Targeting Post-Translational Modifications to Improve Combinatorial Therapies in Breast Cancer: Lub luag hauj lwm ntawm Fucosylation Part 1

Abstract:

Ntau cov qog noj ntshav tso siab rau kev hloov kho tom qab kev txhais lus (PTMs) los txhawb kev cuam tshuam thiab angiogenesis thiab rov tsim cov cellular zog kom txo qis kev tiv thaiv kab mob qog noj ntshav. Ntawm PTMs, fucosylation yog ib hom glycosylation uas tau txuas rau ntau yam ntawm kev tiv thaiv kab mob thiab hormonal physiological functions nrog rau hijacked los ntawm ntau hom qog. Ntau cov qog nqaij hlav, suav nrog mob qog noj ntshav mis, tau txuas rau qhov kev cia siab tsis txaus ntseeg thiab muaj peev xwm metastatic ntxiv vim fucosylation ntawm glycan core, uas yog core-fucosylation.

Aggressiveness yog hais txog lub peev xwm ntawm lub cev kom yuam kev cuam tshuam nrog nws ib puag ncig. Cov hlab ntsha thiab kev tiv thaiv kab mob yog qhov tseem ceeb ntawm tib neeg kev noj qab haus huv. Yog li, dab tsi yog qhov kev sib raug zoo ntawm kev txhoj puab heev thiab cov hlab ntsha thiab kev tiv thaiv?

Raws li peb txhua tus paub, cov hlab ntsha yog cov kav dej uas cov ntshav ntws hauv tib neeg lub cev. Kev tiv thaiv kab mob yog hais txog lub cev muaj peev xwm tiv thaiv kev cuam tshuam ntawm cov kab mob sab nraud thiab cov kab mob. Ob yam no tseem ceeb heev hauv tib neeg lub cev. Lub luag haujlwm ntawm cov hlab ntsha yog thauj cov ntshav mus rau ntau yam kabmob hauv lub cev, muab cov as-ham thiab oxygen rau lawv, thiab tseem pab lub cev tshem tawm cov khib nyiab thiab co toxins. Kev tiv thaiv kab mob yog lub cev thawj kab ntawm kev tiv thaiv cov kab mob sab nraud thiab tiv thaiv qhov tshwm sim ntawm cov kab mob.

Kev tshawb fawb tau pom tias muaj kev sib raug zoo ntawm kev ua phem thiab cov hlab ntsha thiab kev tiv thaiv. Cov neeg txhoj puab heev feem ntau ntsib cov lus teb rau kev ntxhov siab uas tuaj yeem ua rau vascular tension thiab nce ntshav siab, yog li ua rau muaj kev pheej hmoo ntawm cov kab mob plawv. Nyob rau tib lub sijhawm, cov neeg txhoj puab heev ua rau muaj kev ntxhov siab, uas yuav cuam tshuam rau lub cev tiv thaiv kab mob thiab txo lub cev tiv thaiv.

Yog li ntawd, peb yuav tsum ntxiv dag zog rau kev txhim kho peb lub peev xwm, txhim kho peb txoj kev tiv thaiv, thiab txo qhov tsis zoo ntawm kev ua phem rau lub cev. Tshwj xeeb, koj tuaj yeem ua aerobic ce, noj zaub mov hloov, thiab txhim kho tus cwj pwm zoo kom ua tiav kev noj qab haus huv.

Tag nrho hauv tag nrho, peb yuav tsum to taub tag nrho cov kev sib raug zoo ntawm invasiveness, hlab ntsha, thiab kev tiv thaiv, tsim nyog tswj kev cuam tshuam ntawm invasiveness ntawm lub cev thiab nquag tswj lub cev thiab lub hlwb noj qab haus huv. Los ntawm qhov kev xav no, peb yuav tsum txhim kho peb txoj kev tiv thaiv. Cistanche tuaj yeem txhim kho kev tiv thaiv zoo vim tias cov polysaccharides hauv cov nqaij tuaj yeem tswj kev tiv thaiv kab mob ntawm tib neeg lub cev tiv thaiv kab mob, txhim kho kev ntxhov siab ntawm lub cev tiv thaiv kab mob, thiab txhim kho kev tiv thaiv kab mob hauv lub cev. Cov kab mob bactericidal.

