Browsing by Subject "Chemoresistance"
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- PublicationOpen AccessDoxorubicin resistance in breast cancer xenografts and cell lines can be counterweighted by microRNA-140-3p, through PD-L1 suppression(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2023) Zhang, Xia; Wang, Chao; Huang, Cuiping; Yang, Jianbao; Wang, JuanBackground. Doxorubicin, a first-line chemotherapeutic drug for breast cancer, kills cancer cells by inducing DNA-crosslinking damage. Dysregulated micro-RNA (miRNA) is associated with the drug resistance of tumors. However, little is known about the effect of miRNA-140-3p on DOX resistance of breast cancer. Methods. The miRNA microarray was used to sequence the transcripts of DOX-chemoresistant breast cancer tissues and DOX-chemosensitive tissues. Then, the breast cancer tissue chip in the GEO database was also analyzed to screen the target gene. Flow cytometry, in situ hybridisation (ISH), immunohistochemistry (IHC), Western blot, cell proliferation assay, real-time PCR analyses (qRT-PCR), and pull-down assay were used to explore the effects of miRNA-140-3p and programmed death ligand-1 (PD-L1) on the chemoresistance of DOX-resistant breast cancer cells treated with DOX. In vivo, the DOX-resistant breast cancer cell lines treated with miRNA-140-3p overexpression were injected subcutaneously into mice to construct breast cancer subcutaneous xenograft tumor models. Results. Based on miRNA microarray, GEO database, and bioinformatics analysis, it was found that miRNA-140-3p and PD-L1 are the core molecules in the DOX resistance regulatory network in breast cancer, and lower miRNA-140-3p and higher PD-L1 expression levels were observed in DOX-resistant breast cancer tissues and cells. IHC results showed that compared with breast cancer tissues with high miRNA-140-3p expression, PD-L1 protein expression levels in breast cancer tissues with low miRNA-140-3p were significantly higher (P<0.01). Moreover, compared with DOX-sensitive tissues, the levels of PD-L1 protein expression in DOX-resistant tissues were significantly higher (P<0.01). In in vitro and in vivo experiments, the introduction of miRNA-140-3p decreased PD-L1 expression. Mechanically, we found that the MCF7/DOX and HS598T/DOX cells pretreated with miRNA140-3p inhibitor or exosomes containing PD-L1 have higher stemness and lower apoptosis rate, which can be abrogated by co-treating cells with anti-PD-L1 antibody or miRNA-140-3p mimic. Conclusions. MiRNA-140-3p can suppress PD-L1 expression in breast cancer cell-derived exosomes, thereby attenuating the chemoresistance induced by DOX in breast cancer.
- ItemOpen AccessHMMR inhibition by 4-methylumbelliferone is effective in preclinical hepatocellular carcinoma models(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2026) Ge Sang Wang Dui2; Suo Lang Bai Ma; Ci Yang; Wen Xu; Jianguo Xu; Ying Zhu; Biología Celular e HistologíaThe poor prognosis of hepatocellular carcinoma (HCC), especially in advanced stages, underscores the need for new therapeutic strategies. In this study, we show that hyaluronan-mediated motility receptor (HMMR) is highly expressed in HCC tumors compared with normal liver tissues. Knockdown of HMMR using siRNA significantly reduced cell proliferation and migration in both parental and doxorubicin-resistant HCC cell lines without inducing apoptosis. Similarly, treatment with 4-Methyl-umbelliferone (4-MU), a pharmacological HMMR inhibitor, led to dose-dependent decreases in proliferation and migration in vitro. In vivo, 4-MU treatment significantly inhibited tumor growth in a HepG2 xenograft model, resulting in a 44% reduction in tumor volume by day 20 and an 80% decrease in HMMR expression in tumor tissues. These results demonstrate that HMMR promotes growth and migration in HCC, and targeting HMMR effectively inhibits both parental and drug-resistant HCC cells. Additionally, our findings suggest that 4-MU, an approved drug for biliary tract disorders, holds promise as a repurposed therapeutic candidate for HCC treatment.
