The discovery of early diagnosis and prognostic markers for breast cancer can significantly improve survival and reduce mortality. LSM1 is known to be involved in the general process of mRNA ...degradation in complexes containing LSm subunits, but the molecular and biological functions in breast cancer remain unclear. Here, the expression of LSM1 mRNA in breast cancer was estimated using The Cancer Genome Atlas (TCGA), Oncomine, TIMER and bc‐GenExMiner databases. We found that functional LSM1 inactivation caused by mutations and profound deletions predicted poor prognosis in breast cancer (BRCA) patients. LSM1 was highly expressed in both BRCA tissues and cells compared to normal breast tissues/cells. High LSM1 expression is associated with poorer overall survival and disease‐free survival. The association between LSM1 and immune infiltration of breast cancer was assessed by TIMER and CIBERSORT algorithms. LSM1 showed a strong correlation with various immune marker sets. Most importantly, pharmacogenetic analysis of BRCA cell lines revealed that LSM1 inactivation was associated with increased sensitivity to refametinib and trametinib. However, both drugs could mimic the effects of LSM1 inhibition and their drug sensitivity was associated with MEK molecules. Therefore, we investigated the clinical application of LSM1 to provide a basis for sensitive diagnosis, prognosis and targeted treatment of breast cancer.
A novel cancer gene MB21D2, a known intracellular cadherin binder, was found to harbor Q311E recurrent mutation and to be overexpressed in head and neck cancer (HNSCC). Wild‐type MB21D2 and its ...mutant form mediate pro‐oncogenic activities and promote EMT. Blockage of RAS could be used as a strategy for treating cancer with MB21D2 overexpression or mutation, particularly for tumors resistant to DNA‐damaging drugs.
Cadherin‐mediated cell–cell contacts regulated by intracellular binders play critical roles in tissue homeostasis and tumorigenesis. Here, we screened mutational profiles of 312 annotated genes involved in cadherin binding in human squamous cell carcinomas and found MB21D2 to carry a unique recurrent Q311E mutation. MB21D2 overexpression was also frequently found in head and neck cancer (HNSCC) and was associated with poor clinical outcomes. Cell‐based characterizations revealed pro‐oncogenic roles for MB21D2 wild‐type (WT) and its Q311E mutant (Q311E) in cell proliferation, colony formation, sphere growth, and migration/invasion by promoting epithelial–mesenchymal transition. Conversely, MB21D2 knockdown in MB21D2‐overexpressing cells resulted in cell growth arrest and apoptosis. Xenograft tumor models with Q311E‐expressing cells formed larger and more aggressive lesions, compared to models with WT‐MB21D2‐expressing cells or an empty vector. Transcriptome and protein interactome analyses revealed enrichment of KRAS signaling by MB21D2 expression. Immunoblotting confirmed RAS elevation, along with upregulation/phosphorylation of PI3K, AKT, and CREB. Blocking RAS signaling in MB21D2‐expressing cells by manumycin significantly reduced cell growth and survival. Our study thus defined RAS signaling‐dependent pro‐oncogenic roles for MB21D2 overexpression and Q311E MB21D2 expression in HNSCC development.
Transcription factor high‐mobility group box‐containing protein 1 (HBP1) may function as a tumor suppressor in various types of cancer. In a previous study, we demonstrated that HBP1 suppressed cell ...invasion in oral cancer. To further understand the underlying mechanism, the current study is aimed at investigating how HBP1 exerts its antimetastatic potential in oral cancer. In a cell model, ectopic expression of HBP1 potently suppressed epithelial–mesenchymal transition, cellular migration, and invasion; conversely, HBP1 knockdown promoted these malignant phenotypes. The matrix metalloproteinase (MMP) family is highly implicated in tumor metastasis. Therefore, we examined the effect of HBP1 on the activation of the MMP members, MMP‐2, ‐9, and ‐13 that are highly associated with the aggressiveness of oral cancer. Ectopic expression of HBP1 resulted in a mild reduction in the expression and activity of MMP‐2 and ‐9, yet it had a potent inhibitory effect on MMP‐13. In contrast, HBP1 knockdown strongly enhanced the activation of MMP‐13. Further, we demonstrated that MMP‐13 is a target of HBP1 transcription repression as evidenced by the identification of an HBP1 binding site in the cis proximal region of the MMP‐13 promoter. More important, MMP‐13 knockdown significantly alleviated HBP1 small interfering RNA‐mediated promotion in cell invasion. Analysis of oral tumor specimens revealed that the low HBP1 (<0.3‐fold)/high MMP‐13 (>3‐fold) status was associated with metastatic potential. All told, our study provides evidence supporting the idea that the HBP1–MMP‐13 axis is a key regulator of the aggressiveness in oral cancer.
