IUBMB Life [JOURNAL]
Sun
200 papers
Enhanced HER2 status detection in breast and gastric cancers using surrogate DNA methylation markers.
Hu Y, Liu S, Cui C … +11 more , Liu X, Li H, Liu H, Lu S, Lu Z, Chen Z, Pang D, Fan JB, Lin D, Zhang X, Sun Y
IUBMB Life · 2025 Feb · PMID 39988770 · Publisher ↗
There is a limited understanding of specific DNA methylation patterns associated with HER2 overexpression in breast and gastric cancers. Here we aim to solve the problem using inferred DNA methylation markers. DNA methyl...
There is a limited understanding of specific DNA methylation patterns associated with HER2 overexpression in breast and gastric cancers. Here we aim to solve the problem using inferred DNA methylation markers. DNA methylation data from The Cancer Genome Atlas (TCGA) were analyzed for breast and gastric cancers regarding HER2 status. We further applied a targeted bisulfite sequencing approach to elaborate the DNA methylation profile of the HER2 region, covering 7635 CpG sites. Based on these two sets of data, we selected specific DNA methylation markers inferring HER2 status for both breast and gastric cancers and validated their performance in assisting HER2-status determination on a retrospective cohort with 496 breast cancer and 372 gastric cancer. HER2-Meth could well distinguish HER2 IHC0/1+ from HER2 IHC3+ cases in both breast cancer (AUC = 0.983, n = 130) and gastric cancer (AUC = 0.974, n = 63), also could effectively discriminate HER2 IHC2+/FISH+ from HER2 IHC2+/FISH- cases in equivocal situations for both breast cancer (test set AUC = 0.879, n = 74; validation set AUC = 0.875, n = 75) and gastric cancer (test set AUC = 0.910, n = 70; validation set AUC = 0.941, n = 71), outperforming regular HER2 copy number test (An AUC of 0.793 for breast cancer and an AUC of 0.759 for gastric cancer) on HER2 IHC2+ cases. Furthermore, HER2-Meth demonstrated its potential for stratifying HER2-positive patients, enabling predictions regarding overall survivals, and the potential benefits of HER2-targeted therapies in breast cancer. The strong agreement observed between the methylation qPCR test and the results of IHC and FISH indicates significant potential for this approach as a complementary tool in guiding HER2-targeted therapies for patients with breast and gastric cancers.
Adverse fetal and neonatal impact of war conflicts during pregnancy: A systematic review.
Riquelme-Gallego B, Ramos-Soberbio L, Leno-Duran E … +2 more , Martínez-Vázquez S, Caparros-Gonzalez RA
IUBMB Life · 2025 Feb · PMID 39981676 · Publisher ↗
The aim of the present study was to establish the fetal and neonatal impact of war conflicts during pregnancy. A systematic review was conducted according to The Preferred Reporting Items for Systematic reviews and Meta-...
The aim of the present study was to establish the fetal and neonatal impact of war conflicts during pregnancy. A systematic review was conducted according to The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines and relevant publications available in the PubMed, Scopus and Web of Science, and PsycINFO databases. Primary and quantitative studies were eligible for inclusion. To be included, studies had to be redacted in Spanish or English and evaluate maternal exposure to a war or terrorist attack during pregnancy, with consideration being given of the consequences of this for fetal and/or neonatal development. Systematic, narrative and exploratory literature reviews were excluded, as were meta-analyses and studies in which the sample differed from the sample of interest, the focus was on other stressful factors that differed from a war conflict and the consequences examined did not comprise the impact of a war during pregnancy on the fetus or neonate. The methodological quality of included articles was assessed using the CASP (Critical Appraisal Skills Programme) tool. A total of 28 articles were included, with an included sample of n = 664,980 mother-infant dyads, exposed to war conflicts. The adverse impact of prenatal stress suffered by mothers during periods of war revealed that, (1) in the short-term, babies were at greater risk of having a low birth weight and impinged length and being born prematurely, whilst mothers were more likely to suffer a miscarriage. (2) In the long-term, babies exposed to war during the prenatal period had a higher risk of experiencing alterations to their neurodevelopment, mental disorders and pathophysiological diseases. The stress suffered by mothers during the prenatal period can bring about a number of negative consequences over both the short- and long-term in babies, especially, in terms of their physical and neurological development. It is important to conduct further research on the topic with the aim of detecting and treating the early stages of maternal psychological illnesses experienced during pregnancy due to war conflict and, in this way, achieve benefits for pregnant women and future generations.
Hypoxia inducible factor 3-alpha promotes a malignant phenotype in colorectal cancer cells.