Nyem cistanche deserticola ntxiv

Cov kev tshawb fawb ua ntej tau tshuaj xyuas cov txheej txheem molecular tswj cov tub ntxhais-fucosylation hauv cov qauv mob qog noj ntshav, nws cov txiaj ntsig tsis zoo nyob rau ntau theem kab mob, thiab kev ua haujlwm ntawm vivo pharmacological inhibition, qhia kev kho combinatorial thiab kev txhais lus rau kev kho mob. Thoob plaws hauv qhov kev tshuaj xyuas no, peb piav qhia txog lub luag haujlwm ntawm fucosylation hauv cov qog nqaij hlav, nrog rau qhov tshwj xeeb ntawm kev mob qog noj ntshav ntawm lub mis, nrog rau kev mob lub cev ntawm lub cev tiv thaiv kab mob thiab cov tshuaj hormones, muab kev pom rau nws lub peev xwm los ua biomarker rau kev kwv yees lossis kwv yees cov txiaj ntsig mob qog noj ntshav, nrog rau qhov muaj peev xwm kho mob ua tau zoo li biomarker.

Ntsiab lus:

Fucosylation; glycosylation; mob cancer ntawm lub mis; metastasis; biomarkers.

1. Taw qhia

Mob qog noj ntshav mis yog cov qog nqaij hlav ntau tshaj plaws thoob ntiaj teb, suav txog 31 feem pua ​​​​ntawm cov poj niam mob qog noj ntshav [1]. Thaum mob qog noj ntshav thaum ntxov yog tus cwj pwm los ntawm 5- xyoo muaj sia nyob ntawm 96 feem pua ​​​​hauv Tebchaws Europe, kab mob metastatic tseem kho tsis tau, nrog rau 5-xyoo ciaj sia ntawm 38 feem pua. Cov kev kho tshiab tshiab tam sim no nyuaj rau qhov teeb meem no hauv kev mob qog noj ntshav mis metastatic, feem ntau yog los ntawm kev tsom mus rau cov kev hloov pauv ntawm cov molecular tshwj xeeb lossis cov teeb meem metabolic [2,3].

Tsis tas li ntawd, mob qog noj ntshav yog ib hom kab mob heterogeneous uas tuaj yeem muab faib ua peb pawg dav: hormone receptor (HR) cov qog zoo raws li cov tshuaj estrogen thiab / lossis progesterone receptor (ER, PgR) raws li txoj cai; human epidermal growth factor receptor 2 (HER2) cov qog zoo; los yog triple-negative mis cancers (TNBC). Tsis tas li ntawd, qog heterogeneity kuj tau txais los ntawm ntau qhov kev sib cuam tshuam ntawm cov qog hlwb thiab cov tswv tsev muaj feem cuam tshuam, xws li lub cev tiv thaiv kab mob lossis hormonal axis. Zuag qhia tag nrho, cov xwm txheej tam sim no tau siv los txhim kho qhov tshwj xeeb ntawm kev kuaj mob qog noj ntshav mis, kev kuaj mob, thiab kev kho mob [4].

Hauv qhov xwm txheej no, mob qog noj ntshav glycosylation tau raug lees paub tias yog tus neeg ua haujlwm tseem ceeb cuam tshuam nrog cov qog nqaij hlav metabolism, kev coj tus cwj pwm kev kho mob hnyav nrog rau kev kho mob, nrog rau lub luag haujlwm tau hais los ua qhov kev kwv yees thiab kev kuaj mob biomarker [5]. Fucosylation yog ib hom glycosylation tshwj xeeb los ntawm kev hloov pauv ntawm fucose residue los ntawm Guanosine Diphosphate (GDP)-fucose rau oligosaccharide chains [6]. Cancer fucosylation, tshwj xeeb tshaj yog nyob rau hauv lub glycan core, yog txuas mus rau cellular aggressiveness, proliferation, thiab metastatic noob nyob rau hauv txawv pathologies, thiab nws pre-clinical inhibition tau pom tias yuav ncua kev loj hlob ntawm cov qog nqaij hlav thiab synergize nrog ntau yam tshuaj tiv thaiv kab mob [ 7].

