Translational Oncology最新文献

{"title":"CCL22 as an independent prognostic factor in endometrial cancer patients","authors":"","doi":"10.1016/j.tranon.2024.102116","DOIUrl":"10.1016/j.tranon.2024.102116","url":null,"abstract":"<div><h3>Objectives</h3><p>The chemokine CCL22 is recognized for recruiting immunosuppressive regulatory T-cells (Treg) that contribute to disease progression in various tumor entities helping them to evade the host immune response. Our study aims to identify the expressing cell types and to evaluate the prognostic significance of CCL22 secretion and its association with Treg invasion in endometrial cancer (EC), an immunogenic cancer.</p></div><div><h3>Methods</h3><p>Specimens from 275 patients with EC and 28 healthy controls were screened immunohistochemically for CCL22. Immunofluorescence double-staining for CCL22 and different immune cell markers was performed. In vitro regulation of CCL22-expression was examined in EC cell lines (Ishikawa+, RL95–2) and human PBMCs in coculture settings via qPCR and ELISA.</p></div><div><h3>Results</h3><p>Elevated CCL22 staining in tumor cells and CCL22-positive M1-macrophages in tumordistant areas were significantly associated with increased overall survival (OS). Conversely, high, secretory-appearing staining in the peritumoral and intratumoral stroma correlated with reduced OS. Although the analysis of the in vitro coculture model of epithelial tumor- and immune cells revealed PBMCs as the primary source of CCL22, we could confirm expression of the chemokine also in the EC epithelial cells.</p></div><div><h3>Conclusion</h3><p>Our study suggests that CCL22 in EC is associated with OS, dependent on its location and the cell type producing it. Intracellular upregulation and extracellular secretion must be considered separately when investigating CCL22 expressing cell types in EC. These results may provide evidence for CCL22-mediated Treg recruitment in EC as a potential future therapeutic target.</p></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1936523324002432/pdfft?md5=b29186b49bb5434ee8561a1198172e61&pid=1-s2.0-S1936523324002432-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142128274","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}

{"title":"HADH suppresses clear cell renal cell carcinoma progression through reduced NRF2-dependent glutathione synthesis","authors":"","doi":"10.1016/j.tranon.2024.102112","DOIUrl":"10.1016/j.tranon.2024.102112","url":null,"abstract":"<div><h3>Background</h3><p>Clear cell renal cell carcinoma (ccRCC) is a serious threat to human life. It is very important to clarify the pathogenesis of ccRCC. In this study we evaluated the clinical value of HADH and explored its role and mechanism in the malignant progression of ccRCC.</p></div><div><h3>Methods</h3><p>HADH expression and its relationship with prognosis were analyzed using bioinformatics database. RT-PCR, Western blot and immunohistochemistry were used to examine the expression of HADH in ccRCC tissues and tissue microarrays. To examine the cell proliferation, apoptosis, migration and invasion ability, ccRCC cells with HADH overexpressed were constructed. Xenograft experiments were performed to determine the role of HADH. Non-target metabolomics was applied to explore the potential metabolic pathway by which HADH inhibited ccRCC progression. Plasmid pcDNA3.1-NRF2 was used to confirm whether HADH inhibited the process of ccRCC cells through NRF2-related glutathione (GSH) synthesis.</p></div><div><h3>Results</h3><p>Bioinformatics database analysis showed that HADH expression was significantly decreased in ccRCC tissues, and its low expression predicted a poor prognosis. Both ccRCC tissues and tissue microarrays exhibited a significantly decreased HADH level compared with adjacent normal renal tissues. HADH overexpression inhibited the malignant behaviors of ccRCC cells. Furthermore, HADH overexpression attenuated GSH synthesis and induced oxidative stress damage. Exogenously increased NRF2 effectively attenuated the inhibitive effect of HADH overexpression on ccRCC cells.</p></div><div><h3>Conclusion</h3><p>Our data revealed that HADH suppressed the malignant behaviors of ccRCC cells by attenuating GSH synthesis through inhibition of NRF2 nuclear translocation, and HADH might be a novel therapeutic target for ccRCC treatment.</p></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1936523324002390/pdfft?md5=7e4a4d92f8790a91cdddff8088f99cb9&pid=1-s2.0-S1936523324002390-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142122963","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}