We demonstrated here that matrix metalloproteinase‐13 (MMP‐13) is a target of high‐mobility group box‐containing protein 1 (HBP1) transcription repression as evidenced by the identification of an HBP1 binding site in the cis proximal region of the MMP‐13 promoter. More important, MMP‐13 knockdown significantly alleviated HBP1 small interfering RNA‐mediated promotion in cell invasion. All told, our study provides evidence supporting the idea that the HBP1–MMP‐13 axis is a key regulator of the aggressiveness in oral cancer.
The bioflavonoid apigenin has been shown to possess cancer-preventive and anti-cancer activities. In a drug screening, we found that apigenin can inhibit Wnt/β-catenin signaling, a pathway that ...participates in pivotal biological functions, which dis-regulation results in various human diseases including cancers. However, the underlying mechanism of apigenin in this pathway and its link to anti-cancer activities remain largely unknown. Here we showed that apigenin reduced the amount of total, cytoplasmic, and nuclear β-catenin, leading to the suppression in the β-catenin/TCF-mediated transcriptional activity, the expression of Wnt target genes, and cell proliferation of Wnt-stimulated P19 cells and Wnt-driven colorectal cancer cells. Western blotting and immunofluorescent staining analyses further revealed that apigenin could induce autophagy-mediated down-regulation of β-catenin in treated cells. Treatment with autophagy inhibitors wortmannin and chloroquine compromised this effect, substantiating the involvement of autophagy-lysosomal system on the degradation of β-catenin during Wnt signaling through inhibition of the AKT/mTOR signaling pathway. Our data not only pointed out a route for the inhibition of canonical Wnt signaling through the induction of autophagy-lysosomal degradation of key player β-catenin, but also suggested that apigenin or other treatments which can initiate this degradation event are potentially used for the therapy of Wnt-related diseases including cancers.
HOTAIR is a well-known long non-coding RNA (lncRNA) involved in various cellular signaling, whereas its functional impacts on endometriosis development are still largely unknown. To this end, six ...potential functional single nucleotide polymorphisms (SNPs) in HOTAIR, with minor allele frequencies more than 10% in Han population and altered net energy of RNA structures larger than 0.5 kcal/mol, were selected for genotyping study. The study included 207 endometriosis patients and 200 healthy women. Genetic substitutions at rs1838169 and rs17720428 were frequently found in endometriosis patients, and rs1838169 showed statistical significance (p = 0.0174). The G-G (rs1838169-rs17720428) haplotype showed the most significant association with endometriosis (p < 0.0001) with enhanced HOTAIR stability, and patients who harbor such haplotype tended to show higher CA125. Data mining further revealed higher mRNA HOTAIR levels in the endometria of patients with severe endometriosis which consistently showed reduced HOXD10 and HOXA5 levels. HOTAIR knockdown with specific shRNAs down-regulated cell proliferation and migration with the induction of HOXD10 and HOXA5 expression in human ovarian clear cancer cells. Our study therefore provided evidence to indicate a prominent role of HOTAIR in promoting endometriosis, which could be used as a potential target for clinical applications.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
LSM1 is part of the cytoplasmic protein complex Lsm1-7-Pat1 and is likely involved in pre-mRNA degradation by aiding U4/U6 snRNP formation. More research is needed to uncover LSM1's potential in ...breast cancer (BRCA) clinical pathology, the tumor immune microenvironment, and precision oncology. We discovered LSM1 as a diagnostic marker for advanced BRCA with poor survival, using a multi-omics approach. We studied LSM1 expression across BRCA regions and its link to immune cells through various methods, including spatial transcriptomics and single-cell RNA-sequencing. We also examined how silencing LSM1 affects mitochondrial function and energy metabolism in the tumor environment. These findings were confirmed using 54 BRCA patient biopsies and tissue microarrays. Immunofluorescence and bioinformatics assessed LSM1's connection to clinicopathological features and prognosis. This study uncovers gene patterns linked to breast cancer, with LSM1 linked to macrophage energy processes. Silencing LSM1 in breast cancer cells disrupts mitochondria and energy metabolism. Spatial analysis aligns with previous results, showing LSM1's connection to macrophages. Biopsies confirm LSM1 elevation in advanced breast cancer with increased macrophage presence. To summarize, LSM1 changes may drive BRCA progression, making it a potential diagnostic and prognostic marker. It also influences energy metabolism and the tumor's immune environment during metastasis, showing promise for precision medicine and drug screening in BRCA.