Hauv kev ua haujlwm tam sim no, peb tham txog lub luag haujlwm ntawm fucosylation hauv kev mob qog noj ntshav, nrog rau qhov tshwj xeeb ntawm kev mob qog noj ntshav mis thiab nws cov kev cuam tshuam nrog lub cev tsis muaj zog thiab hormonal, muab kev pom zoo rau nws cov ntawv thov raws li biomarker nrog rau cov kev kho tshiab tsis zoo.

2. Fucosylation: General Principles & Regulation

2.1. Fucose-Synthesis Pathways

Fucose (6-deoxy-L-galactose) tsuas yog levorotatory qab zib synthesized thiab siv los ntawm cov tsiaj nyeg thiab ua lub luag haujlwm tseem ceeb hauv cov txheej txheem ntawm oligosaccharides tom qab kev hloov pauv. Nws tuaj yeem muab tso rau hauv qhov chaw nres nkoj ntawm N-, O- lossis lipid-txuas oligosaccharide chains los ntawm lub davhlau ya nyob twg-fucosylation, nws tuaj yeem hloov kho cov tub ntxhais ntawm txoj haujlwm N-glycans ntawm core-fucosylation, lossis nws tuaj yeem txuas ncaj qha rau threonine lossis serine. residue hauv qee cov glycoproteins [8] Tag nrho cov txheej txheem no yog orchestrated los ntawm fucose synthesis, fucose thauj los ntawm cytoplasm mus rau Golgi apparatus, thiab, ib zaug muaj, fucose residues hloov mus rau glycan chains (Daim duab 1).

Qhov qub tshwm sim ntawm txoj kev de novo rau 90 feem pua ​​​​ntawm GDP-fucose biosynthesis thaum D-mannose tau hloov kho los ntawm peb enzymes: GDP-mannose phosphorylase A (GMPPA), GDP-mannose 4, 6-dehydratase (GMDS) thiab Cov ntaub so ntswg tshwj xeeb hloov pauv antigen p35B (TSTA3). Qhov seem 10 feem pua ​​​​ntawm GDP-fucose synthesis cia siab rau txoj hauv kev khaws cia, uas fucose kinase (FUK) thiab fucose-1-phosphate guanylyltransferase (FPGT) siv cov fucose dawb tau los ntawm kev noj haus [9]. Qhov tsuas yog GDP-fucose transporter tau txheeb xyuas txog tam sim no yog SLC35C1, uas tau pom tias tau hloov kho hauv cov kab mob hepatocellular thiab mob plab hnyuv [5]. GDP-fucose txuas rau glycopeptides yog kho los ntawm kaum peb fucosyltransferase enzymes (FUTs), categorized ua tsib pawg nyob ntawm seb hom kev sib txuas, uas tsuas yog FUT8 (a1-6} fucosyltransferase) catalyzes core-fucosylation ntawm sab hauv N- Acetylglucosamine (GlcNAc) residue ntawm N-glycans ntawm C6 txoj hauj lwm (Daim duab 1) [7–9].

2.2. Fucosylation nyob rau hauv ntau yam mob qog noj ntshav

Core-fucosylation yog hom fucosylation ntau tshaj plaws thiab tau cuam tshuam nrog o thiab mob qog noj ntshav [9]. Tshwj xeeb, cov tub ntxhais-fucosylation tau cuam tshuam nrog kev ua haujlwm tsis zoo, nrog rau kev loj hlob ntxiv, metastatic peev xwm, thiab kev kho mob hauv melanoma [10], hepatocellular carcinoma [11], mob ntsws cancer [12–14], prostate cancer [15] ,16], pancreatic ductal adenocarcinoma [17], glioblastoma [18] thiab mob cancer mis [19,20]

Kev sib txuas ntawm cov tub ntxhais tsis zoo-fucosylation thiab kev nthuav tawm melanoma tau raug pov thawj ob qho tib si hauv vitro thiab hauv vivo, thawj zaug koom nrog FUT8 overexpression nrog cov qog nqaij hlav metastatic los ntawm glycomics thiab tom qab ntawd 'ntub' validating nws lub luag haujlwm hauv kev tswj hwm ntawm tes ntxeem tau thiab tsiv teb tsaws. L1CAM tau txheeb xyuas tias yog ib qho ntawm cov proteins tseem ceeb uas, ib zaug core-fucosylated, mediates pro-invasive phenotype hauv melanoma [10].