{"title":"Effect of tumor-derived extracellular vesicle-shuttled lncRNA MALAT1 on proliferation, invasion and metastasis of triple-negative breast cancer by regulating macrophage M2 polarization via the POSTN/Hippo/YAP axis","authors":"","doi":"10.1016/j.tranon.2024.102076","DOIUrl":"10.1016/j.tranon.2024.102076","url":null,"abstract":"<div><h3>Objectives</h3><p>Triple-negative breast cancer (TNBC) is the deadliest subtype of breast cancer (BC). Tumor-derived extracellular vesicles (EVs) trigger tumor progression by promoting M2 polarization. Some lncRNAs can be encapsulated into EVs for intercellular communication. Herein, we investigated the mechanism of TNBC-derived EV-shuttled lncRNA MALAT1 on macrophage polarization/tumorigenesis.</p></div><div><h3>Methods</h3><p>BC-associated targeted EV-derived lncRNAs were screened. Tumor tissues/tissues adjacent to cancer of TNBC patients, and blood samples of all subjects were collected. MALAT1/POSTN mRNA levels in tumor tissues/tissues adjacent to cancer, and MALAT1 expression in EVs and its correlation with TNBC patient overall survival were assessed by RT-qPCR/Kaplan-Meier survival analysis/log-rank test. TNBC patient M2 infiltration was detected by flow cytometry. MALAT1/POSTN levels in EVs/macrophages were regulated by transfection. Hippo/YAP activation was determined by Western blot. Nude mouse xenograft model was established and metastasis was detected by H&amp;E staining.</p></div><div><h3>Results</h3><p>MALAT1/POSTN were up-regulated and correlated with M2 infiltration/poor prognosis in TNBC patients. TNBC-derived EVs induced M2 polarization. MALAT1 was highly expressed in TNBC-derived EVs and could be transferred to macrophages via EVs to induce M2 polarization. POSTN overexpression diminished the inhibitory effect of MALAT1 knockdown on M2 markers. EVs activated the Hippo/YAP pathway in macrophages. The Hippo/YAP pathway inhibition abrogated the effect of POSTN overexpression on M2 marker expression. TNBC-EV-derived MALAT1 facilitated M2 polarization, and thus promoting occurrence and metastasis of TNBC <em>in vitro</em> and <em>in vivo</em>.</p></div><div><h3>Conclusions</h3><p>TNBC-EV-derived MALAT1 activated the Hippo/YAP axis by up-regulating POSTN, thereby inducing M2 polarization to promote TNBC occurrence and metastasis <em>in vivo</em>.</p></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1936523324002031/pdfft?md5=6f57ccde0c22a156c7d194a23faa9804&pid=1-s2.0-S1936523324002031-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142117427","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}

{"title":"Metavert synergises with standard cytotoxics in human PDAC organoids and is associated with transcriptomic signatures of therapeutic response","authors":"","doi":"10.1016/j.tranon.2024.102109","DOIUrl":"10.1016/j.tranon.2024.102109","url":null,"abstract":"<div><h3>Background</h3><p>Despite some recent advances, pancreatic ductal adenocarcinoma (PDAC) remains a growing oncological challenge. New drugs capable of targeting more than one oncogenic pathway may be one way to improve patient outcomes. This study characterizes the effectiveness of Metavert a first-in-class dual inhibitor of GSK3-β and histone deacetylase in treating PDAC as a single agent or in combination with standard cytotoxics.</p></div><div><h3>Methods</h3><p>Thirty-six Patient-Derived Organoids (hPDOs) characterised by RNASeq and whole exome sequencing were treated with Metavert alone or in combination with standard cytotoxics. Transcriptomic signatures (TS) representing sensitivity to Metavert alone or sensitivity to Metavert + irinotecan (IR) were evaluated in 47 patient samples, chemo-naïve in 26 and post-chemotherapy in 21 (gemcitabine=5; FOLFIRINOX=14, both=2) with companion multiplexed immunofluorescence and RNASeq data.</p></div><div><h3>Results</h3><p>Metavert combined with gemcitabine, irinotecan, 5FU, oxaliplatin, and paclitaxel was synergistic in the hPDOs. Basal-subtype hPDOs were more sensitive to Metavert alone whereas the Metavert+IR combination exhibited synergy in Classical-subtype hPDOs with increased apoptosis and autophagy. hPDO-derived TS evaluated in PDAC tissues demonstrated that Metavert-TS^Hi samples were enriched for mRNA splicing and DNA repair processes; they were associated with Basal-like tissues but also with GATA6^+ve-chemo-naïve samples and were higher following gemcitabine but not FOLFIRINOX treatment. In contrast, Metavert+IR-TS^HI samples were enriched for TP53 pathways; they were associated with Classical-like pretreatment samples and with GATA6^+ve/KRT17^+ve hybrid cell types following FOLFIRINOX, but not gemcitabine treatment, and were unrelated to transcriptional subtypes.</p></div><div><h3>Conclusions</h3><p>Metavert as a single agent and in combination with irinotecan offers novel strategies for treating pancreatic cancer.</p></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1936523324002365/pdfft?md5=f85533617deafcbac6264f8bce5bbb23&pid=1-s2.0-S1936523324002365-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142095503","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}