Lopez-Mejia A, Moreno-Londoño AP, Fonseca Camarillo G … +5 more , Yamamoto-Furusho JK, Villanueva-Herrero JA, de Leon-Rendón JL, Castañeda Patlán MC, Robles-Flores M
IUBMB Life · 2025 Feb · PMID 39981666 · Full text
Colorectal cancer (CRC) is the third most common cancer worldwide. Hypoxia is a hallmark of the tumor microenvironment, and cellular adaptation to it is primarily mediated by the family of Hypoxia-inducible factors (HIFs...
Colorectal cancer (CRC) is the third most common cancer worldwide. Hypoxia is a hallmark of the tumor microenvironment, and cellular adaptation to it is primarily mediated by the family of Hypoxia-inducible factors (HIFs) HIF-1α, HIF-2α, and HIF-3α. However, in contrast to HIF-1α and HIF-2α, a specific role for HIF-3α in cancer biology has not yet been clearly established. This research was aimed to elucidate the role of HIF-3α in colon cancer. As reported previously for HIF-1α and HIF-2α, we found that HIF-3α is also overexpressed under normoxic conditions in all cancer cell lines examined and in patient-derived tumor tissue samples compared with non-malignant cells and normal tissue, but remarkably, pulse-chase experiments demonstrated that HIF-3α displays high stability in cells compared with HIF-1α and HIF-2α. Progno Scan data analysis showed that overexpression of HIF-3α correlated with a patient's lower survival rate and a poor prognosis in colon adenocarcinoma patients. Knockdown of HIF-3α expression was carried out to investigate the effects derived from its silencing on malignant phenotype. We found a significative decrease in the Hypoxia Response Element (HRE) reporter transcriptional activity mediated by HIF-3α and a reduction in cell viability under oxidative stress in colon cancer cells with HIF-3α knockdown compared with control HIF-3α expressing cells. In addition, HIF-3α silencing also produced an increase in apoptotic rate, decreased clonogenic capacity, altered autophagy flux, and modulated the canonical Wnt/β pathway in an isoform-dependent and cell context-dependent manner in colon cancer cells. Overall, these data show that transcriptional activity mediated by HI3-3α plays an essential role in promoting the malignant phenotype, cell survival, and resistance to cell death in CRC cells.
Structure-function relationships between the human bitter taste receptor TAS2R38 and propylthiouracil: An in-silico investigation.
Subramanian G, Ponnusamy V, Murugesan J … +5 more , Vedagiri H, Panneerselvan P, Vasanthakumar K, Krishnan V, Subramaniam S
IUBMB Life · 2025 Feb · PMID 39970077 · Publisher ↗
Taster categorisation uses bitter thiourea compounds like propylthiouracil (PROP) and phenylthiocarbamide (PTC), which are frequently associated with amino acid alterations at positions 49, 262 and 296 in human taste 2 r...
Taster categorisation uses bitter thiourea compounds like propylthiouracil (PROP) and phenylthiocarbamide (PTC), which are frequently associated with amino acid alterations at positions 49, 262 and 296 in human taste 2 receptor member 38 (hTAS2R38). Since the hTAS2R38 protein lacked a crystallographic structure, it was modelled using contact-guided iterative threading assembly refinement, its residues were mutated and refined, and the binding pocket area and volume were assessed using CASTp. Bitter thiourea molecules were docked using the ligand extra precision module and the receptor-ligand complex was manually positioned in a fully hydrated, equilibrated 1-palmitoyl-2-oleoylphosphatidylcholine bilayer using the CHARMM GUI membrane constructor, a 100 ns simulation was carried out using the Desmond program. Analysis revealed that the PROP binds to the allosteric hydrophobic pocket of hTAS2R38 and forms a hydrogen bond with ASN190. The native structure (hTAS2R38) has a higher glide energy (-24.164 kcal/mol) and docking score (-7.212 kcal/mol) than mutants, corroborating our taste preference study. In contrast, PTC lacks hydrogen bonds in the binding pocket but exhibits pi-pi stacking interactions with the native structure. Structures with mutations at the 49th or 296th position showed the largest root mean square deviations and fluctuations. A triple mutation increases surface area and volume, making the 262nd position critical to the binding pocket. These results highlight the functional roles of these three residues in hTAS2R38.
Correction to "Caffeic acid phenethyl ester synergistically enhances docetaxel and paclitaxel cytotoxicity in prostate cancer cells".
IUBMB Life · 2025 Feb · PMID 39967002 · Publisher ↗
Abstract loading — click title to view on PubMed.
Genomic landscaping of receptor tyrosine kinase ALK with highly frequent rearrangements in cancers.
Ye W, Ou WB
IUBMB Life · 2025 Feb · PMID 39917830 · Publisher ↗
Anaplastic lymphoma kinase (ALK) fusion tyrosine kinases (TKs) are commonly found in various cancers and are considered as promising targets for therapy due to their intricate biological processes. However, the reasons f...
