Molecular and Cellular Biochemistry最新文献

Bladder cancer (BC) is one of the top ten most common tumors, with recurrence and metastasis being major causes of mortality among patients. A high recurrence rate is a hallmark of BC. Epithelial-mesenchymal transition (EMT) plays a role in the formation of cancer stem cells, tumor metastasis, and immune evasion. In our preliminary research, single-cell sequencing identified TCF7 as a gene associated with EMT. However, its biological function and transcriptional regulation mechanisms in BC remain unclear. This study aims to investigate TCF7's role and regulatory mechanisms in BC progression. TCF7 is a critical transcription factor promoting BC progression. High TCF7 expression in BC is significantly linked to poor patient prognosis. We uncovered a novel mechanism by which TCF7 drives EMT and stemness in BC through transcriptional regulation of TGFBR1, impacting the TGF-β/SMAD3 pathway. These findings enhance our understanding of BC progression and offer potential strategies for diagnosis, treatment, and prognosis.

The lymphocyte adaptor protein LNK is predominantly found in endothelial and hematopoietic cells and is linked to cardiovascular and autoimmune diseases. LNK functions as a negative regulator of cytokine signaling and cell proliferation, but its impact on hypertensive vascular smooth muscle cells (HVSMC) remains unclear. This study aimed to explore the influence of LNK on HVSMC function. To achieve this, vascular smooth muscle cells (VSMCs) from rat thoracic aorta were isolated and identified using immunofluorescence. A hypertensive cell model was established by treatment with angiotensin-II, confirmed through the MTT method. Lentivirus was utilized to create stable silencing and overexpression of the LNK gene. Flow cytometry assessed VSMC cycle, proliferation, and migration levels, while ELISA measured IL-6, TNF-α, and IFN-γ expression levels. Real-time quantitative PCR and western blot were employed to analyze LNK, STAT3, JAK1, JAK2, JAK3 mRNA, and protein expression in rat VSMC. Immunofluorescence results indicated that most VSMCs expressed vimentin, with a proliferation rate of 48.5% in VSMCs treated with 100 nM angiotensin-II, confirming successful isolation and model construction of HVSMC. Compared to the control group, the angiotensin-II group exhibited increased HVSMCs in S and G2/M-phases of the cell cycle, decreased in G0/G1 phases, higher proliferation and migration capacity, and elevated inflammation levels. Additionally, JAK1, JAK2, and STAT3 signaling pathway-related mRNA and protein expression were significantly elevated. These effects were further intensified by the combined action of angiotensin-II and LNK silencing virus. Conversely, these effects were notably reduced when angiotensin-II was combined with the LNK overexpressing virus. These findings suggest that LNK mitigates the impact of hypertension and inflammation by inhibiting the proliferation, migration, and JAK-STAT signaling pathway of HVSMCs.

Irisin, an exercise-induced myokine, exhibits elevated levels during physical activity, yet its role in modulating the unfolded protein response (UPR) remains poorly understood. This comprehensive review pioneers an in-depth examination of irisin-mediated endoplasmic reticulum (ER) stress mitigation across various diseases. We provide a nuanced characterization of irisin's molecular profile, biological activity, and significance as a skeletal muscle-derived cytokine analogue. Our discussion elucidates the complex interplay between exercise, irisin signalling, and metabolic outcomes, highlighting key molecular interactions driving salutary effects. Moreover, we delineate the UPR's role as a critical ER stress countermeasure and underscore irisin's pivotal function in alleviating this stress, revealing potential therapeutic avenues for disease management. Exercise-induced release of irisin ameliorates ER stress through AMPK phosphorylation during various diseases (Icon image source: www.flaticon.com ).