{"title":"Bulk and single-cell RNA sequencing analyses coupled with multiple machine learning to develop a glycosyltransferase associated signature in colorectal cancer","authors":"","doi":"10.1016/j.tranon.2024.102093","DOIUrl":"10.1016/j.tranon.2024.102093","url":null,"abstract":"<div><h3>Background</h3><p>This study aims to identify key glycosyltransferases (GTs) in colorectal cancer (CRC) and establish a robust prognostic signature derived from GTs.</p></div><div><h3>Methods</h3><p>Utilizing the AUCell, UCell, singscore, ssgsea, and AddModuleScore algorithms, along with correlation analysis, we redefined genes related to GTs in CRC at the single-cell RNA level. To improve risk model accuracy, univariate Cox and lasso regression were employed to discover a more clinically subset of GTs in CRC. Subsequently, the efficacy of seven machine learning algorithms for CRC prognosis was assessed, focusing on survival outcomes through nested cross-validation. The model was then validated across four independent external cohorts, exploring variations in the tumor microenvironment (TME), response to immunotherapy, mutational profiles, and pathways of each risk group. Importantly, we identified potential therapeutic agents targeting patients categorized into the high-GARS group.</p></div><div><h3>Results</h3><p>In our research, we classified CRC patients into distinct subgroups, each exhibiting variations in prognosis, clinical characteristics, pathway enrichments, immune infiltration, and immune checkpoint genes expression. Additionally, we established a Glycosyltransferase-Associated Risk Signature (GARS) based on machine learning. GARS surpasses traditional clinicopathological features in both prognostic power and survival prediction accuracy, and it correlates with higher malignancy levels, providing valuable insights into CRC patients. Furthermore, we explored the association between the risk score and the efficacy of immunotherapy.</p></div><div><h3>Conclusion</h3><p>A prognostic model based on GTs was developed to forecast the response to immunotherapy, offering a novel approach to CRC management.</p></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1936523324002201/pdfft?md5=9416db9a299d204e6a87e7324cbb1a5f&pid=1-s2.0-S1936523324002201-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142096207","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}

{"title":"Tumor perfusion enhancement by focus ultrasound-induced blood-brain barrier opening to potentiate anti-PD-1 immunotherapy of glioma","authors":"","doi":"10.1016/j.tranon.2024.102115","DOIUrl":"10.1016/j.tranon.2024.102115","url":null,"abstract":"<div><h3>Objective</h3><p>To demonstrate the feasibility of using focused ultrasound to enhance delivery of PD-1 inhibitors in glioma rats and determine if such an approach increases treatment efficacy.</p></div><div><h3>Methods</h3><p>C6 glioma <em>in situ</em> rat model was used in this study. Transcranial irradiation with FUS combined with microbubbles was administered to open the blood-brain barrier (BBB). The efficacy of BBB opening was evaluated in normal rats. The rats with glioma were grouped to evaluate the role of PD-1 inhibitors combined with FUS-induced immune responses in suppressing glioma when the BBB opens. Flow cytometry was used to examine the changes of immune cell populations of lymphocytes in peripheral blood, tumor tissue and spleen tissue of the rats. A section of rat brain tissue was also used for histological and immunohistochemical analysis. The survival of the rats was then monitored; the tumor progression and changes in blood perfusion of tumor were dynamically observed <em>in vivo</em> using multimodal MRI.</p></div><div><h3>Results</h3><p>FUS combined with microbubbles could enhance the blood perfusion of tumors by increasing the permeability of BBB (<em>p &lt;</em> 0.0001), thus promoting the infiltration of CD4⁺ T lymphocytes (<em>p &lt;</em> 0.01). Compared with the control group, the combination treatment group had increased in the infiltration number of CD4⁺(<em>p &lt;</em> 0.05) and CD8⁺ T (<em>p &lt;</em> 0.05); the tumor volume of the combined treatment group was smaller than that of the control group (<em>p &lt;</em> 0.01) and the survival rate of the rats was prolonged (<em>p &lt;</em> 0.05).</p></div><div><h3>Conclusions</h3><p>In this study, we demonstrated that the transient opening of the BBB induced by FUS enhanced tumor vascular perfusion and facilitated the delivery of PD-1 inhibitors, ultimately improving the therapeutic efficacy for glioblastoma.</p></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1936523324002420/pdfft?md5=5f84095f56fbaf09ddffe45e6c72753d&pid=1-s2.0-S1936523324002420-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142095504","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}