Background
Epidermal growth factor receptor (EGFR) is often hyperactivated in head and neck squamous cell carcinoma (HNSCC); however, its downstream mediators are not fully identified. Here, we ...investigate the role of transcription factor HBP1 in the anticancer efficacy of EGFR inhibitor erlotinib in HNSCC.
Methods
The effect of erlotinib and HBP1 on cell proliferation and invasion was examined by flow cytometric analysis and a Matrigel invasion assay, respectively. Oral tumor specimens were used to evaluate the association between the expression level of EGFR and HBP1, and metastatic potential.
Results
Erlotinib caused cell growth arrest in the G1 phase and sluggish invasion with a concomitant increase in HBP1 and p27 expression. The erlotinib effect was attenuated upon HBP1 knockdown. Analysis of oral tumor specimens revealed that the low HBP1/high EGFR status can predict metastatic potential.
Conclusions
Our data support HBP1 as a crucial mediator of EGFR‐targeting inhibitors in HNSCC.
The decline in oocyte quality with age is an irreversible process that results in low fertility. Reproductive aging causes an increase in oocyte aneuploidy leading to a decrease in embryo quality and ...an increase in the incidence of miscarriage and congenital defects. Here, we show that the dysfunction associated with aging is not limited to the oocyte, as oocyte granulosa cells also show a range of defects related to mitochondrial activity. The addition of Y-27632 and Vitamin C combination drugs to aging germ cells was effective in enhancing the quality of aging cells. We observed that supplement treatment significantly decreased the production of reactive oxygen species (ROS) and restored the balance of mitochondrial membrane potential. Supplementation treatment reduces excessive mitochondrial fragmentation in aging cells by upregulating mitochondrial fusion. Moreover, it regulated the energy metabolism within cells, favoring oxygen respiration and reducing anaerobic respiration, thereby increasing cellular ATP production. In an experiment with aged mice, supplement treatment improved the maturation of oocytes in vitro and prevented the buildup of ROS in aging oocytes in culture. Additionally, this treatment resulted in an increased concentration of anti-mullerian hormone (AMH) in the culture medium. By improving mitochondrial metabolism in aging females, supplement treatment has the potential to increase quality of oocytes during in vitro fertilization.
•Y-27632/Vitamin C ameliorates ROS-induced mitochondrial dynamic imbalance.•Supplements regulates reprogramming of energy metabolism.•Supplements improves cellular oxygen consumption rate.
Endometriosis is a hormone-associated disease which has been considered as the precursor for certain types of ovarian cancer. In recent years, emerging evidence demonstrated potent roles of lncRNA in ...regulating cancer development. Since endometriosis shares several features with cancer, we investigated the possible involvement of cancer-related lncRNAs in endometriosis, including UCA1, GAS5 and PTENP1. By using massARRAY system, we investigated certain genetic variations in cancer-related lncRNAs that can change the thermo-stability, leading to up-regulation or down-regulation of those lncRNAs. Our data indicated three risk genetic haplotypes in UCA1 which can stabilize the RNA structure and increase the susceptibility of endometriosis. Of note, such alterations were found to be associated with long-term pain and infertility in patients. It has been known that UCA1 can function as a ceRNA to sponge and inhibit miRNAs, resulting in loss-of-control on downstream target genes. Gene network analyses revealed fatty acid metabolism and mitochondria beta-oxidation as the major pathways associated with altered UCA1 expression in endometriosis patients. Our study thus provides evidence to highlight functional/epigenetic roles of UCA1 in endometriosis development via regulating fatty acid metabolism in women.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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