关键词： P53-R273H   EGR1   EMT   NSCLC   CANCER   GAIN   GENE  

摘要： The epithelial-mesenchymal transition (EMT) plays a crucial role in lung cancer metastasis, rendering it a promising therapeutic target. Research has shown that non-small cell lung cancer (NSCLC) with p53 mutations exhibits an increased tendency for cancer metastasis. However, the exact contribution of the p53-R273H mutation to tumor metastasis remains uncertain in the current literature. Our study established the H1299-p53R273H cell model successfully by transfecting the p53-R273H plasmid into H1299 cells. We observed that p53-R273H promotes cell proliferation, migration, invasion, and EMT through CCK-8, wound healing, transwell, western blot and immunofluorescence assays. Notably, the expression of EGR1 was increased in H1299-p53R273H cells. Knocking out EGR1 in these cells hindered the progression of EMT. ChIP-PCR experiments revealed that p53-R273H binds to the EGR1 promoter sequence, thereby regulating its expression. These findings suggest that p53-R273H triggers EMT by activating EGR1, thereby offering a potential therapeutic approach for lung cancer treatment.

关键词： Senile osteoporosis   Radial extracorporeal shockwave   Bone marrow stromal cells   Piezo1   WAVE THERAPY   OSTEOBLAST DIFFERENTIATION   STEM-CELLS   CALMODULIN  

摘要： Radial extracorporeal shockwave (r-ESW) and bone marrow stromal cells (BMSCs) have been reported to alleviate senile osteoporosis (SOP), but its regulatory mechanism remains unclear. In this study, we firstly isolated human BMSCs from bone marrow samples and treated with varying r-ESW doses. And we found that r-ESW could enhance the proliferation of SOP-BMSCs in a dose-dependent manner by EdU assay. Subsequently, the impact of r-ESW on the proliferation, apoptosis and multipotency of BMSCs was assessed. And the outcomes of flow cytometry, Alizarin red S (ARS), and tube formation test demonstrated that the optimal shockwave obviously boosted SOP-BMSCs osteogenesis and angiogenesis but exhibited no significant impact on cell apoptosis. Additionally, the signaling of Piezo1 and CaMKII/CREB was examined by Western blotting, qPCR and immunofluorescence. And the results showed that r-ESW promoted the expression of Piezo1, increased intracellular Ca2+ and activated the CaMKII/CREB signaling pathway. Then, the application of Piezo1 siRNA hindered the r-ESWinduced enhancement ability of osteogenesis coupling with angiogenesis of SOP-BMSCs. The use of the CaMKII/ CREB signaling pathway inhibitor KN93 suppressed the Piezo1-induced increase in osteogenesis and angiogenesis in SOP-BMSCs. Finally, we also found that r-ESW might alleviate SOP in the senescence-accelerated mouse prone 6 (SAMP6) model by activating Piezo1. In conclusion, our research offers experimental evidence and an elucidated underlying molecular mechanism to support the use of r-ESW as a credible rehabilitative treatment for senile osteoporosis.

关键词： Incense-burning smoke   Chemoresistance   GQ structure   Long non-coding RNA   TP53   MUTANT P53   OXIDATIVE STRESS   DNA   RATS   IDENTIFICATION   GENOTOXICITY   CHEMOTHERAPY   TELOMERASE   INDUCTION   APOPTOSIS  

摘要： Incense-burning smoke is a deleterious air pollutant that initiates cytotoxic effects by inducing apoptosis in lung epithelial cells and also acts as a risk factor for lung cancers. Auramine, an ingredient of incense smoke, has been implicated in tumor progression and cellular sensitivity in non-small cell lung cancer (NSCLC) towards anticancer agents through unclear mechanisms. Tumor protein p53 (TP53)-activated long intergenic non-coding RNAp21 (lincRNA-p21) undertakes a pivotal role in regulating cell apoptosis and chemosensitivity. TP53 mutations prevalent in 50% of NSCLC, contribute to diminished therapeutic efficacy. However, the influence of auramine on chemotherapy-induced lincRNA-p21 expression and apoptosis in NSCLC with different TP53 genetic statuses remains unexplored. This study disclosed that both wild-type p53 (wtp53) and mutant p53 (mutp53) mediate lincRNA-p21 expression, albeit through distinct promoter enhancers, p53-response element (p53RE) and non-B DNA structure G-quadruplex (GQ), respectively. Intriguingly, auramine functions as an effective stabilizer of the GQ structure, augmenting mutp53-mediated lincRNA-p21 expression and enhancing apoptosis and cellular sensitivity to chemotherapy in mutp53-expressing NSCLC cells. These findings suggest a mechanism by which mutp53, in the presence of auramine, is endowed with tumor-suppressing function akin to wtp53, thereby aiding in combating chemoresistance in NSCLC cells harboring TP53 mutations.