{"title":"Collagen extracellular matrix promotes gastric cancer immune evasion by activating IL4I1-AHR signaling","authors":"","doi":"10.1016/j.tranon.2024.102113","DOIUrl":"10.1016/j.tranon.2024.102113","url":null,"abstract":"<div><h3>Background</h3><p>Gastric cancer (GC) remains a significant global health challenge with poor prognosis, partly due to its ability to evade the immune system. The extracellular matrix (ECM), particularly collagen, plays a crucial role in tumor immune evasion, but the underlying mechanisms are not fully understood. This study investigates the role of collagen ECM in promoting immune evasion in gastric cancer by activating the IL4I1-AHR signaling pathway.</p></div><div><h3>Methods</h3><p>We cultured gastric cancer cells in 3D collagen gels and assessed their immune evasion capabilities by co-culturing with HER2-specific CAR-T cells. The expression of IL4I1 and its metabolites was analyzed, and the role of integrin αvβ1 in mediating the effects of collagen was explored. Additionally, the impact of IL4I1-induced AHR activation on CAR-T cell exhaustion was evaluated, both <em>in vitro</em> and <em>in vivo</em>.</p></div><div><h3>Results</h3><p>We found that gastric cancer cells cultured on collagen exhibited increased resistance to CAR-T cell cytotoxicity, which was associated with upregulated immune checkpoint molecules and downregulated effector cytokines on CAR-T cells. This was linked to increased IL4I1 expression, which was further induced by integrin αvβ1 signaling within the 3D collagen environment. IL4I1 metabolites, particularly KynA, promoted CAR-T cell exhaustion by activating the AHR pathway, leading to decreased cytotoxicity and tumor growth inhibition.</p></div><div><h3>Conclusions</h3><p>Our study reveals a novel mechanism by which the collagen ECM facilitates immune evasion in gastric cancer through the activation of IL4I1-AHR signaling, contributing to CAR-T cell exhaustion. Targeting this pathway could potentially enhance the efficacy of CAR-T cell therapy in gastric cancer.</p></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1936523324002407/pdfft?md5=b2186aa04e3df43ed12146efc5f454bf&pid=1-s2.0-S1936523324002407-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142095502","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}

{"title":"The role of deubiquitinase USP2 in driving bladder cancer progression by stabilizing EZH2 to epigenetically silence SOX1 expression","authors":"","doi":"10.1016/j.tranon.2024.102104","DOIUrl":"10.1016/j.tranon.2024.102104","url":null,"abstract":"<div><h3>Background</h3><p>The Ubiquitin-proteasome system (UPS) is known to participate in multiple cellular events. The deubiquitinating enzyme USP2 (ubiquitin-specific protease 2) is involved in the vasculature remodeling process associated with bladder cancer (BLCA). However, the role of USP2 in BLCA progression has not been clearly defined and whether its regulatory mechanism involving EZH2 (Enhancer of Zeste Homolog 2) remains elusive yet.</p></div><div><h3>Methods</h3><p>Differential expression patterns of USP2 and EZH2 were examined in 46 pairs of BLCA and adjacent normal tissues. USP2 knockdown plasmids were transfected into 5637 and J82 cells to detect its impact on cell proliferation, migration and invasion using CCK-8, EdU, wound healing and transwell assays. The USP2-EZH2-SOX1 cascade was confirmed through Co-immunoprecipitation (Co-IP) and chromatin immunoprecipitation (ChIP) assays. An <em>in vivo</em> verification was conducted using a xenograft model of nude mice.</p></div><div><h3>Results</h3><p>USP2 was significantly upregulated in BLCA tissues and cells, which was associated with poor clinical prognosis in BLCA patients. USP2 depletion resulted in decreased cell proliferation, migration and invasion in BLCA cells. USP2 stabilized the EZH2 protein by directly binding to it, thereby reducing its ubiquitination. Ectopic introduction of EZH2 restored cell growth and invasion of BLCA cells, which had been inhibited by USP2 silencing. USP2-mediated stabilization of EZH2 promoted the enrichment of histone H3K27me3 and repression of SOX1. Involvement of the USP2-EZH2-SOX1 axis in tumor formation was ultimately verified <em>in vivo</em>.</p></div><div><h3>Conclusion</h3><p>Our findings reveal that a USP2-EZH2-SOX1 axis orchestrates the interplay between dysregulated USP2 and EZH2-mediated gene epigenetic silencing in BLCA progression.</p></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1936523324002316/pdfft?md5=ebbfc99a8a5c065a0d6f95c5e88f2de3&pid=1-s2.0-S1936523324002316-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142089701","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}