Lwm cov txheej txheem tseem ceeb qhia tau hais tias muaj feem xyuam rau FUT8 kev tswj hwm yog qhov kev hloov pauv ntawm epithelial-to-mesenchymal (EMT), tau kawm hauv cov ntsiab lus ntawm cov qog nqaij hlav tsis me me (NSCLC). Dhau li ntawm kev sib raug zoo nrog cov qog rov tshwm sim thiab metastases, FUT8 nce zoo li tshwm sim los ntawm -catenin/lymphoid enhancer-binding factor-1 (LEF-1) signaling [14]. Cov txheej txheem EMT sib raug zoo hauv glioblastoma yog hu ua proneural-to-mesenchymal kev hloov pauv (PMT), txhais tau hais tias cov qog nqaij hlav qog nqaij hlav hauv neural / oligodendrocytes-progenitor-zoo li lub xeev yuav hloov mus rau hypoxic ib puag ncig thiab ua chemo-radioresistant los ntawm kev hloov mus rau ntau dua. malignant mesenchymal zoo li lub xeev.

Raws li qhov kev tshawb pom ntawm EMT hauv NSCLC, kuj tseem PMT hauv GBM tsis ntev los no tau cuam tshuam nrog kev nce hauv FUT8 qhia thiab core-fucosylation, nyob rau tib lub sijhawm nrog kev loj hlob sai ntawm cov qog thiab matrix ntxeem tau. Thaum kuaj ntawm cov ntaub so ntswg los ntawm tus neeg mob, FUT8 cov protein, thiab cov tub ntxhais-fucosylation ua rau feem ntau hloov kho nyob rau hauv qhov txwv tsis pub muaj mesenchymal-zoo li GBM, thiab nws tau cuam tshuam nrog kev tsis txaus siab [18].

Daim duab 1. Fucose biosynthetic cellular txoj kev. Tus neeg sawv cev daim duab qhia txog txoj hauv kev fucose biosynthetic, uas yog txoj kev khaws cia (sab saum toj) thiab txoj kev de novo (hauv qab). Ntawm ib sab, 90 feem pua ​​​​ntawm GDP-L-fucose biosynthesis muab los ntawm txoj kev de novo: D-mannose yog ua tiav los ntawm GDPmannose-phosphorylase A (GMPPA), GDP-mannose 4, 6-dehydratase (GMDS) thiab Cov ntaub so ntswg tshwj xeeb hloov pauv antigen p35B (TSTA3). Ntawm qhov tod tes, 10 feem pua ​​​​ntawm GDP-L-fucose biosynthesis muab los ntawm txoj kev khaws cia, uas cov fucose dawb tau los ntawm kev noj haus yog rov ua dua los ntawm fucose kinase (FUK) thiab fucose-1-phosphate guanyltransferase (FPGT).

Tom qab ntawd, qhov kev sib txuas tshiab ntawm GDP-Lfucose yog nqa los ntawm cytoplasm mus rau Golgi apparatus los ntawm cov khoom thauj tshwj xeeb SLC35C1. Nws yog thaum kawg nyob rau hauv Golgi uas GDP-L-fucose yog conjugated rau glycopeptides los ntawm cov enzymes tshwj xeeb hu ua FUTs. Cov ntawv luv: PMM2: phosphomannomutase 2; GMPPA: GDP-mannosephosphorylase A; GMDS: GDP-mannose 4, 6-dehydratase; TSTA3: cov ntaub so ntswg tshwj xeeb transplantation antigen p35B; FUK: fucose kinase; FPGT: fucose{13}}phosphate guanylyltransferase; SLC35C1: Solute Carrier Family 35 Tswvcuab C1; FUTs: fucosyltransferase enzymes.