Anaplastic lymphoma kinase (ALK) fusion tyrosine kinases (TKs) are commonly found in various cancers and are considered as promising targets for therapy due to their intricate biological processes. However, the reasons for the higher frequency of ALKs fusion compared to other TKs are not well elucidated. Physicochemical properties, secondary and tertiary structures, and phylogenetic trees, along with protein sequence alignments of receptor tyrosine kinases (RTKs) and ALK fused partner genes, were examined using the resources provided by the National Center for Biotechnology Information (NCBI) and the Catalogue of Somatic Mutations in Cancer (COSMIC). Sequence alignments were performed to identify common sequences between partner genes and search for common breakpoints within the COSMIC database. ALK is a large, unstable, acidic protein with similarly conservation among RTKs. ALK fusion partners are mostly acidic, unstable proteins, mostly consisting of α-helices and random coil. However, EML4 and NPM1 are the most frequently occurring partner genes and have their own unique structural characteristics. By functional domain analysis, we found that the functions of the first half of the ALK partner gene (the part fused to ALK) are mostly focused on signaling. ALK is identified as a large hydrophilic protein，exhibits a higher proportion of random coils. Compared to other RTKs, ALK has fewer structural domains (PTKC_ALK_LTK domain). Pairwise comparison with fusion partner genes revealed a conserved sequence predicted to have structural stability and act as a common binding site for nucleases. Exon 20 of ALK is a fusion frequent site according to COSMIC database analysis. The structural instability of ALK and partner genes, coupled with the inherent variability of breakpoint sequences, leads to the formation of potent kinase-activated oncogenes, which play a critical role in tumorigenesis. While the occurrence of ALK fusions with partner genes is random, specific combinations lead to the generation of oncogenes.
Possible new mechanisms of primary drug resistance in NSCLC with EGFR mutation treated with Osimertinib.
Shao L, Li T, Jia X … +3 more , Zhang X, Li Q, Dong C
IUBMB Life · 2025 Feb · PMID 39907312 · Full text
In this study, a patient with lung adenocarcinoma harboring an EGFR mutation exhibited primary resistance to the targeted EGFR inhibitor Osimertinib after 2 months of treatment. As the disease advanced, further genetic a...
In this study, a patient with lung adenocarcinoma harboring an EGFR mutation exhibited primary resistance to the targeted EGFR inhibitor Osimertinib after 2 months of treatment. As the disease advanced, further genetic analysis revealed the emergence of additional mutations in ARID1A, NTRK1, and ZRSR2, alongside the existing EGFR mutation. Subsequent treatment with Pemetrexed resulted in a significant reduction in liver metastases. Protein mass spectrometry sequencing and immunohistochemical analysis collectively indicated that the PI3K/mTOR pathway mediates the mechanism through which these gene mutations confer primary drug resistance. Evidence demonstrates that the co-occurrence of EGFR and ARID1A mutations diminishes the efficacy of EGFR tyrosine kinase inhibitors (EGFR TKIs). Consequently, it is hypothesized that mutations in NTRK1 and ZRSR2, which are implicated in the PI3K/mTOR pathway, contribute to the primary resistance observed with Osimertinib treatment. In this case, the illness was effectively managed through prompt adjustments to the treatment regimen and the rapid administration of chemotherapy drugs. This finding also constitutes the first evidence that mutations in NTRK1 and ZRSR2 are pivotal in the development of primary resistance to Osimertinib. Consequently, it is imperative to conduct genetic testing at the earliest opportunity and modify the treatment plan accordingly.
Zinc finger protein 169 promotes tumor progress of hepatocellular cancer via up-regulating cyclin-dependent kinase 19.
Hu C, Ainiwaer A, Lu Y … +10 more , Li J, Fu Y, Luo J, Wu B, Yin P, Hu X, Sun Y, Li H, Lu H, Dong Z
IUBMB Life · 2025 Jan · PMID 39868893 · Publisher ↗
Hepatocellular carcinoma (HCC) ranks among the most prevalent types of cancer globally. Zinc finger protein 169 (ZNF169) holds significant importance as a transcription factor, yet its precise function in HCC remains to...
