Lub luag haujlwm ntawm Defensins hauv Tumor Biology Part 2
May 25, 2023
3. Kev tiv thaiv kab mob muaj feem cuam tshuam rau hauv cov qog microenvironment
Tau txais kev pom ntawm cov qog microenvironment yog qhov tseem ceeb los txhim kho kev nkag siab ntawm cov kab mob qog noj ntshav-tiv thaiv kab mob sib cuam tshuam, thiab cov teebmeem ntawm kev tiv thaiv kab mob tiv thaiv kom pib, a-defensins muaj chemotactic zog (Daim duab 3). Cov a-defensins HNP-1rau 3 muaj cov nyhuv chemotactic ntawm CD4 ntxiv / CD45RA ntxiv rau qhov tsis zoo thiab CD8 ntxiv rau T hlwb, monocytes tsis paub qab hau dendritic hlwb (duab), thiab mast cells (53-581. Chemoattraction ntawm T. hlwb andimDCs los ntawm HNPs tuaj yeem cuam tshuam nrog pertussis toxin, qhia tias qhov no yog kho los ntawm Gxi protein-coupled receptor (57]. Cov 3-defensins kuj chemoattract subsets ntawm lub cev tiv thaiv kab mob (Daim duab 3). hBD-1 rau 3 muaj peev xwm nyiam cov hlwb hloov nrog CC chemokine receptor 6 (CCR6), uas qhia tias Th cells, Treg, imDCs, thiab neutrophils tuaj yeem raug xaiv los ntawm hBD-1 [59-611. immunoglobulin-fusion cov proteins ntawm hBD-2 thiab hBD{23}} kuj cuam tshuam nrog CC chemokine receptor 2 (CCR2) thiab tuaj yeem nyiam CCR2 ntxiv rau peripheral ntshav mononuclear hlwb (PBMCs) (621.
Interestingly CCR2 thiab CCR6 yog cov receptors tseem ceeb rau kev nrhiav cov tshuaj tiv thaiv kab mob rau cov ntaub so ntswg, xws li cov qog (63Synthetic thiab tawv-derived hBD-2 chemoattracted lub cim xeeb subset ntawm tib neeg peripheral ntshav T (CD4 ntxiv / CD45RO ntxiv) cov hlwb thiab CD34 ntxiv rau cov progenitor-derived DCs [59]. Tsis tas li ntawd, hBD-2 tau nyiam mast hlwb hauv G protein-phospholipase C (PLC) kev sib kho (64. Ob leeg hBD-3 thiab 4 induced migration ntawm monocytes, tab sis tsis yog neutrophils los yog eosinophils (65,661. Rau ob qho tib si peptides no tshwm sim, nthuav, tsis muaj mobilization ntawm intracellular Ca' ntxiv .
Cov qog microenvironment hais txog ib qho chaw tshwj xeeb thiab nyuaj nrog rau cov qog hlwb, cov hlwb nyob ib puag ncig, cov hlab ntsha, thiab cov kab mob extracellular. Cov qog hlwb thiab lawv cov hlwb nyob ib puag ncig thiab cov molecules tuaj yeem cuam tshuam los tsim microenvironment uas txhawb cov qog loj hlob thiab kis tau.
Cov qog microenvironment plays lub luag haujlwm tseem ceeb hauv kev txhim kho thiab kho cov qog. Nyob rau hauv xyoo tas los no, cov kev tshawb fawb tau pom tias muaj ntau hom kev tiv thaiv kab mob hauv cov qog microenvironment, suav nrog T lymphocytes, B lymphocytes, cov cell killer ntuj, thiab cov hlwb dendritic, uas koom nrog hauv cov txheej txheem ntawm cov qog tiv thaiv kab mob.
Txawm li cas los xij, cov qog hlwb thiab lwm cov tshuaj tiv thaiv kab mob xws li MDSCs thiab M2 macrophages tuaj yeem ua rau lub cev tiv thaiv kab mob los ntawm cov txheej txheem xws li secreting immunosuppressive molecules thiab inhibiting lymphocyte muaj nuj nqi, yog li evading qhov kev tawm tsam ntawm lub cev. Yog li ntawd, cov qog microenvironment muaj kev cuam tshuam zoo rau kev ua tiav ntawm cov qog immunotherapy.
