Long non-coding RNAs(lncRNAs)have been implicated in cancer progression and drug resistance development.Moreover,there is evidence that lncRNA HOX transcript antisense intergenic RNA(HOTAIR)is involved in colorectal cancer(CRC)progression.The present study aimed to examine the functional role of lncRNA HOTAIR in conferring radiotherapy resistance in CRC cells,as well as the underlying mechanism.The relative expression levels of HOTAIR were examined in 70 pairs of CRC tumor and para-cancerous tissues,as well as in radiosensitive and radioresistant samples.The correlations between HOTAIR expression levels and clinical features of patients with CRC were assessed using the Chi-square test.Functional assays such as cell proliferation,colony formation and apoptosis assays were conducted to determine the radiosensitivity in CRC cells with HOTAIR silencing after treatment with different doses of radiation.RNA pull-down assay andfluorescence in situ hybridization(FISH)were used to determine the interaction between HOTAIR and DNA damage response mediator ataxia-telangiectasia mutated-and Rad3-related(ATR).HOTAIR was significantly upregulated in CRC tumor tissues,especially in radioresistant tumor samples.The elevated expression of HOTAIR was correlated with more advanced histological grades,distance metastasis and the poor prognosis in patients with CRC.Silencing HOTAIR suppressed the proliferation and promoted apoptosis and radiosensitivity in CRC cells.HOTAIR knockdown also inhibited the tumorigenesis of CRC cells and enhanced the sensitivity to radiotherapy in a mouse xenograft model.Moreover,the data showed that HOTAIR could interact with ATR to regulate the DNA damage repair signaling pathway.Silencing HOTAIR impaired the ATR-ATR interacting protein(ATRIP)complex and signaling in cell cycle progression.Collectively,the present results indicate that lncRNA HOTAIR facilitates the DNA damage response pathway and promotes radioresistance in CRC cells by targeting ATR.
HAIQING HUHAO YANGSHUAISHUAI FANXUE JIAYING ZHAOHONGRUI LI
BACKGROUND Gliomas pose a significant challenge to effective treatment despite advancements in chemotherapy and radiotherapy.Glioma stem cells(GSCs),a subset within tumors,contribute to resistance,tumor heterogeneity,and plasticity.Recent studies reveal GSCs’role in therapeutic resistance,driven by DNA repair mechanisms and dynamic transitions between cellular states.Resistance mechanisms can involve different cellular pathways,most of which have been recently reported in the literature.Despite progress,targeted therapeutic approaches lack consensus due to GSCs’high plasticity.AIM To analyze targeted therapies against GSC-mediated resistance to radio-and chemotherapy in gliomas,focusing on underlying mechanisms.METHODS A systematic search was conducted across major medical databases(PubMed,Embase,and Cochrane Library)up to September 30,2023.The search strategy utilized relevant Medical Subject Heading terms and keywords related to including“glioma stem cells”,“radiotherapy”,“chemotherapy”,“resistance”,and“targeted therapies”.Studies included in this review were publications focusing on targeted therapies against the molecular mechanism of GSC-mediated re-sistance to radiotherapy resistance(RTR).RESULTS In a comprehensive review of 66 studies on stem cell therapies for SCI,452 papers were initially identified,with 203 chosen for full-text analysis.Among them,201 were deemed eligible after excluding 168 for various reasons.The temporal breakdown of studies illustrates this trend:2005-2010(33.3%),2011-2015(36.4%),and 2016-2022(30.3%).Key GSC models,particularly U87(33.3%),U251(15.2%),and T98G(15.2%),emerge as significant in research,reflecting their representativeness of glioma characteristics.Pathway analysis indicates a focus on phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin(mTOR)(27.3%)and Notch(12.1%)pathways,suggesting their crucial roles in resistance development.Targeted molecules with mTOR(18.2%),CHK1/2(15.2%),and ATP binding cassette G2(12.1%)as frequent tar
Edoardo AgostiMarco ZeppieriMattia GhidoniTamara IusAlessandro TelMarco Maria FontanellaPier Paolo Panciani
Marginal zone(MZ)B cells,which are splenic innate-like B cells that rapidly secrete antibodies(Abs)against blood-borne pathogens,are composed of heterogeneous subpopulations.Here,we showed that MZ B cells can be divided into two distinct subpopulations according to their CD80 expression levels.CD80^(high)MZ B cells exhibited greater Ab-producing,proliferative,and IL-10-secreting capacities than did CD80^(low)MZ B cells.Notably,CD80^(high)MZ B cells survived 2-Gy whole-body irradiation,whereas CD80^(low)MZ B cells were depleted by irradiation and then repleted with one month after irradiation.Depletion of CD80^(low)MZ B cells led to accelerated development of type II collagen(CII)-induced arthritis upon immunization with bovine CII.CD80^(high)MZ B cells exhibited higher expression of genes involved in proliferation,plasma cell differentiation,and the antioxidant response.CD80^(high)MZ B cells expressed more autoreactive B cell receptors(BCRs)that recognized double-stranded DNA or CII,expressed more immunoglobulin heavy chain sequences with shorter complementarity-determining region 3 sequences,and included more clonotypes with no N-nucleotides or with B-1a BCR sequences than CD80^(low)MZ B cells.Adoptive transfer experiments showed that CD21^(+)CD23^(+)transitional 2 MZ precursors preferentially generated CD80^(low)MZ B cells and that a proportion of CD80^(low)MZ B cells were converted into CD80^(high)MZ B cells;in contrast,CD80^(high)MZ B cells stably remained CD80^(high)MZ B cells.In summary,MZ B cells can be divided into two subpopulations according to their CD80 expression levels,Ab-producing capacity,radioresistance,and autoreactivity,and these findings may suggest a hierarchical composition of MZ B cells with differential stability and BCR specificity.