Hepatocellular carcinoma (HCC) ranks among the most prevalent types of cancer globally. Zinc finger protein 169 (ZNF169) holds significant importance as a transcription factor, yet its precise function in HCC remains to be elucidated. This study aims to examine the clinical importance, biological functions, and molecular pathways associated with ZNF169 in the development of HCC. The study employed lentiviral transduction for ZNF169 overexpression and the use of small interfering RNAs (siRNAs) to suppress its expression. ZNF169 was upregulated in HCC tissues and cell lines. Additionally, HCC patients exhibiting elevated ZNF169 levels experienced reduced overall survival, shorter disease-free survival, and diminished progression-free survival. Silencing of ZNF169 inhibited cell proliferation, migration, and cell cycle progression. Whereas ectopic expression of ZNF169 promoted HCC progression in vivo and ex vivo. Subsequently, Pearson analysis results showed that cyclin-dependent kinase 19 (CDK19) was positively correlated with ZNF169 levels in HCC using TCGA dataset. Luciferase assay findings indicated a potential interaction between ZNF169 and CDK19 promoter. Additionally, our data showed that CDK19 expression levels were elevated in HCC tissues, and patients with higher CDK19 expression faced a poorer prognosis. Furthermore, recovery experiments demonstrated that CDK19 could reverse the impact of ZNF169 on HCC cell amplification. Our findings indicate that ZNF169 promotes HCC progression by upregulating CDK19, highlighting its role as a therapeutic target or prognostic biomarker for HCC.
Deciphering the senescence-based tumoral heterogeneity and characteristics in pancreatic cancer: Results from parallel bulk and single-cell transcriptome data.
Lu Y, Han S, Hu J … +7 more , Lv K, Ruan Y, Cheng G, Zhang J, Wu X, Weng Z, Zhou X
IUBMB Life · 2025 Jan · PMID 39865528 · Publisher ↗
The prevalent intra- and intertumoral heterogeneity results in undesirable prognosis and therapy failure of pancreatic cancer, potentially resulting from cellular senescence. Herein, integrated analysis of bulk and singl...
The prevalent intra- and intertumoral heterogeneity results in undesirable prognosis and therapy failure of pancreatic cancer, potentially resulting from cellular senescence. Herein, integrated analysis of bulk and single-cell RNA-seq profiling was conducted to characterize senescence-based heterogeneity in pancreatic cancer. Publicly available bulk and single-cell RNA sequencing from pancreatic cancer patients were gathered from TCGA-PAAD, PACA-AU, PACA-CA, and GSE154778 datasets. The activity of three senescence-related pathways (cell cycle, DNA repair, and inflammation) was scored utilizing ssGSEA algorithm. A series of functional verifications of crucial genes were accomplished in patient tissue and pancreatic cancer cells. Based upon them, unsupervised clustering analysis was executed to classify pancreatic cancer samples into distinct senescence-based clusters at the bulk and single-cell levels. For single-cell transcriptome profiling, cell clustering and annotation were implemented, and malignant cells were recognized utilizing infercnv algorithm. Two senescence-based clusters were established and highly reproducible at the bulk level, with the heterogeneity in prognosis, clinicopathological features, genomic CNVs, oncogenic pathway activity, immune microenvironment and immune checkpoints. Senescence-relevant gene CHGA, UBE2C and MCM10 were proved to correlate with the migration and prognosis of pancreatic cancer. At the single-cell level, seven cell types were annotated, comprising ductal cells 1, ductal cells 2, fibroblasts, macrophages, T cells, stellate cells, and endothelial cells. The senescence-based classification was also proven at the single-cell level. Ductal cells were classified as malignant cells and non-malignant cells. In the tumor microenvironment of malignant cells, hypoxia and angiogenesis affected senescent phenotype. The heterogeneity in senescence was also observed between and within cell types. Altogether, our findings unveil that cellular senescence contributes to intra- and intertumoral heterogeneity in pancreatic cancer, which might facilitate the development of therapeutics and precision therapy in pancreatic cancer.
CDKN3 as a key regulator of G2M phase in triple-negative breast cancer: Insights from multi-transcriptomic analysis.
Ma H, Dong Y, Zheng J … +11 more , Zhang S, Tang S, Wang J, Qu Z, Li X, Zeng L, Song K, Liu C, Shi L, Yin Q, Zheng X
IUBMB Life · 2025 Jan · PMID 39865508 · Publisher ↗
Triple-negative breast cancer (TNBC) remains a significant global health challenge, emphasizing the need for precise identification of patients with specific therapeutic targets and those at high risk of metastasis. This...
