in vitro and in vivo. Mechanistically, SPC25 facilitated tumorigenesis through promoting CCND1 expression. As the transcription factor for CCND1, E2F1 is stabilized by SPC25 through binding the ubiquitin ligase MDM2, resulting in enhanced E2F1 expression, which in turn promotes the expression of CCND1. In addition, overexpression of CCND1 counteracted the effects of SPC25 silencing. Collectively, we demonstrated that the aberrant expression of SPC25 inhibited E2F1 ubiquitination and promoted CCND1 expression, thus accelerating the progression of ESCC. These findings propose novel insights into the role of SPC25 in ESCC and provide potential therapeutic strategies for targeting SPC25 in ESCC patients.
{"title":"SPC25 upregulates CCND1 to promote the progression of esophageal squamous cell carcinoma by inhibiting MDM2-mediated E2F1 ubiquitination","authors":"Haoyao Jiang , Xiangfeng Jin , Haiyong Gu , Bin Li , Zhigang Li , Yifeng Sun","doi":"10.1016/j.tranon.2025.102300","DOIUrl":"10.1016/j.tranon.2025.102300","url":null,"abstract":"<div><div>Esophageal squamous cell carcinoma (ESCC) is highly malignant worldwide. Despite significant advances in the treatment of ESCC, the prognosis remains unfavourable, necessitating research into its mechanisms and treatments. Spindle component 25 (SPC25) can ensure the fidelity of mitotic progression and the accurate segregation of chromosomes, thus plays an important role in the development of malignant tumors, but its role in ESCC is yet to be determined. In this study, the expression of SPC25 was assessed by IHC in 88 primary ESCC samples, with its expression being correlated with advanced clinical features. The function of SPC25 in the proliferation, migration and tumorigenicity of ESCC cells was verified in vitro and in vivo. Mechanistically, SPC25 facilitated tumorigenesis through promoting CCND1 expression. As the transcription factor for CCND1, E2F1 is stabilized by SPC25 through binding the ubiquitin ligase MDM2, resulting in enhanced E2F1 expression, which in turn promotes the expression of CCND1. In addition, overexpression of CCND1 counteracted the effects of SPC25 silencing. Collectively, we demonstrated that the aberrant expression of SPC25 inhibited E2F1 ubiquitination and promoted CCND1 expression, thus accelerating the progression of ESCC. These findings propose novel insights into the role of SPC25 in ESCC and provide potential therapeutic strategies for targeting SPC25 in ESCC patients.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"53 ","pages":"Article 102300"},"PeriodicalIF":5.0,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143196695","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号