- PublicationOpen AccessHuman equilibrative nucleoside transporter 1 and concentrative nucleoside transporter 1 in colorectal cancer: What do we know? A systematic review(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2025) McKenna, Matthew; Linganathan, Saranya; Li, Amber; Ruge, Fiona; Lane, Jane; Ye, Lin; Jiang, Wen; Hargest, Rachel; Biología Celular e HistologíaColorectal cancer (CRC) remains a major global health challenge despite advances in screening, diagnosis, and treatment. This systematic review examines the roles of Human Equilibrative Nucleoside Transporter 1 (hENT1) and Human Concentrative Nucleoside Transporter 1 (hCNT1) in CRC, focusing on their expression, regulation, and impact on chemo-therapeutic efficacy, particularly with nucleoside analogues like 5-fluorouracil (5-FU). We conducted a comprehensive literature search following PRISMA guidelines, yielding 29 studies that met our inclusion criteria. The review reveals variable expression of hENT1 and hCNT1 in CRC tissues compared with normal tissues, with implications for treatment response and development of resistance. Increased hENT1 expression is associated with poor outcomes and resistance to 5-FU, suggesting its potential as a biomarker for predicting treatment response. Conversely, hCNT1's role appears more complex, with its expression influencing the efficacy of other chemotherapeutic agents like gemcitabine and capecitabine. The review also highlights the lack of robust, standardised methods for assessing mRNA and protein levels, which complicates the interpretation of data and the establishment of these transporters as reliable clinical markers. Key findings include the potential therapeutic benefits of modulating hENT1 and hCNT1 expression to enhance drug efficacy and overcome resistance. The study underscores the need for further research using standardised and advanced methodologies, such as 3D cell culture assays, to better understand the mechanistic pathways and clinical implications of nucleoside transporter expression in CRC. Future research should aim to clarify the roles of hENT1 and hCNT1 in CRC and chemoresistance to develop targeted therapies and improve patient outcomes.
- PublicationOpen AccessLHPP promotes the intracellular reactive oxygen species accumulation and sensitivity of gastric cancer to cisplatin via JNK and p38 MAPK pathways(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2023) Gao, Kai; Yin, Ning; Shen, Zhaolong; Li, Qiqing; Chen, Peng; Yang, KaiyanBackground. Cisplatin is the first-line chemotherapy drug for the treatment of gastric cancer (GC) patients. However, GC patients who are resistant to cisplatin often do not benefit from it. Therefore, finding a key molecule that affects cisplatin sensitivity is expected to enhance the efficacy of cisplatin in GC treatment. Methods. The human GC cell lines SGC-7901 and BGC-823 were used. The protein chip array was used to screen the cisplatin-resistance genes from the complete response and non-complete response GC patients’ tissues, then, the differential gene expression analysis, GO function annotation analysis, and KEGG pathway enrichment analysis were performed. The GC tissue chip in the GEO database was analyzed to screen the target gene. Flow cytometry, Hoechst 33342 staining assay, Western Blot, MTT, tumor sphere formation, cell cycle, and apoptosis assays were performed to explore the effect of Phospholysine Phosphohistidine Inorganic Pyrophosphate Phosphatase (LHPP) on the apoptosis, stemness, and reactive oxygen species (ROS) accumulation of cisplatin-resistant GC cells treated with cisplatin. In vivo, the cisplatin-resistant GC cell lines transfected with pcDNA-LHPP or si-LHPP were injected subcutaneously into mice to construct GC subcutaneous xenograft GC models. Results. Based on protein chip array and bioinformatics analysis, it was found that LHPP is the core molecule in the cisplatin resistance regulatory network in GC, and its expression is down-regulated in GC cisplatin-resistant tissues and cells. In vitro and in vivo experimental results show that the up-regulated expression of LHPP is closely related to the increase in sensitivity of GC to cisplatin. Mechanically, we found that overexpression of LHPP may inhibit the activation of the JNK and p38 MAPK pathways, promote cisplatininduced ROS accumulation, suppress stemness, and enhance the sensitivity of GC to cisplatin. Conclusions. Up-regulation of LHPP may inhibit the activation of the JNK and p38 MAPK pathways, attenuate stemness, and enhance the accumulation of intracellular ROS, thereby promoting cisplatin-mediated GC cell apoptosis and enhancing cisplatin sensitivity.
- PublicationOpen AccessNovel biomarkers in primary breast core biopsies to predict poor response to neoadjuvant chemotherapy and appearance of metastases(Universidad de Murcia. Departamento de Biología Celular e Histología, 2017) Novell, Anna; Morales, Serafin; Valls, Joan; Panadés, Maria José; Salud, Antonieta; Iglesias, Edelmiro; Vilardell, Felip; Matias Guiu, Xavier; Llombart Cussac, AntonioDrug resistance has been one of the major obstacles limiting the success of cancer chemotherapy. In two thirds of breast cancer patients, large (>1cm) residual tumors are present after neoadjuvant chemotherapy (NCT). The residual tumor and involved nodes have been indicators of relapse and survival very important in breast cancer. The goal of this preliminary study was to assess the predictive significance of a panel of molecular biomarkers, related with the response to treatment or drug resistance to NCT, as determined on the diagnostic tumor. The expression of 22 proteins was examined using immunohistochemistry in tissue microarrays (TMA) from 115 patients of stage II-III breast cancer, treated with NCT. Among studied proteins, there are some that are anti-apoptotic, pro-proliferative, cancer stem cell markers and the Vitamin D Receptor. Other proteins are involved in the identification of molecular subtype, cell cycle regulation or DNA repair. Next, a predictive signature of poor response was generated from independent markers of predictive value. Tumors that expressed four or five conditions (biomarkers of chemoresistance with a determinated cutoff) were associated with a 9-fold increase in the chances of these patients of having a poor response to NCT. Additionally, we also found a worse prognostic signature, generated from independent markers of prognostic value. Tumors which expressed two or three conditions of worst prognostic, were associated with a 6-fold reduction in Distant Disease Free Survival. In conclusion, finding biomarkers of chemoresitance (ypTNM II-III) and metastases can become a stepping stone for future studies that will need to be assessed in a bigger scale.