Tam sim no, qog tshuaj tiv thaiv kab mob tau dhau los ua ib qho tseem ceeb ntawm kev kho cov qog, xws li CTLA-4, PD-1, PD-L, thiab lwm yam tshuaj tiv thaiv kab mob tiv thaiv kab mob tau siv dav hauv kev kho mob. Los ntawm inhibiting immunosuppressive molecules thiab inhibitory yam nyob rau hauv cov hlwb, txhim khu kev ua haujlwm ntawm lub cev tiv thaiv kab mob, thiab txhawb kev tiv thaiv qog nqaij hlav, kom ua tiav lub hom phiaj ntawm kev kho cov qog. Yog li ntawd, kev nkag siab tob txog kev tswj hwm ntawm cov qog microenvironment ntawm lub cev tiv thaiv kab mob thiab nws txoj kev sib raug zoo nrog cov qog nqaij hlav tuaj yeem muab cov tswv yim tshiab thiab cov lus qhia rau kev tshawb fawb thiab kev loj hlob ntawm qog immunotherapy. Los ntawm qhov no, peb tuaj yeem pom qhov tseem ceeb ntawm kev txhim kho kev tiv thaiv. Cistanche muaj cov txiaj ntsig ntawm kev txhim kho kev tiv thaiv. Cov polysaccharides hauv cov nqaij tuaj yeem tswj hwm 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
Defensins tsis tsuas yog tuaj yeem nyiam lub cev tiv thaiv kab mob xwb, tab sis lawv kuj ua rau muaj kev cuam tshuam ncaj qha (Daim duab 4). HNPs ua rau lub degranulation ntawm mast hlwb, ua rau tso tawm ntawm histamine, ua ke nrog ntau yam cytokines thiab chemokines [67]. Qhov loj spectrum ntawm cov neeg kho kom haum xeeb tso tawm los ntawm mast hlwb tuaj yeem nrhiav DCs, eosinophils, thiab neutrophils thaum sib txuas ua ke nce endothelial permeability [68,69]. Dhau li ntawm chemoattracting monocytes, HNPs kuj nce kev sib cuam tshuam ntawm monocyte-endothelial, ua kom yooj yim rau lawv cov extravasation thiab nkag mus rau hauv cov ntaub so ntswg [70].
Lub oxidative tawg ntawm monocytes kuj nce ntxiv thaum HNPs nyob. Kev kho mob ntawm cov hlab ntsws epithelial nrog HNP-1–3 txhim kho CXCL8 thiab CXCL5 qhia thiab tso tawm [71,72], thiab ob qho tib si CXC-chemokines paub txog cov tshuaj tua kab mob neutrophils [73,74]. Hauv plasmacytoid DCs (pDCs), HNP-1 tau raug tshaj tawm los ua kom muaj kev cuam tshuam rau hom I interferons (IFNs) thiab IL-6, ua ke nrog kev txhim kho TLR9 ua kom [75,76]. Hom I IFNs muaj lub luag haujlwm tseem ceeb hauv kev tiv thaiv kab mob qog noj ntshav, nce DC maturation, DC-CD8 ntxiv rau T cell cross-priming, T cell cytotoxicity, natural killer (NK) cell cytotoxicity, macrophage o, thiab ntau dua [77]. Tsis tas li ntawd, hauv LPS-primed macrophages, HNP{20}} tuaj yeem txhawb nqa pyroptosis thiab nce IL-1 tso tawm los ntawm kev ua kom mob plab los ntawm P2X7 receptor [78]. HNP-1 tau tshaj tawm tias yuav ua rau muaj kev ntxhov siab oxidative thiab autophagy ntsig txog cov noob, thiab nrog qhov kev txhim kho endocytosis ntau cov antigens tuaj yeem ua tiav thiab nthuav tawm [79]. Los ntawm P2Y6 receptor signaling pathway, HNP-1 suppresses neutrophil apoptosis, ua rau lawv lub neej ntev [80]. Jurkat T hlwb, thaum raug HD-5 thiab HNP-1, hloov cell zoo thiab rov kho ntawm actin cytoskeleton.
Ob leeg peptides kuj nce cell adhesion rau fibronectin, thiab yog li ntawd, Caco-2 hlwb kho nrog HD-5 los yog HNP-1 khaws cia ntau T hlwb ntau dua li cov hlwb tsis kho [81]. Co-cultures muaj xws li non-small cell lung cancer (NSCLC) cells thiab peripheral blood mononuclear cells tau pom tias tsim ntau IFN- thaum HNP-1 tau ntxiv [82]. Txij li thaum IFN- yog ib qho tseem ceeb ua rau lub cev tiv thaiv kab mob, nws qhov nce hauv cov qog microenvironment tuaj yeem ua lub luag haujlwm tseem ceeb hauv kev tiv thaiv kab mob qog noj ntshav. IFN- yog txuas rau T cell thiab NK cell tsiv teb tsaws, poob ntawm kev ua haujlwm thiab kev tawm tsam ntawm Treg hlwb, kev loj hlob ntawm NK hlwb, thiab nce hauv priming thiab antigen nthuav tawm los ntawm antigen-presenting cells [83].
Ib qho kev txhim kho ntawm lub cev tiv thaiv kab mob, kev nce hauv kev nthuav qhia antigen, thiab ntau dua antigen tso tawm vim cov qog hlwb tuag tuaj yeem xav tias yuav ua rau muaj zog tiv thaiv qog noj ntshav. Yog li, tib neeg -defensins ob qho tib si ncaj qha thiab ncaj qha nce lub cev tiv thaiv kab mob qhov chaw uas lawv tau nthuav tawm lossis tso tawm, suav nrog hauv cov qog microenvironment.