Cov txiaj ntsig kev ntseeg tau ntawm cov tub ntxhais kawm tshwj xeeb-fucosylated antigens siv los ua cov kab mob qog noj ntshav tshiab tau tshwm sim hauv cov haujlwm tsis ntev los no. Tseeb, qhov nce hauv core-fucosylated alpha-fetoprotein (AFP) hauv cov ntshav ntawm HCC cov neeg mob tuaj yeem qhia txog kev mob qog noj ntshav tshwj xeeb tshaj li qhov nce ntawm tag nrho AFP [21]; Tsis tas li ntawd, lub luag haujlwm ntawm core-fucosylated haptoglobin tau piav qhia hauv kev kuaj mob qog nqaij hlav pancreatic [22].

Txawm hais tias nyob rau ob peb xyoos dhau los, ntau qhov haujlwm tau pom tias cov tub ntxhais-fucosylation modulates ntau cov txheej xwm oncological, nws yog ib qho tseem ceeb uas yuav tsum tau hais tias kuj tsis zoo O- thiab N-txuas glycan cov qauv qhia los ntawm cov hlwb hloov pauv tuaj yeem cuam tshuam kev loj hlob ntawm cov qog nqaij hlav sib txawv thiab tau ua. taw tes raws li cov hom phiaj kho mob muaj peev xwm [23–27].

2.3. Tsom ntsoov rau Fucosylation nyob rau hauv lub mis Cancer

Ntau qhov kev tshawb fawb tau tshawb xyuas lub luag haujlwm ntawm lub davhlau ya nyob twg- thiab core-fucosylation hauv cov qauv kuaj mob tau los ntawm cov neeg mob qog noj ntshav mis siv cov txheej txheem sib txawv.

Thaum xub thawj, kua chromatography thiab huab hwm coj spectrometry (LC-MS) yog cov kev xaiv los kawm cov qauv ntawm glycosylation. Txawm li cas los xij, cov txheej txheem no tsis tuaj yeem khaws cov ntaub so ntswg histology [28]. Tsim los ntawm qhov no, lub matrix-pab laser desorption ionization MS imaging (MALDI-MSI) tau qhia kom tso cai rau kev tshawb nrhiav N-glycans hauv zos ncaj qha los ntawm cov ntaub so ntswg thaum khaws cov histopathological architecture [29].

Thawj daim ntawv thov ntawm MALDI-MSI hauv kev kuaj mob qog noj ntshav hauv lub mis koom nrog kev tshuaj xyuas ntawm cov qog thawj zaug. Qhov tseeb, thaj chaw mob qog noj ntshav tau tshwm sim los ntawm cov kab mob fucosylated, high-mannose, branched glycans nrog ntau hom N-glycans faib ntawm HER2 ntxiv thiab TNBC cov qauv [30]. Tsis tas li ntawd, kev hloov pauv hauv glycosylation qauv kuj tau kuaj pom hauv cov ntaub so ntswg necrotic, uas tsis muaj kev hloov kho fucose thiab pom cov ceg txwv tsis pub muaj kev hloov pauv ntawm sialic acid [31]. Los ntawm kev sib txuas MALDI-MSI nrog hydrophilic sib cuam tshuam ultra-siab ua kua chromatography, Herrera li al. kuj tau txheeb xyuas qhov tsis zoo ntawm tus nqi ntawm ib qho tseem ceeb-fucosylated tetra-antennary Nglycan (F(6)A4G4Lac1), kuj cuam tshuam nrog lymph node metastasis thiab kab mob rov ua dua, hauv cov neeg mob qog noj ntshav [32]. Los ntawm cov haujlwm no, Šˇcupáková et al. siv MALDI-MSI los kawm txog glycosylation variations ntawm thawj cov kab mob metastatic los ntawm 17 cov neeg mob uas mob qog noj ntshav siab los ntawm kev kho mob ceev ceev.

Ntawm cov ntawv sau tseg, cov kws sau ntawv pom tias muaj kev nce ntxiv hauv N-glycan los ntawm cov ntaub so ntswg ntawm lub mis mus rau cov qog ua ntej mus txog cov kab mob metastatic, tawm tswv yim rau yav tom ntej kev kuaj mob thiab kev kho mob tsis muaj peev xwm ntawm high-mannose, fucosylated, thiab complex N-glycans hauv kev kho mob siab heev. kev teeb tsa. Hauv particular, cov pob txha metastases tau pom qhov pom tau tias muaj kev nce ntxiv hauv cov tub ntxhais-fucosylation, mirrored los ntawm kev txo qis hauv high-mannose glycans [33].