- PublicationOpen AccessProinflammatory macrophage secretome enhances temozolomide sensitivity in glioblastoma via pSTAT3-mediated downregulation of DNA repair enzymes(Nature Research, 2025-11-06) López-López, Susana; Castro-Robles, Beatriz; García-Flores, Natalia; Díaz-Guerra, María José M.; Arias-Salazar, Lourdes; Sandoval, Hernán; García Pérez, Daniel; Klein-Zampaña, Christoph J.; Barbella-Aponte, Rosa A.; Segura, Tomás; Serrano-Heras, Gemma; Farmacología; Facultad de FarmaciaThe mechanisms by which tumor-associated macrophages, key components of the glioblastoma (GBM) microenvironment, impair chemotherapy efficacy remain poorly understood. Resistance to temozolomide (TMZ), the standard chemotherapeutic agent for GBM, is associated with poor prognosis due to efficient DNA repair mechanisms. While low expression of the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) has been linked to improved TMZ response, our previous findings suggest that N-methylpurine-DNA glycosylase (MPG) may also contribute to chemoresistance in GBM. Here, we report for the first time that conditioned medium from pro-inflammatory macrophages (CM-M1) enhances TMZ cytotoxicity by suppressing STAT3 phosphorylation, resulting in decreased MGMT and MPG expression in GBM cells. Proteomic profiling of CM-M1 revealed a unique, cytokine-rich secretome that may promote STAT1 activation, thereby inhibiting pSTAT3 and reducing DNA repair enzymes levels. Clinically, elevated MGMT and MPG protein levels were associated with increased pSTAT3 in our GBM patient cohort, and analysis of the TCGA database further showed that their combined overexpression correlates with significantly reduced progression-free survival. Gene silencing experiments confirmed the contribution of both enzymes to TMZ resistance, with dual knockdown producing a synergistic sensitizing effect. These findings uncover a novel mechanism of macrophage secretome–mediated chemoresistance and support the development of M1-based strategies to improve TMZ efficacy in GBM.
- PublicationOpen AccessTargeting PEAK1 sensitizes anaplastic thyroid carcinoma cells harboring BRAFV600E to Vemurafenib by Bim upregulation(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2024) Wang, Qiuhan; Hao, Fengyun; Ning, Liang; Sun, ChongPseudopodium-enriched atypical kinase 1 (PEAK1) has been demonstrated to be upregulated in human malignancies and cells. Enhanced PEAK1 expression facilitates tumor cell survival and chemoresistance. However, the role of PEAK1 inhibition to anaplastic thyroid carcinoma cell (ATC) and vemurafenib resistance is still unknown. Here, we observed that targeting PEAK1 inhibited cell viability and colony formation, but not cell apoptosis in both of the 8505C and Hth74 cells in vitro. Targeting PEAK1 sensitized 8505C and Hth74 cells to Vemurafenib by inducing cell apoptosis, and thereby decreasing cell viability. Mechanistically, Vemurafenib treatment upregulated PEAK1 expression. Combined PEAK1 depletion and Vemurafenib treatment upregulated Bim expression. Targeting PEAK1 sensitized Vemurafenib-induced apoptosis by upregulating Bim. In conclusion, Vemurafenib resistance in ATC cells harboring BRAFV600E is associated with PEAK1 activation, resulting in the inhibition of pro-apoptotic Bim protein. Therefore, targeting PEAK1 may be an effective strategy to sensitize ATC harboring BRAFV600E to Vemurafenib.
- PublicationOpen AccessTumor heterogeneity has important consequences for personalized medicine in ovarian cancer(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2015) Gui, Ting; Cao, Dongyan; Yang, Jiaxin; Shen, KengMost patients with ovarian cancers relapse, and treatment failure has often been attributed to chemoresistance in tumor cells. Emerging evidence indicates that tumor heterogeneity may play an equally important role. Although the idea of tumor heterogeneity is not new, little attention has been focused on applying it to understand and control ovarian cancer progression. Recent advances in understanding its generation model, original basis, consequent problems, and derived therapies provide great potential for tumor heterogeneity to be a new insight in treatment of ovarian cancers.