Prostate cancer (PCa) is the most common non-cutaneous malignancy and the second leading cause of cancer-related death in men. Despite its prevalence, treatment outcomes are often unsatisfactory, necessitating the search for more effective therapeutic approaches. mTOR inhibitor Rapamycin (RAPA) has shown promise in managing PCa, but the emergence of resistance often undermines its long-term effectiveness. Recent studies suggest that poly ADP-ribose polymerase (PARP) inhibitor Olaparib (OLP) may overcome drug resistance in various tumor types. This study aims to assess the efficacy of OLP in treating RAPA-resistant PCa, with a specific focus on elucidating its underlying molecular mechanisms. This study utilized drug exposure and concentration escalation experiments to establish human RAPA-resistant PCa cell line (PC-3R) based on the human PCa cell line (PC-3). PC-3R cell lines were screened through a cloning assay. The efficacy of OLP in RAPA-resistant PCa, as well as its regulatory impact on tumor-associated macrophages (TAMs), was evaluated through a combination of real-time PCR, ELISA, immunohistochemistry, and fluorescence experiments. This study unveiled that the combination of OLP and RAPA effectively suppressed the proliferation, stemness, invasion, angiogenesis, apoptosis resistance, and anti-oxidative stress capacity of RAPA-resistant PCa. Additionally, it demonstrated the capacity of OLP to regulate macrophage polarization within the tumor microenvironment and reverse drug resistance to RAPA in PCa. The findings of this study lay a theoretical foundation for the potential utilization of OLP in the treatment of RAPA-resistant PCa, offering substantial academic significance and promising application prospects.

The incidence of atherosclerosis (AS) remains high, and iron-dependent cell death (termed ferroptosis) is thought to play a key role in the progression of AS. Studies have shown that cathepsin B (CTSB) is an important regulatory molecule in atherosclerosis. However, how CTSB regulates AS progression has not been reported, and whether it is related to ferroptosis is poorly studied. In the present study, we observed a significant upregulation of CTSB expression in two AS models, ApoE knockout mice and SD rats given a HFD. According to our findings, CTSB can promote development of the AS plaque region, while inhibition of CTSB showed a reduction of AS lesion area and lipid deposition. Single-cell transcriptome analysis of AS tissue from humans revealed that CTSB is primarily expressed in macrophages. Oxidized low-density lipoprotein (ox-LDL) significantly enhanced macrophage CTSB expression, and induced ferroptosis in vitro. Mechanistically, Ferroportin (FPN) is the binding target of CTSB. CTSB can negatively regulate the protein level of FPN and promote its degradation, which further leads to ferroptosis of macrophages. We confirmed that ferroptosis in macrophages could be effectively inhibited by knockdown or pharmacological inhibition of CTSB, which in turn slowed the progression of AS. In conclusion, our study suggests that CTSB disrupts iron homeostasis in macrophages by degrading FPN and induces ferroptosis, thereby exacerbating the development of AS. Targeting CTSB may become an important potential strategy for the treatment of AS.

The transcription factor YY1 is significantly upregulated in M2 macrophages, which can facilitate the malignant progression of multiple cancers. However, the precise mechanisms underlying the influence of YY1-high M2 macrophages on prostate cancer (PCa) progression remain elusive. Therefore, this study aims to elucidate the specific mechanisms by which YY1-high M2 macrophages influence PCa progression. Cell proliferation was assessed through colony formation and CCK8 assays. To evaluate cell invasion and migration, Transwell and wound healing assays were utilized. We investigated the effects of exosomes derived from M2 macrophages overexpressing YY1 on PCa cells. Subsequently, circRNA microarrays and qRT-PCR identified a high level of hsa-circ-0000326 in exosomes. Nucleoplasmic isolation, luciferase reporter, RNA-pulldown assays elucidated the functions and downstream targets (miR-338-3p and AR) of hsa-circ-0000326. Chromatin immunoprecipitation sequencing, chromatin conformation capture, qRT-PCR, western blotting, and agarose-electrophoresis assays examined YY1's role in transcribing the hsa-circ-0000326 maternal gene MALAT1 as well as its modulation of QKI expression. Our results demonstrated that the secretion of exosomes enriched with hsa-circ-0000326 by YY1-overexpressing M2 macrophages contributes to PCa metastasis. Hsa-circ-0000326 functions as a competitive endogenous RNA against miR-338-3p to promote androgen receptor levels in PCa cells. Mechanistic investigations revealed that YY1 binds to the super-enhancer region of MALAT1 enhancing transcriptional activity for this gene. Simultaneously, YY1 upregulates QKI expression, facilitating splicing events leading to the formation of hsa-circ-0000326. Inhibiting exosomal hsa-circ-0000326 presents a potential therapeutic approach for treating metastatic PCa.