Lwm lub luag haujlwm lees paub ntawm fucosylation hauv kev mob qog noj ntshav mis tau pom nyob rau hauv cov qog angiogenesis thiab vascularization. Nyob rau hauv cov lus no, lub davhlau ya nyob twg-fucosylation ntawm cov clusterin glycoprotein yog kev kho mob qog noj ntshav tshwj xeeb tom qab kev hloov pauv pom feem ntau hauv tib neeg lub mis mob qog noj ntshav. Qhov kev hloov pauv no tso cai rau kev sib cuam tshuam ntawm pawg fucosylated thiab C-hom lectin (DC-SIGN), pom ntawm macrophages / myeloid hlwb, txhawb kev tsim cov pro-angiogenic cytokines (ie, vascular endothelial kev loj hlob yam, VEGF; IL{{ 6}}) thaum cuam tshuam qhov kev qhia ntawm HLA-DR [34].

Hais txog lub luag haujlwm ntawm fucosylation ua biomarker hauv kev mob qog noj ntshav mis, kev tshuaj ntsuam xyuas immunohistochemical thiab cov ntaub so ntswg microarray ntawm FUT8 tau pom tias muaj kev sib koom ua ke ntawm FUT8 qib siab, lymph node metastases, thiab theem kab mob, kuj tseem khaws cov txiaj ntsig tsis zoo los ntawm kev koom nrog txo cov kab mob- dawb thiab tag nrho cov ciaj sia [35] Txawm li cas los xij, txog niaj hnub no, tsis muaj core-fucosylated biomarker tau raug lees paub rau lub mis, tsis yog rau kev kwv yees lossis rau lub hom phiaj prognostic [36]. Kev soj ntsuam glycoproteomic los ntawm cov qog nqaij hlav thiab los ntawm cov ntshav ntshav ntawm cov neeg mob qog noj ntshav tuaj yeem qhia cov biomarkers tshiab thiab muab cov kev kho mob tshwj xeeb.

2.4. Kev cai ntawm FUT8 thiab Core-Fucosylation

Txij li thaum FUT8 yog qhov tseem ceeb hauv kev tswj cov tub ntxhais-fucosylation, qhov kev ntsuam xyuas meej ntawm nws cov kev cai ntawm qib cellular yog qhov tseem ceeb tshaj plaws. Kev tshuaj ntsuam Epigenetic tau qhia txog qib qis ntawm FUT8 methylation hauv cov qog nqaij hlav xws li hepatocellular carcinoma, qhia tias feem cuam tshuam ntawm FUT8 txoj cai yuav nyob ntawm qib transcriptional thiab posttranscriptional [37], ib qho kev tshawb nrhiav loj heev.

2.4.1. Kev cai Transcriptional

Cov neeg tseem ceeb ntawm FUT8 transcription tseem tsis tau piav qhia tag nrho. Kev soj ntsuam genomic ntawm FUT8 noob, encoded ntawm chromosome 14q23.3, tau qhia txog qhov muaj tsawg kawg yog cuaj exons, nrog yim exons hla cov txheej txheem coding, nrog rau qhov muaj tsawg kawg yog peb tus neeg txhawb nqa sib txawv [38]. Xav paub ntau ntxiv, exon 1 encodes tsuas yog rau 50 Untranslated Regions (UTR) sequences uas muaj peev xwm losis tswvyim dabtsi qhov chaw rau transcription yam (ie, TATA-box, cMyb, GATA-1, bHLH) [39].

Ntawm qhov kev ceeb toom, qhov kev hloov pauv ntawm qhov zoo tau raug lees paub hauv melanoma nrog Transforming Growth Factor (TGF- )-Induced Factor homeobox 2 (TGIF2) [10], whereas ib qho tsis zoo tau piav qhia nrog qhov transcription factor ASCL1 nyob rau hauv me me cell ntsws cancer [ 40] thiab glioblastoma [18]. Cov ntaub ntawv hais txog qhov cuam tshuam ntawm TGIF2 thiab ASCL1 hauv FUT8 txoj cai hauv kev mob qog noj ntshav mis tseem tsis muaj [10,40].