Triple-negative breast cancer (TNBC) remains a significant global health challenge, emphasizing the need for precise identification of patients with specific therapeutic targets and those at high risk of metastasis. This study aimed to identify novel therapeutic targets for personalized treatment of TNBC patients by elucidating their roles in cell cycle regulation. Using weighted gene co-expression network analysis (WGCNA), we identified 83 hub genes by integrating gene expression profiles with clinical pathological grades. A machine learning-based integrative approach further pinpointed 12 prognostic genes, among which CDKN3 exhibited the highest hazard ratio and the most adverse impact on overall survival (OS) in BC patients. Additionally, CDKN3 was identified as an independent prognostic factor for OS prediction. CDKN3 overexpression was confirmed in BC patients and validated at both mRNA and protein levels in BC cells. Knockdown of CDKN3 significantly inhibited the migration and proliferation of BC cells. Cell cycle pathway analysis revealed significant enrichment in G2M-associated pathways in BC patients, with multi-transcriptomic data indicating a close association between enhanced G2M cell cycle activity and CDKN3 upregulation in basal cancer subtypes. Pseudotime analysis further suggested CDKN3 upregulation during the G2M phase at the terminal trajectory of basal cancer subtypes, implying that CDKN3 may drive BC cell progression by promoting G2M cell cycle activity. Mechanistically, CDKN3 knockdown induced G2M cell cycle arrest in TNBC cells by downregulating CCNB2. In conclusion, CDKN3 knockdown effectively inhibits TNBC by arresting the G2M cell cycle, underscoring CDKN3 as a promising therapeutic target in TNBC treatment.
The up-regulation of RIPK3 mediated by ac4C modification promotes oxidative stress-induced granulosa cell senescence by inhibiting the Nrf2/HO-1 pathway.
Zhang W, Zhang J, Zhang Y … +4 more , Zhai J, Sun B, Guo Y, Wang F
IUBMB Life · 2025 Jan · PMID 39865380 · Publisher ↗
Abnormality of granulosa cells (GCs) is the critical cause of follicular atresia in premature ovarian failure (POF). RIPK3 is highly expressed in GCs derived from atretic follicles. We focus on uncovering how RIPK3 contr...
Abnormality of granulosa cells (GCs) is the critical cause of follicular atresia in premature ovarian failure (POF). RIPK3 is highly expressed in GCs derived from atretic follicles. We focus on uncovering how RIPK3 contributes to ovarian GC senescence. Primary GCs were treated with H₂O₂ to induce senescence. ROS was detected via DCFH-DA staining. Levels of senescence-related molecules and SA-β-Gal activity were examined. Cyclophosphamide was administered to mice to induce POF. The impact of RIPK3 on atretic follicles and sex hormones was evaluated through HE staining and ELISA, respectively. The acRIP-qPCR analysis of RIPK3 ac4C levels, RIP detection for interaction between RIPK3 and NAT10, and actinomycin D treatment to detect RIPK3 degradation were conducted. In HO-treated GCs and POF mouse ovaries, levels of RIPK3, ROS, senescence-related molecules, as well as SA-β-Gal activity, were all up-regulated, and this effect was suppressed by RIPK3 inhibition. RIPK3 interference reduced atretic follicles and FSH levels while increasing AMH and E2 levels. Nrf2 and HO-1 content were diminished in the models, whereas si-RIPK3 facilitated their expression. The effect of si-RIPK3 on decreased levels of ROS and senescence-related molecules was reversed by ML385. HO decreased RIPK3 mRNA degradation and increased its ac4C modification. The ac4C modifying enzyme NAT10 was up-regulated in the models, and NAT10 enhanced RIPK3 mRNA stability through ac4C modification. NAT10 knockdown mitigated ovarian GC senescence by inhibiting RIPK3 expression. The promotion of RIPK3 mRNA stability through ac4C modification by NAT10, in turn, affects the Nrf2/HO-1 pathway and promotes ovarian GC senescence.
CRYAB is upregulated and predicts clinical prognosis in kidney renal clear cell carcinoma.
Ren H, Chen X, Ji M … +3 more , Song W, Cao L, Guo X
IUBMB Life · 2025 Jan · PMID 39854102 · Publisher ↗
Clear cell renal cell carcinoma (KIRC) is the most prevalent subtype of renal cell carcinoma (RCC), accounting for 70% to 80% of all RCC cases. The CRYAB (αB-crystallin) gene is broadly expressed across various human tis...
Clear cell renal cell carcinoma (KIRC) is the most prevalent subtype of renal cell carcinoma (RCC), accounting for 70% to 80% of all RCC cases. The CRYAB (αB-crystallin) gene is broadly expressed across various human tissues, yet its role in KIRC progression remains unclear. This study aims to elucidate the function of CRYAB in KIRC progression and to assess its potential as a biomarker for early diagnosis, therapeutic targeting, and prognosis. In our report, we found that CRYAB was dramatically upregulated in KIRC, and its expression was associated with TNM stage, pathological stage, and age. Also, patients with higher CRYAB expression exhibited poor survival and prognosis. CRYAB overexpression led to enhanced tumor cell proliferation. Vice versa, CRYAB downregulation resulted in decreased cell proliferation in vitro. Mechanistically, Gene set enrichment analysis plots showed the enrichment of cell survival. Consistently, these effects were associated with increased AKT signaling and BCL-2 expression. Furthermore, we also observed that CRYAB expression levels were negatively correlated with immunocyte infiltration. In conclusion, these findings suggested that CRYAB could be regarded as a latent biomarker for early diagnosis, therapeutic targeting, and prognosis.