{"title":"LncRNA LINC00173 inhibits the development of endometrial cancer by interacting with HNRNPC","authors":"","doi":"10.1016/j.tranon.2024.102105","DOIUrl":"10.1016/j.tranon.2024.102105","url":null,"abstract":"<div><h3>Background</h3><p>Previous research has elaborated on the role of long non-coding RNA LINC00173 in the pathogenesis of various cancers; however, our knowledge of its clinical consequences and mechanisms in endometrial cancer (EC) is limited. Our current work is aimed at investigating the effect of LINC00173 in combination with its upstream gene HNRNPC on EC progression.</p></div><div><h3>Methods</h3><p>LINC00173 and HNRNPC levels were investigated by qRT-PCR or western blotting in EC tissues. The functional roles of HNRNPC and LINC00173 were assessed using transwell, colony formation and CCK-8 assays. A xenograft was used to verify the phenotype of LINC00173 after its overexpression. The regulatory role between HNRNPC and LINC00173 was investigated using RIP and RNA pull-down analysis.</p></div><div><h3>Results</h3><p>In EC tissues, LINC00173 expression was down-regulated. We observed that increased LINC00173 inhibited EC cell growth and migration. LINC00173 was a downstream target of HNRNPC, and its expression level was elevated by HNRNPC silencing. LINC00173 overexpression shifted part of HNRNPC into the cytoplasm from the nucleus of EC cells. Furthermore, HNRNPC expression was upregulated in EC and its silencing inhibited EC cell malignancy <em>in vitro</em>.</p></div><div><h3>Conclusion</h3><p>LINC00173 can impair the malignancy of EC cell by interacting with HNRNPC. This finding may contribute to the understanding of the tumorigenic effects of HNRNPC and LINC00173 on EC.</p></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1936523324002328/pdfft?md5=14dc400e2bd75aba64ce82f6b23b2b15&pid=1-s2.0-S1936523324002328-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142076772","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}

{"title":"Neratinib plus dasatinib is highly synergistic in HER2-positive breast cancer in vitro and in vivo","authors":"","doi":"10.1016/j.tranon.2024.102073","DOIUrl":"10.1016/j.tranon.2024.102073","url":null,"abstract":"<div><h3>Background</h3><p>HER2-targeted therapies have revolutionised the treatment of HER2-positive breast cancer. However, <em>de novo</em> resistance or the emergence of acquired resistance is a persistent clinical problem. Here we report that neratinib, an irreversible pan-HER inhibitor, in combination with the multi-kinase inhibitor dasatinib, currently used to treat certain leukemias, has strong anti-proliferative effects against models of HER2-positive breast cancer that are innately resistant to trastuzumab or have acquired resistance to neratinib.</p></div><div><h3>Methods</h3><p>Neratinib plus dasatinib was examined in a panel of 20 breast cancer cell lines, including HER2-positive, estrogen-receptor-positive, triple negative, and acquired HER2-targeted therapy resistant models. Drug effects on migration and apoptosis induction was evaluated and signaling alterations were determined by reverse phase protein array (RPPA). <em>In vivo</em> efficacy was examined using orthotopically-implanted HCC1954 cells.</p></div><div><h3>Results</h3><p>Synergy was observed in cell lines innately resistant to trastuzumab, models with acquired resistance to neratinib, and in triple negative breast cancer cell lines. Further investigation showed that neratinib plus dasatinib induced apoptosis and inhibited cell migration to a greater degree than either drug alone. RPPA revealed that the combination caused suppression of key survival signaling through EGFR, Akt, and MAPK inhibition. <em>In vivo</em>, neratinib plus dasatinib was well tolerated and had a prolonged anti-tumor effect against HCC1954 xenografts.</p></div><div><h3>Conclusions</h3><p>This study provides a strong pre-clinical rationale for the clinical investigation neratinib and dasatinib in HER2+ breast cancer.</p></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1936523324002006/pdfft?md5=8714f7eb08b0c65d849078a50d99b7be&pid=1-s2.0-S1936523324002006-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142076774","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}