Ib lub tswv yim tswv yim ntawm FUT8 induction nyob rau hauv lub mis mob cancer tau raug lees paub raws li TGF -induced EMT (Daim duab 2). Thaum FUT8 overexpression ua raws li kev txhawb nqa rau TGF -induced EMT, FUT8 knockdown suppresses cell invasiveness thiab metastatic peev xwm. Txawm li cas los xij, qhov tseeb cov neeg ua si uas tsav lub axis no tseem tsis tau txheeb xyuas, nrog -catenin/lymphoid enhancer-binding factor-1 lossis E-box-binding transcription factor (ie, SNAIL lossis TWIST) yog thawj tus neeg sib tw vim yog Cov txheej txheem txhawb nqa cov txheej txheem thiab cov ntaub ntawv tau txais hauv lwm cov qog nqaij hlav [14,20].

Daim duab 2. Fucosylation hauv Breast Cancer (BC): Biomarker thiab Therapeutic Vulnerability. Lub luag haujlwm ntawm Fucosylation hauv BC. Sab saum toj: Kev hloov pauv thiab xa rov qab cov kev cai ntawm FUT8 qhia hauv BC (liab: txhawb FUT8 cov ntawv sau; ntsuab: inhibiting FUT8 transcription / txhais). Nruab nrab: Fucosylation raws li biomarker hla cov kab mob, tsis qhia cov qog nqaij hlav noj qab haus huv, kev qhia nruab nrab hauv cov kab mob hauv zos (txuas nrog lymph node metastasis), thiab kev qhia siab tshaj plaws hauv cov kab mob metastatic. Hauv qab: Pharmacological inhibition hauv cov qauv qog ua ntej ntawm 2FF induces CTL-/NK-mediated qog tua, thiab kev sib koom ua ke nrog cov tshuaj tiv thaiv kab mob (piv txwv li, anti-PDL1 mAb), thaum kawg txo cov qog loj hlob kinetics.

Cov ntawv luv: LN: lymph node; TGF: Hloov Kev Loj Hlob Factor beta; miR: microRNA; circERBB2: ncig ERBB2 RNA; EMT: epithelial hloov mus rau mesenchymal; AP-2 : activator protein 2 ; STAT3: Teeb liab Transducer thiab Activator ntawm Transcription 3; FUT8: fucosyltransferase 8; PDL1, Programmed Tuag Ligand 1; mAb, monoclonal antibody; Mφ: macrophage; VEGF: vascular endothelial loj hlob yam; CTL: cytotoxic T-lymphocytes; ICB: tiv thaiv qhov chaw tiv thaiv; HLA-DR: Human-leukocyte-associated Antigen-DR; IL: interleukin; IFN: interferon-gamma; 2FF: 2-fluoro fucose; G-CSF: granulocyte colony-stimulating factor; DC-SIGN: Dendritic Cell-Specific Intercellular adhesion molecule-3-Tau qhov tsis yog-integrin. Tsim nrog BioRender.com.

Lwm qhov haujlwm tau nthuav tawm FUT8 txoj cai axis hauv kev mob qog noj ntshav ntawm lub mis raws li qhov hloov pauv ntawm cov activator protein 2 (AP-2 ) khi rau Signal Transducer thiab Activator of Transcription 3 (STAT3) [41]. Cov complex no tiv thaiv STAT3 phosphorylation thiab STAT3-mediated FUT8 transcription. Co-immunoprecipitation assays tau pom muaj kev sib cuam tshuam ntawm AP-2 thiab STAT3 (tab sis tsis yog phospho-STAT3), thiab chromatin immunoprecipitation tsom xam tau qhia phospho-STAT3 khi rau FUT8 tus txhawb nqa (Daim duab 2) [41]. Ntawm qhov kev ceeb toom, sib nrug los ntawm kev txhawb nqa lub cev tiv thaiv kab mob microenvironment, STAT3 teeb liab hauv cov qog nqaij hlav cancer mis tsis yog tsuas yog txhawb nqa kev loj hlob thiab kev coj tus cwj pwm metastatic tab sis kuj txhawb kev tiv thaiv kab mob thiab tiv thaiv cyclin-dependent kinase inhibitors (CDKi) [42,43]. Rau cov laj thawj uas tau hais los saum no, STAT3 yog suav tias yog lub hom phiaj kho mob qog noj ntshav hauv lub mis, txawm hais tias kev tsom ncaj qha tau pom muaj teeb meem loj hauv cov tshuaj pharmacokinetic, nrog kev tsis ncaj lossis kev sib xyaw ua ke tam sim no nkag mus rau kev kuaj mob [44–46].