Esophageal squamous cell carcinoma (ESCC) is a common and aggressive subtype of esophageal cancer. This research investigates the functions of cancer-associated fibroblasts (CAFs) in the malignant phenotype of ESCC and probes the underpinning mechanism. Key CAF-associated proteins in ESCC were identified using bioinformatics analyses. ESCC cell lines were co-cultured with CAFs, followed by the addition of neutralizing antibodies against WNT family member 5A (WNT5A) (Anti-WNT5A; AW) and frizzled class receptor 5 (FZD5) (Anti-FZD5; AF), or a human recombinant protein of WNT5A (rWNT5A; rW). The effects of CAF stimulation and the neutralizing or recombinant proteins on the growth and dissemination of ESCC cells were investigated. In addition, ESCC cells were transplanted into nude mice for in vivo assessment of tumor growth and metastasis. WNT5A was identified as a CAF-associated protein linked to poor prognosis in ESCC. Co-culturing with CAFs augmented proliferation, mobility, and apoptosis resistance of ESCC cells. These effects were negated by the AW or AF but restored by rW. WNT5A interacted with FZD5 to activate the WNT signaling in ESCC cells. The rW treatment also enhanced tumorigenesis and metastasis of xenograft tumors in nude mice, with these effects diminished by AW or AF treatment. This study suggests that CAFs promote growth and dissemination of ESCC cell primarily through the secretion of WNT5A.

MicroRNAs (miRNAs) have emerged as promising tools for diagnosis and treatment in numerous pathophysiological processes, including cardiovascular diseases (CVD). In this context, acute myocardial infarction (AMI) is one of the leading causes of death by CVD worldwide. In this sense, physical exercise (PE) is considered a non-pharmacological strategy to reduce the complex alterations in AMI. This study is an integrative review of the literature to explore the effects of PE on the cardiomyocyte post-AMI, including an understanding of the mechanisms by which the PE acts on the miRNAs expression. A review was performed on PubMed, Scopus, and Web of Science. After the searches, all records were imported into the Mendeley software, and duplicate articles were removed. The year of publication of the papers was not limited. 19 studies were performed on animal models, 10 in experimental models using rats, and 08 in models with mice and only one study was carried out on patients with AMI. The results showed the potential use of miRNAs as diagnostic tools and attractive biomarkers for treating AMI. In addition, PE can regulate miRNAs expression in the myocardial cell, promotes apoptosis resistance, autophagy regulation, lower cardiac fibrosis and cardiac hypertrophy, and higher angiogenesis through the signaling of miRNAs. The main microRNAs mitigating the deleterious effects of AMI and modulated by PE were miRNA-222, miRNA-1192, miRNA-146, and miRNA-126. PE modulates the expression of specific miRNAs that support cardiac function, promoting cardioprotective effects or facilitating cardiac recovery post-AMI.

Studies have shown that decorin is a potent pan-cancer tumor suppressor that is under-expressed in most cancers. Decorin interacts with receptor tyrosine kinases and functions as a pan-receptor tyrosine kinase inhibitor, thereby suppressing oncogenic signals. Decorin deficiency promotes epithelial-to-mesenchymal transition and enhances cancer dissemination and metastasis. According to recent GLOBOCAN estimates, the most common cancers worldwide are breast, lung, prostate, colorectal, skin (non-melanoma), and stomach. Considering the burden of rising cancer incidence and the importance of discovering novel molecular markers and potential therapeutic agents for cancer management, we have outlined the possible expressional and clinicopathological significance of decorin in major cancers based on available pre-clinical and clinical studies. Measuring plasma decorin is a minimally invasive technique, and human studies have shown that it is useful in predicting clinical outcomes in cancer though it needs further validation. Oncolytic virus-mediated decorin gene transfer has shown significant anti-tumorigenic effects in pre-clinical studies, though its implication in human subjects is yet to be understood. Exogenous decorin delivery in experimental studies has been shown to mitigate cancer growth, but its therapeutic efficacy and safety are poorly understood. Future research is required to translate the tumor-suppressive action of decorin observed in preclinical experiments to therapeutic interventions in human subjects.