Tinagl1 restores tamoxifen sensitivity and blocks fibronectin-induced EMT by simultaneously blocking the EGFR and β1-integrin/FAK signaling pathways in tamoxifen-resistant breast cancer cells.
Yuan J, Yuan L, Yang L … +7 more , Chinnathambi A, Alharbi SA, Huang J, Wang B, Zhang S, Wei C, Luo C
IUBMB Life · 2025 Jan · PMID 39817673 · Publisher ↗
Tamoxifen (TAM) is employed to treat premenopausal ER-positive breast cancer patients, but TAM resistance is the main reason affecting its efficacy. Thus, addressing TAM resistance is crucial for improving therapeutic ou...
Tamoxifen (TAM) is employed to treat premenopausal ER-positive breast cancer patients, but TAM resistance is the main reason affecting its efficacy. Thus, addressing TAM resistance is crucial for improving therapeutic outcomes. This study explored the potential role of Tinagl1, a secreted extracellular matrix protein, whose expression is compromised in TAM-resistant MCF-7 breast cancer cells (MCF-7R). We discovered that Tinagl1 plays a pivotal role in countering TAM resistance by inhibiting the EGFR and β1-integrin/focal adhesion kinase (FAK) signaling pathways, both of which are abnormally activated in MCF-7R cells and contribute to the resistance mechanism. Our data showed that the expression level of Tinagl1 in MCF-7R cells was lower compared to their wild-type counterparts, and TAM could further reduce Tinagl1 expression in MCF-7R cells, which was consistent with our microarray results. Moreover, Tinagl1 could restore the sensitivity of MCF-7R cells to TAM and inhibit the motility of MCF-7R cells by regulating epithelial-mesenchymal transition (EMT) in vitro and in vivo experiments. In addition, the level of Tinagl1 in TAM-resistant breast cancer samples was significantly lower than that in their matched primary tumors. Analysis of an online database further indicated that high Tinagl1 expression correlates with better recurrence-free survival (RFS), particularly in patients with ER-positive, HER2-negative breast cancer. Overall, this study positions Tinagl1 not only as a potential prognostic marker but also as a promising therapeutic target.
APOC1 inhibit NKTCL doxorubicin sensitivity by promoting mitophagy.
Xiao S, Kuang J, Yang J … +10 more , Wang H, Sun Y, Zhang H, Zhang Z, Shi M, Qi K, Jiang M, Zhang Y, Chen Q, Zhang X
IUBMB Life · 2025 Jan · PMID 39817465 · Publisher ↗
NKTCL is a highly aggressive malignant tumor, especially prevalent in the southern regions of China. Although chemotherapy regimens based on ADM have achieved certain therapeutic effects in early treatment, the issue of...
NKTCL is a highly aggressive malignant tumor, especially prevalent in the southern regions of China. Although chemotherapy regimens based on ADM have achieved certain therapeutic effects in early treatment, the issue of ADM resistance severely limits the therapeutic efficacy and makes it difficult to improve patient survival rates. Our research results indicate that the expression level of APOC1 is closely related to the sensitivity of NKTCL cells to ADM. The upregulation of APOC1 may promote mitophagy, clear damaged mitochondria, stabilize the intracellular environment, and enhance the tolerance of tumor cells to ADM. Furthermore, APOC1 may further affect the formation of mitophagy and drug resistance by activating specific signaling pathways, such as the STAT3 signaling pathway. Animal experiments further confirm the conclusions of in vitro experiments, showing that APOC1 regulates mitophagy through p-STAT3, thereby promoting the drug resistance of NKTCL. These findings provide a new perspective for the development of novel therapeutic strategies targeting APOC1 and its associated signaling pathways, which may help overcome the issue of ADM resistance in NKTCL.
Overexpression of RGPR-p117 reveals anticancer effects by regulating multiple signaling pathways in bone metastatic human breast cancer MDA-MB-231 cells.
Yamaguchi M, Murata T, Shimokawa N
IUBMB Life · 2025 Jan · PMID 39780531 · Publisher ↗
The role of RGPR-p117, a transcription factor, which binds to the TTGGC motif in the promoter region of the regucalcin gene, in cell regulation remains to be investigated. This study elucidated whether RGPR-p117 regulate...