2.4.2. Post-Transcriptional Regulation: miRNAs

Cov kev tshawb fawb hauv vitro siv cov kab mob hepatocellular carcinoma cell tau pom los ntawm luciferase tus kws tshaj xov xwm thev naus laus zis uas ob microRNA, miR-34a thiab miR-122, ua lub luag haujlwm tsis zoo hauv FUT8 kev tswj hwm tom qab hloov pauv los ntawm kev cuam tshuam nrog FUT{{ 4}}UTR thiab thaum kawg lawv tuaj yeem hloov kho cov qauv glycosylation [47]. Interestingly, nyob rau hauv ib pawg ntawm 25 tus neeg mob qog noj ntshav mis, ob qho tib si miR-34a thiab miR-122 tau kuaj pom tias muaj microRNAs nyob rau hauv cov tshuaj kho mob neo-adjuvant. Lawv cov qib tau nce qib hauv cov neeg mob cancer mis, ua tiav cov lus teb ua tiav (pCR) tom qab siv tshuaj kho mob neoadjuvant [48]. Cov koom tes tshwj xeeb ntawm tes rau miR-34a thiab miR{12}} kev qhia yuav tsum tau ua kom tiav thiab tsom mus rau (Daim duab 2).

Lwm tus miRNA tus cwj pwm raws li qhov ua tau FUT8 regulator yog miR-10b, nrog rau cov lus pom zoo rau cov tub ntxhais-fucosylation, cellular motility, thiab proliferation [19]. Mechanistically, miR-10b tau pom tias yuav txo qis qhov kev hloov pauv hloov pauv AP-2 , uas tig mus rau STAT3, tiv thaiv nws cov phosphorylation, yog li FUT8 transcription [41]. miR-10 b lub luag haujlwm hauv cov neeg mob qog noj ntshav hauv lub mis metastatic tau pom tias yog qhov tseem ceeb hauv cov kab mob siab heev raws li kev ua kom lub Twist transcription factor [49]. Txawm li cas los xij, cov ntaub ntawv tsis sib haum xeeb tau sau los ntawm kev ntsuam xyuas lub luag haujlwm prognostic ntawm miR-10b hauv cov neeg mob qog noj ntshav mis [50,51]. Zuag qhia tag nrho, cov ntaub ntawv glycosylation thiab kev soj ntsuam proteomic piav qhia txog kev cuam tshuam ntawm miR-10b ntawm FUT8 thiab cov qauv ntawm tes fucosylation tseem tsis muaj thiab yuav tsum tau soj ntsuam kom meej.

miR-198 kuj tseem ua raws li kev tswj hwm tsis zoo ntawm FUT8 qhia ob qho tib si hauv cov kab mob hauv plab thiab cov qog nqaij hlav qog nqaij hlav tsis me me, nrog miR-198 inhibition ua rau muaj kev txhoj puab heev phenotype thiab kev muaj sia nyob tsis zoo [52, 53] ib. Thaum lub tshuab txuas ntawm miR198 thiab FUT8 tseem tsis tau tshawb nrhiav, nws tau pom tias ncig ERBB2 RNA (circ-ERBB2) txhawb nqa cov txheej txheem mob qog noj ntshav mis, kev cuam tshuam ntawm tes, thiab kev loj hlob los ntawm kev sib tw nrog miR-198 thiab miR{ {12}}p raws li ib qho endogenous RNA daim txhuam cev (Daim duab 2) [54,55].

For more information:1950477648nn@gmail.com