Unveiling the therapeutic potential:KBU2046 halts triple-negative breast cancer cell migration by constricting TGF-β1 activation in vitro

Background:Triple-negative breast cancer(TNBC)is a heterogeneous,recurring cancer characterized by a high rate of metastasis,poor prognosis,and lack of efficient therapies.KBU2046,a small molecule inhibitor,can inhibit cell motility in malignant tumors,including breast cancer.However,the specific targets and the corresponding mechanism of its function remain unclear.Methods:In this study,we employed(3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H tetrazolium)(MTS)assay and transwell assay to investigate the impact of KBU2046 on the proliferation and migration of TNBC cells in vitro.RNA-Seq was used to explore the targets of KBU2046 that inhibit the motility of TNBC.Finally,confirmed the predicted important signaling pathways through RT-qPCR and western blotting.Results:In this study,we found that KBU2046 functioned as a novel transforming growth factor-β(TGF-β1)inhibitor,effectively suppressing tumor cell motility in vitro.Mechanistically,it directly down-regulated leucine-rich repeat-containing 8 family,member E(LRRC8E),latent TGFβ-binding protein 3(LTBP3),dynein light chain 1(DNAL1),and MAF family of bZIP transcription factors(MAFF)genes,along with reduced protein expression of the integrin family.Additionally,KBU2046 decreased phosphorylation levels of Raf and ERK.This deactivation of the ERK signaling pathway impeded cancer invasion and metastasis.Conclusions:In summary,these findings advocate for the utilization of TGF-β1 as a diagnostic and prognostic biomarker and as a therapeutic target in TNBC.Furthermore,our data underscore the potential of KBU2046 as a novel therapeutic strategy for combating cancer metastasis.

Flotillin1 promotes EMT of human small cell lung cancer via TGF-β signaling pathway

Objective:Small cell lung carcinoma(SCLC)is considered one of the most aggressive types of lung cancer due to its rapid growth and early metastasis.No tumor markers or therapeutic targets have been demonstrated to be specific or effective in SCLC to date.This study aims to evaluate the potential of Flotillin1(Flot1)as a target of SCLC treatment.Methods:Flot1 expression level in the tissue of SCLC and other tissue of lung disease was detected using immunohistochemical staining.Transwell and Matrigel assays were employed to examine migration and invasion of cancer cells.Flow cytometry and xCELLigence system were used to evaluate cell apoptosis and cell viability,respectively.Expression levels of Flot1,epithelialmesenchymal transition(EMT)marker E-cadherin,vimentin,cyclinD1,TGF-β-Smad2/3,and p-AKT were examined using Western blot.Furthermore,xenograft tumor in nude mice was used to evaluate the growth and metastasis of NCI-H446 cells in vivo.Results:Our results demonstrated that Flot1 is highly expressed in SCLC samples and that its expression correlates strongly with clinical stage,distant metastasis,and poor survival.The knockdown of Flot1 decreased the growth,migration,and invasiveness of SCLC cells and reversed EMT phenotype in vitro and in vivo,while enhanced Flot1 expression exhibited the opposite behavior.Gene expression profile analysis demonstrated that Flot1-regulated genes frequently mapped to the AKT and TGF-β-Smad2/3pathways.Our results further revealed that Flot1 affected the progression of SCLC via regulation of EMT progression.Conclusions:These findings indicated an oncogenic role of Flot1 via promoting EMT in SCLC and suggested its potential as a tumor marker and prognostic indicator.

Genomic characterization and risk stratification of esophageal squamous dysplasia

Objectives:The majority of esophageal squamous dysplasia(ESD)patients progress slowly,while a subset of patients can undergo recurrence rapidly or progress to invasive cancer even after proper treatment.However,the molecular mechanisms underlying these clinical observations are still largely unknown.Methods:By sequencing the genomic data of 160 clinical samples from 49 tumor-free ESD patients and 88 esophageal squamous cell carcinoma(ESCC)patients,we demonstrated lower somatic mutation and copy number alteration(CNA)burden in ESD compared with ESCC.Results:Cross-species screening and functional assays identified ACSM5 as a novel driver gene for ESD progression.Furthermore,we revealed that miR-4292 promoted ESD progression and could serve as a non-invasive diagnostic marker for ESD.Conclusions:These findings largely expanded our understanding of ESD genetics and tumorigenesis,which possessed promising significance for improving early diagnosis,reducing overtreatment,and identifying high-risk ESD patients.

RBM4 dictates ESCC cell fate switch from cellular senescence to glutamine-addiction survival through inhibiting LKB1-AMPK-axis

Cellular senescence provides a protective barrier against tumorigenesis in precancerous or normal tissues upon distinct stressors.However,the detailed mechanisms by which tumor cells evade premature senescence to malignant progression remain largely elusive.Here we reported that RBM4 adversely impacted cellular senescence to favor glutamine-dependent survival of esophageal squamous cell carcinoma(ESCC)cells by dictating the activity of LKB1,a critical governor of cancer metabolism.The level of RBM4 was specifically elevated in ESCC compared to normal tissues,and RBM4 overexpression promoted the malignant phenotype.RBM4 contributed to overcome H-RAS-or doxorubicin-induced senescence,while its depletion caused P27-dependent senescence and proliferation arrest by activating LKB1-AMPK-mTOR cascade.Mechanistically,RBM4 competitively bound LKB1 to disrupt the LKB1/STRAD/MO25 heterotrimeric complex,subsequently recruiting the E3 ligase TRIM26 to LKB1,promoting LKB1 ubiquitination and degradation in nucleus.Therefore,such molecular process leads to bypassing senescence and sustaining cell proliferation through the activation of glutamine metabolism.Clinically,the ESCC patients with high RBM4 and low LKB1 have significantly worse overall survival than those with low RBM4 and high LKB1.The RBM4 high/LKB1 low expression confers increased sensitivity of ESCC cells to glutaminase inhibitor CB-839,providing a novel insight into mechanisms underlying the glutamine-dependency to improve the efficacy of glutamine inhibitors in ESCC therapeutics.