The role of RGPR-p117, a transcription factor, which binds to the TTGGC motif in the promoter region of the regucalcin gene, in cell regulation remains to be investigated. This study elucidated whether RGPR-p117 regulates the activity of triple-negative human breast cancer MDA-MB-231 cells in vitro. The wild-type and RGPR-p117-overexpressing cancer cells were cultured in DMEM supplemented with fetal bovine serum. RGPR-p117 overexpression suppressed colony formation and growth of cancer cells. Stimulatory effects of epidermal growth factor on cell growth were blocked by RGPR-p117 overexpression. Wild-type cell proliferation was repressed by cell cycle and intracellular signaling inhibitors. These effects were not potentiated in transfectants. Overexpressed RGPR-p117 protected cancer cells against apoptosis inducers. Mechanistic results showed that RGPR-p117 overexpression decreased the expression of Ras, PI3-kinase, Akt, mitogen-activated protein kinase, and mTOR, which are involved in cell growth, while it elevated the levels of the cancer cell suppressor p53, Rb, p21, and regucalcin. Overexpression of RGPR-p117 suppressed cancer cell migration and adhesion. Interestingly, osteoblastic MC3T3-E1 cells or macrophage RAW264.7 cells involved in the bone microenvironment were impaired by coculture with MDA-MB-231 cells. The effects of cancer cells were blocked by transfection. Coculture with conditioned medium obtained from breast cancer cells repressed proliferation and enhanced the death of osteoblastic cells and macrophages. A TNF-α signaling inhibitor blocked these effects. Thus, overexpressed RGPR-p117 was found to suppress the activity of breast cancer cells by regulating various signaling processes, providing new insight into cellular signaling regulation.
RETRACTION: Amp-Kinase Inhibitor Dorsomorphin Reduces the Proliferation and Migration Behavior of Colorectal Cancer Cells by Targeting the Akt/mTOR Pathway.
IUBMB Life · 2025 Jan · PMID 39757774 · Publisher ↗
Abstract loading — click title to view on PubMed.
Simultaneous blockade of the CD73/EGFR axis inhibits tumor growth.
Ardeshiri K, Hassannia H, Ghalamfarsa G … +2 more , Jafary H, Jadidi F
IUBMB Life · 2025 Jan · PMID 39745208 · Publisher ↗
Targeting the influencing factors in tumor growth and expansion in the tumor microenvironment is one of the key approaches to cancer immunotherapy. Various factors in the tumor microenvironment can in cooperation stimula...
Targeting the influencing factors in tumor growth and expansion in the tumor microenvironment is one of the key approaches to cancer immunotherapy. Various factors in the tumor microenvironment can in cooperation stimulate tumor growth, suppress anti-tumor immune responses, promote drug resistance, and ultimately enhance tumor recurrence. Therefore, due to the dependence and close cooperation of these axes, their combined targeting can have a greater effect compared to their individual targeting. Among the important factors affecting tumor growth in the tumor region, CD73 and EGFR play an important role in tumor growth by stimulating each other's expression and function. Therefore, we intended to use the nanocarriers that we had previously produced and characterized to deliver anti-CD73 and EGFR siRNAs to murine breast cancer 4T1 cells. Silencing CD73 and EGFR could significantly induce cell death in cancer cells. Downregulation of the CD73/EGFR axis also suppressed the migratory and proliferative potential of cancer cells. This therapeutic strategy also inhibited tumor growth in in ovo model. These findings imply that simultaneous targeting of CD73 and EGFR in breast cancer can be considered a novel immunotherapeutic approach that needs further investigation in future studies.
The therapeutic effects of induced pluripotent stem cell-derived mesenchymal stem cells on Parkinson's disease.
Ren H, Wang Y, Chen Y … +6 more , Ma F, Shi Q, Wang Z, Gui Y, Liu J, Tang H
IUBMB Life · 2025 Jan · PMID 39740935 · Publisher ↗
Parkinson's disease (PD), characterized by progressive degeneration of dopaminergic neurons in substantia nigra, has no disease-modifying therapy. Mesenchymal stem cell (MSC) therapy has shown great promise as a disease-...
Parkinson's disease (PD), characterized by progressive degeneration of dopaminergic neurons in substantia nigra, has no disease-modifying therapy. Mesenchymal stem cell (MSC) therapy has shown great promise as a disease-modifying solution for PD. Induced pluripotent stem cell-derived MSC (iMSC) not only has stronger neural repair function, but also helps solve the problem of MSC heterogeneity. So we evaluated the therapeutic effects of iMSCs on PD. iMSCs were administered by tail vein in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced PD models of C57BL/6 mice. The results showed iMSCs increased body weights, inhibited the prolongation of latencies to descend in pole tests, the decrease of grip strength in grip strength tests and increase of open arm entries in elevated plus maze test, and showed a trend to alleviate striatal dopamine loss. They indicate iMSCs might improve functions partially by preserving striatal dopamine in PD. We for the first time (1) found that iMSC has therapeutic effects on PD; (2) tested specifically muscle strength in cell therapy for PD and found it increases muscle strength; (3) found cell therapy alleviated the increase of entries into the open arms in PD. It suggests iMSC is a promising candidate for clinical investigations and drug development for PD.
