VX-509 attenuates the stemness characteristics of colorectal cancer stem-like cells by regulating the epithelial-mesenchymal transition through Nodal/Smad2/3 signaling

BACKGROUND Colorectal cancer stem cells(CCSCs)are heterogeneous cells that can self-renew and undergo multidirectional differentiation in colorectal cancer(CRC)patients.CCSCs are generally accepted to be important sources of CRC and are responsible for the progression,metastasis,and therapeutic resistance of CRC.Therefore,targeting this specific subpopulation has been recognized as a promising strategy for overcoming CRC.AIM To investigate the effect of VX-509 on CCSCs and elucidate the underlying mechanism.METHODS CCSCs were enriched from CRC cell lines by in conditioned serum-free medium.Western blot,Aldefluor,transwell and tumorigenesis assays were performed to verify the phenotypic characteristics of the CCSCs.The anticancer efficacy of VX-509 was assessed in HCT116 CCSCs and HT29 CCSCs by performing cell viability analysis,colony formation,sphere formation,flow cytometry,and western blotting assessments in vitro and tumor growth,immunohistochemistry and immunofluorescence assessments in vivo.RESULTS Compared with parental cells,sphere cells derived from HCT116 and HT29 cells presented increased expression of stem cell transcription factors and stem cell markers and were more potent at promoting migration and tumori-genesis,demonstrating that the CRC sphere cells displayed CSC features.VX-509 inhibited the tumor malignant biological behavior of CRC-stem-like cells,as indicated by their proliferation,migration and clonality in vitro,and suppressed the tumor of CCSC-derived xenograft tumors in vivo.Besides,VX-509 suppressed the CSC character-istics of CRC-stem-like cells and inhibited the progression of epithelial-mesenchymal transition(EMT)signaling in vitro.Nodal was identified as the regulatory factor of VX-509 on CRC stem-like cells through analyses of differen-tially expressed genes and CSC-related database information.VX-509 markedly downregulated the expression of Nodal and its downstream phosphorylated Smad2/3 to inhibit EMT progression.Moreover,VX-509 reversed the dedifferentiation of CCSCs and inhibited the progression of EMT induced by Nodal overexpression.CONCLUSION VX-509 prevents the EMT process in CCSCs by inhibiting the transcription and protein expression of Nodal,and inhibits the dedifferentiated self-renewal of CCSCs.

Gossypol acetic acid regulates leukemia stem cells by degrading LRPPRC via inhibiting IL-6/JAK1/STAT3 signaling or resulting mitochondrial dysfunction

BACKGROUND Leukemia stem cells(LSCs)are found to be one of the main factors contributing to poor therapeutic effects in acute myeloid leukemia(AML),as they are protected by the bone marrow microenvironment(BMM)against conventional therapies.Gossypol acetic acid(GAA),which is extracted from the seeds of cotton plants,exerts anti-tumor roles in several types of cancer and has been reported to induce apoptosis of LSCs by inhibiting Bcl2.AIM To investigate the exact roles of GAA in regulating LSCs under different microenvironments and the exact mechanism.METHODS In this study,LSCs were magnetically sorted from AML cell lines and the CD34+CD38-population was obtained.The expression of leucine-rich pentatricopeptide repeat-containing protein(LRPPRC)and forkhead box M1(FOXM1)was evaluated in LSCs,and the effects of GAA on malignancies and mitochondrial RESULTS LRPPRC was found to be upregulated,and GAA inhibited cell proliferation by degrading LRPPRC.GAA induced LRPPRC degradation and inhibited the activation of interleukin 6(IL-6)/janus kinase(JAK)1/signal transducer and activator of transcription(STAT)3 signaling,enhancing chemosensitivity in LSCs against conventional chemotherapies,including L-Asparaginase,Dexamethasone,and cytarabine.GAA was also found to downregulate FOXM1 indirectly by regulating LRPPRC.Furthermore,GAA induced reactive oxygen species accumulation,disturbed mitochondrial homeostasis,and caused mitochondrial dysfunction.By inhibiting IL-6/JAK1/STAT3 signaling via degrading LRPPRC,GAA resulted in the elimination of LSCs.Meanwhile,GAA induced oxidative stress and subsequent cell damage by causing mitochondrial damage.CONCLUSION Taken together,the results indicate that GAA might overcome the BMM protective effect and be considered as a novel and effective combination therapy for AML.

Malignant melanoma resection and reconstruction with the first manifestation of lumbar metastasis:A case report

BACKGROUND Malignant melanoma(MM)has shown an increasing incidence worldwide,and a potential to metastasize to almost any part of the body.Clinically,MM with bone metastasis as the initial manifestation is extremely rare.Spinal metastatic MM can cause spinal cord or nerve root compression,resulting in severe pain and paralysis.Currently,the primary clinical treatments for MM are surgical resection in conjunction with chemotherapy,radiotherapy,and immunotherapy.CASE SUMMARY Here,we report the case of a 52-year-old male who presented to the clinic with progressive low back pain and limited nerve function.No primary lesion or spinal cord compression was detected from computed tomography and magnetic resonance imaging of the lumbar vertebrae and positron emission tomography scan.A lumbar puncture biopsy confirmed the diagnosis of lumbar spine metastatic MM.Following surgical resection,the patient’s quality of life improved,symptoms were relieved,and comprehensive treatment was initiated,which prevented recurrence.CONCLUSION Spinal metastatic MM is clinically rare,and may cause neurological symptoms,including paraplegia.Currently,the clinical treatment plan consists of surgical resection in combination with chemotherapy,radiotherapy,and immunotherapy.

Effective regulation mechanisms of Fe-Ni(oxy)hydroxide:Ni-rich heteroatomic bonding(Ni–O–Fe–O–Ni)is essential

Although Fe-Ni combination performs well in transition metal-based oxygen evolution reaction(OER)electrocatalysts,there are lack of clear and general regulations mechanism to fully play the synergistic catalytic effect.Here,we made the utmost of the interaction of Fe–Ni heteroatomic pair to obtain a highly active Fe-Ni(oxy)hydroxide catalytic layer on iron foam(IF)and nickel foam(NF)by in-situ electrochemical deposition and rapid surface reconstruction,which only required 327 and 351 mV overpotential to provide a large current of 1,000 mA·cm^(−2),respectively.The results confirm that the moderate Ni-rich heteroatomic bonding(Ni–O–Fe–O–Ni)formed by adjusting the Ni/Fe ratio on the catalyst surface is important to offer predominant OER performance.Fe is a key component that enhances OER activity of Ni(O)OH,but Fe-rich structural surface formed by Fe–O–Ni–O–Fe bonding is not ideal.Finally,the remarkable oxygen evolution performance of the prepared Ni2Fe(O)OH/IF and FeNi2(O)OH/NF can be chalked up to the optimized electronic structure of Fe–Ni heteroatomic bonding,the efficient gas spillover,the fast electron transport,and nanosheet clusters morphology.In summary,our work suggests a comprehensive regulation mechanism for the construction of efficient Fe-Ni(oxy)hydroxide catalytic layer on inexpensive,stable,and self-supporting metallic material surface.