Sujin LeeYeunjung KoHyun Woo LeeWon Joon OhHun Gi HongDinuka AriyaratneSe Jin ImTae Jin Kim
Objective:To investigate the potential role of the regulator of G protein signaling 20(RGS20)in radioresistance of non-small cell lung cancer(NSCLC).Methods:A total of 35 lung adenocarcinoma(LUAD)patients from The Cancer Genome Atlas(TCGA),who un-derwent radiotherapy,were enrolled and divided into radiosensitive(n=16)and radioresistant(n=19)groups based on clinical prognosis.The expression and prognosis of RGS20 were analyzed by Gene Expression Profiling Interactive Analysis(GEPIA)database.A radioresistant cell line(A549R)was constructed by irradiating A549 cells with 6 Gy X-rays for 10 fractions.Cell survival was measured by colony formation assay.The regulatory effect of RGS20 on pyroptosis were verified by LDH release and Western blot assay,and the underlying mech-anism was investigated by transfecting RGS20 siRNA and applying a GSDMD inhibitor.Results:A total of 2,181 differentially expressed genes(DEGs)were identified by analyzing the data of radio-sensitive and radioresistant individuals from the TCGA-LUAD dataset.These DEGs were enriched in G alpha(z)signalling events analyzed by Reactome database.RGS20 exhibited significant upregulation among the DEGs,and its higher expression predicted poor prognosis in LUAD patients.In vitro,the expression of RGS20 protein was increased by irradiation in A549 cells,whereas it remained at much high levels in A549R cells regardless of irradiation.After irradiation,the expressions of pyroptosis-related proteins were significantly increased in A549 cells(P<0.05),with no significant changes were observed in A549R cells.Treatment with LDC7559 significantly reduced LDH release(P<0.01)and improved the survival rate of irradiated A549 cells(P<0.01).Furthermore,knockdown of RGS20 gene in A549R cells significantly increased LDH release(P<0.001)and enhanced radiosensitivity(P<0.01),while LDC7559 administration reversed LDH release(P<0.01)and radiation-induced cell death increased by siRGS20(P<0.05).Meantime,the increased expression level of GSDMD-NT was observed in A549 and A549R c
Tumor cells establish a robust self-defense system characterized by hypoxia,antioxidant overexpression,DNA damage repair,and so forth to resist radiotherapy.Targeting one of these features is insufficient to overcome radioresistance due to the feedback mechanisms initiated by tumor cells under radiotherapy.Therefore,we herein developed an engineering biomimetic nanosystem(M@HHPt)masked with tumor cell membranes and loaded with a hybridized protein-based nanoparticle carrying oxygens(O_(2))and cisplatin prodrugs(Pt(Ⅳ))to target multiple tumor radioresistance hallmarks for enhanced radiotherapy.After administration,M@HHPt actively targeted and smoothly accumulated in tumor cells by virtue of its innate homing abilities to realize efficient co-delivery of O_(2)and Pt(Ⅳ).O_(2)introduction induced hypoxia alleviation cooperated with Pt(Ⅳ)reduction caused glutathione consumption greatly amplified radiotherapy-ignited cellular oxidative stress.Moreover,the released cisplatin effectively hindered DNA damage repair by crosslinking with radiotherapy-produced DNA fragments.Consequently,M@HHPt-sensitized radiotherapy significantly suppressed the proliferation of lung cancer H1975 cells with an extremely high sensitizer enhancement ratio of 1.91 and the progression of H1975 tumor models with an excellent tumor inhibition rate of 94.7%.Overall,this work provided a feasible strategy for tumor radiosensitization by overcoming multiple radioresistance mechanisms.
Shuxiang WangHongmei CaoCui-Cui ZhaoQian WangDianyu WangJinjian LiuLijun YangJianfeng Liu
Objective:To investigate the contribution of YWHAZ gene on the radioresistance and metastasis ability of oral squamous cell carcinoma(OSCC)cells.Mathods:The relationship between the expression level of YWHAZ gene and the survival of head and neck squamous cell carcinoma(HNSC)patients was analyzed using Gene Expression Profiling Interactive Analysis(GEPIA)database.A radioresistance cell line(CAL-27R)was constructed by irradiating CAL-27 cells with frac-tional doses.Cell survival was measured by colony formation assay.Cell migration and invasion were detected by transwell assay.The formation of yH2AX foci was detected by immunofluorescence assay,The protein expressions were detected by Westemn blot assay.In some experiments,CAL-27R cells were effectively transferred with siRNA YWHAZ(siYWHAZ).Results:GEPIA database showed that the expression level of YWHAZ in HNSC tumors was higher than that in adjacent normal tissues,and the HNSC patients with higher level of YWHAZ had a shorter survival.In vitro experiments demonstrated that the expression of YWHAZ protein in CAL-27 cells was lower than HSC-3 cells(t=18.89,P<0.01)and radioresistant CAL-27R cells(t=25.70,P<0.01).Knockdown of YWHAZ gene significantly increased radiation-induced cell killing effect,apoptosis induction,and yH2AX foci formation inCAL-27R and HSC-3 cells.Moreover,siRNA YWHAZ transfection also reduced the invasion and migration abilities of the irradiated CAL 27R[t=21.09,P<0.01(migration);t=6.16,P<0.05(invasion)]and HSC-3 cells[t=34.53,P<0.001(migration);t=4.92,P<0.05(invasion)]and attenuated radiation-induced expressions of metastasis-related proteins,Conclusion:YWHAZ contributes to the radioresistance of oral squamous cells and thus it may applicable to be a potential target for OSOC radiotherapy.