Keratinocyte exosomal LOC285194 ameliorates psoriasis by inhibiting the differentiation of CD4T cells to Th17 cells through regulating miR-211-5p/SIRT1 axis.
Lin J, Cao Y, Ma L … +2 more , Tao M, Yang X
IUBMB Life · 2025 Jan · PMID 39736106 · Publisher ↗
Keratinocytes exosome participates in the pathogenesis of psoriasis and exosomes always carry long non-coding RNAs (lncRNAs) into target cells to function as an essential immune regulator in psoriasis-related diseases. L...
Keratinocytes exosome participates in the pathogenesis of psoriasis and exosomes always carry long non-coding RNAs (lncRNAs) into target cells to function as an essential immune regulator in psoriasis-related diseases. LncRNA LOC285194 is closely associated with the occurrence of psoriasis. However, whether keratinocyte exosomal LOC285194 participates in the process of psoriasis remains vague. Exosomes were authenticated by transmission electron microscope and nanoparticle tracking analysis (NTA). Relative gene expression was determined by reverse transcription-polymerase chain reaction (RT-PCR). Flow cytometry was used to monitor the proportion of immune cells. Fluorescence in situ hybridization was employed to determine the colocalization of lncRNA and miRNA. Keratinocyte exosomal LOC285194 was reduced in psoriasis patients and had a negative association with Th17 cell infiltration in psoriasis patients. LOC285194-downregulation contributed to the differentiation of CD4T cells to Th17 cells. Cytokine cocktail treatment reduced LOC285194 expression in keratinocytes and keratinocyte exosome, subsequently promoted the differentiation of CD4T cells to Th17 cells and Th17 cells-related molecular levels including IL-17A, IL-22 and TNF-α, which were notably abrogated by LOC285194-upregulation in keratinocytes. As a sponge of LOC285194, miR-211-5p inhibition induced the increase of Th17 cell proportion in CD4T cells, while exosomes treatment isolated from cytokine cocktail-exposed keratinocytes further enhanced Th17 cell proportion, which were abolished by LOC285194 overexpressed-exosome treatment. Furthermore, silent information regulator 1 (SIRT1) mediated the regulation role of miR-211-5p on Th17 cell production. Combined with the imiquimod-induced psoriasis animal model, exosomes isolated from LOC285194-overexpressing keratinocytes relieved psoriasis symptom through regulating miR-211-5p/SIRT1 axis. LOC285194 upregulation in keratinocytes promoted the keratinocyte exosomal LOC285194, that could be absorbed by CD4T cells, leading to the inhibition of Th17 cell differentiation through targeting miR-211-5p/SIRT1 axis. This study provides a novel molecular mechanism of Th17 cell accumulation-mediated psoriasis.
Ketorolac disturbs proteasome functions and induces mitochondrial abnormality-associated apoptosis.
Kumar P, Kinger S, Dubey AR … +8 more , Jagtap YA, Choudhary A, Karmakar S, Lal G, Kumar A, Bhattacharyya S, Poluri KM, Mishra A
IUBMB Life · 2025 Jan · PMID 39723629 · Publisher ↗
Non-steroidal anti-inflammatory drugs (NSAIDs) are recommended to treat moderate-to-severe pain. Previous studies suggest that NSAIDs can suppress cellular proliferation and elevate apoptosis in different cancer cells. K...
Non-steroidal anti-inflammatory drugs (NSAIDs) are recommended to treat moderate-to-severe pain. Previous studies suggest that NSAIDs can suppress cellular proliferation and elevate apoptosis in different cancer cells. Ketorolac is an NSAID and can reduce the cancer cells' viability. However, molecular mechanisms by which Ketorolac can induce apoptosis and be helpful as an anti-tumor agent against carcinogenesis are unclear. Here, we observed treatment with Ketorolac disturbs proteasome functions, which induces aggregation of aberrant ubiquitinated proteins. Ketorolac exposure also induced the aggregation of expanded polyglutamine proteins, results cellular proteostasis disturbance. We found that the treatment of Ketorolac aggravates the accumulation of various cell cycle-linked proteins, which results in pro-apoptotic induction in cells. Ketorolac-mediated proteasome disturbance leads to mitochondrial abnormalities. Finally, we have observed that Ketorolac treatment depolarized mitochondrial membrane potential, released cytochrome c into cytoplasm, and induced apoptosis in cells, which could be due to proteasome functional depletion. Perhaps more in-depth research is required to understand the details of NSAID-based anti-proliferative molecular mechanisms that can elevate apoptosis in cancer cells and generate anti-tumor potential with the combination of putative cancer drugs.
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