关键词： circulating tumor cells   ESR1 (estrogen receptor 1)   ERCC1 (ERCC excision repair 1 endonuclease non-catalytic subunit)   Hsp90 inhibitor   CIRCULATING TUMOR-CELLS   EPITHELIAL OVARIAN   LUNG-CANCER   ERCC1 PROTEIN   DNA-REPAIR   MUTANT P53   PROGRESSION   BIOMARKER   SURVIVAL  

摘要： Disease progression is a major problem in ovarian cancer. There are very few treatment options for patients with platinum-resistant ovarian cancer (PROC), and therefore, these patients have a particularly poor prognosis. The aim of the present study was to identify markers for monitoring the response of 123 PROC patients enrolled in the Phase I/II GANNET53 clinical trial, which evaluated the efficacy of Ganetespib in combination with standard chemotherapy versus standard chemotherapy alone. In total, 474 blood samples were collected, comprising baseline samples taken before the first administration of the study drugs and serial samples taken during treatment until further disease progression (PD). After microfluidic enrichment, 27 gene transcripts were analyzed using quantitative polymerase chain reaction and their utility for disease monitoring was evaluated. At baseline, ERCC1 was associated with an increased risk of PD (hazard ratio [HR] 1.75, 95% confidence interval [CI]: 1.20-2.55; p = 0.005), while baseline CDH1 and ESR1 may have a risk-reducing effect (CDH1 HR 0.66, 95% CI: 0.46-0.96; p = 0.024; ESR1 HR 0.58, 95% CI: 0.39-0.86; p = 0.002). ERCC1 was observed significantly more often (72.7% vs. 53.9%; p = 0.032) and ESR1 significantly less frequently (59.1% vs. 78.3%; p = 0.018) in blood samples taken at radiologically confirmed PD than at controlled disease. At any time during treatment, ERCC1-presence and ESR1-absence were associated with short PFS and with higher odds of PD within 6 months (odds ratio 12.77, 95% CI: 4.08-39.97; p < 0.001). Our study demonstrates the clinical relevance of ESR1 and ERCC1 and may encourage the analysis of liquid biopsy samples for the management of PROC patients.

关键词： p53 protein   Tumor   Electrochemical immunosensor   MXene   Ti   3   C   2   T   x   Ferrocene  

摘要： Since the p53 protein is an important promising biomarker of lung tumor and colorectal tumor, it is very essential to design a highly effective mean to monitor the degree of p53 for the early clinical analysis/therapy of the related tumors. In this work, a sandwich-type electrochemical immunosensing (SES) platform is proposed for the first time to detect p53 via synthesizing Ti 3 C 2 T x MXene nanoribbons (Ti 3 C 2 T x Nb) and ferrocene/gold nanoparticles (Fc/Au) respectively as the sensing substrate and signal-amplifier. The superior electrical property and large surface area of Ti 3 C 2 T x Nb are beneficial to assemble the initial p53-antibodies (Ab 1 ), while the synthesized Fc/Au is devoted to assemble the secondary p53 antibodies (Ab 2 ) and gives a magnified signal. By adopting the Fc molecules as the probes, the experiments reveal the response current of Fc resulted from the SES structure increases along with the p53 increase from 1.0 to 200.0 pg mL −1 . A considerable low detection limit (1.0 pg mL −1 ) is achieved after optimizing several key conditions, it is thus confirmed the as-proposed SES mean exhibits significant application in the detection of p53 protein and other targets.