Lwm qhov kev sib cuam tshuam uas tuaj yeem cuam tshuam rau hauv cov qog microenvironment yog kev sib cuam tshuam ntawm cov tshuaj tiv thaiv thiab cov khoom ntxiv, txawm tias cov qauv kev sib cuam tshuam tsis sib haum tau raug npaj. Ua ntej, kev khi ntawm HNP-1 rau kev ua kom muaj txiaj ntsig ntxiv 1 (C1) thiab C1 inhibitor (C1i) complexes tau raug tshaj tawm. Qhov pib inactivation ntawm C1 los ntawm C1i yog yuav tsum tau, raws li C1i yuav hloov lub conformation ntawm C1 tso cai rau defensin khi. Cov C1-C1i complexes tuaj yeem khi thiab tshem tawm cov tshuaj tiv thaiv ntawm lawv lub cev muaj zog hauv tib neeg plasma los ntawm kev txhawb nqa cellular uptake ntawm HNP-C1-C1i complexes, yog li ua txoj kev tiv thaiv rov ua dua tshiab. Qhov kev txhawb nqa no tuaj yeem tiv thaiv qhov tsis xav tau cytotoxic raug mob rau cov ntaub so ntswg ib puag ncig [84].
Txawm li cas los xij, tsab ntawv tshaj tawm tom qab tau piav qhia tias HNP-1 tshwj xeeb khi rau collagen zoo li stalks ntawm C1q, inhibiting nws cov haujlwm hemolytic. Hauv tsab ntawv tshaj tawm tom kawg no qhov kev xav rov ua dua tshiab tau sib tw, thiab nws tau pom tias HNP-1 ua haujlwm ua ib qho kev tiv thaiv ntxiv hauv microenvironment ntawm neutrophils uas tso tawm cov defensin [85]. Xwb, thaum HNP-1 rau 3 tau kho rau lub phaj, C1q tuaj yeem khi, ua rau txoj hauv kev zoo sib xws thiab ua rau C4b khi rau phaj [86]. Kev tshawb fawb ntxiv hauv ELISA-raws li system tau thov tias HNP-1 hauv cov tshuaj khi ob leeg mannose-binding lectin (MBL) thiab C1q. Cov txiaj ntsig tau raug txhais raws li inhibition ntawm ob qho tib si classical thiab lectin txoj kev [87].
Li no, zoo li muaj qhov sib txawv ntawm hom kev ua haujlwm ntawm qhov chaw sib khi lossis ua kua-theem HNP-1. Nto-bound HNP-1 tuaj yeem ua raws li opsonin los ntawm kev khi thiab ua kom muaj zog ntxiv, thaum lub sij hawm ua kua HNP-1 tej zaum yuav adsorbed los ntawm cov ntshav cov protein, xws li C1-C1i complexes, los yog tej zaum yuav ua raws li ib tug ntxiv inhibitor [84–87]. HNP-1 tsis yog tib qho kev tiv thaiv uas khi C1q, raws li hBD-2 tau piav qhia tsis ntev los no los cuam tshuam txoj hauv kev ntxiv los ntawm kev khi ruaj khov rau C1q, tiv thaiv cov ntaub so ntswg mob tiv thaiv kev ua kom tsis muaj zog ntawm cov txheej txheem ntxiv [88 ]. Txawm li cas los xij, hBD-2 tsis cuam tshuam rau lwm txoj hauv kev. Kev sib cuam tshuam ntawm cov defensins thiab cov ntsiab lus ntxiv yuav tsum tau tshawb xyuas ntxiv. Yog tias defensins yuav ua kom lub zog ntxiv, qhov no yuav ua rau muaj mob ntau dua hauv cov ntaub so ntswg uas lawv tso tawm, ua rau muaj cov ntaub so ntswg ntau dua thiab muaj peev xwm tso tawm antigen los ntawm cov qog hlwb. Txawm li cas los xij, yog tias defensins inhibit qhov kev sib txuas ntxiv, nws yuav yog ib txoj hauv kev los tiv thaiv cov ntaub so ntswg, tab sis qhov no txhais tau tias cov qog hlwb kuj tuaj yeem tau txais txiaj ntsig los ntawm kev tiv thaiv no.
-defensins muaj ntau yam cuam tshuam rau (immune) hlwb ib yam nkaus (Daim duab 5). Ib sab ntawm qhov induction ntawm kev tsiv teb tsaws, hBD-2 kuj tuaj yeem ua rau cov tshuaj histamine tso tawm, intracellular Ca2 ntxiv rau kev mob, thiab cyclooxygenase-1 kho kom haum xeeb prostaglandin D2 ntau lawm los ntawm mast cells [89]. Cov teebmeem no tuaj yeem raug tshem tawm los ntawm pertussis toxin, qhia tias hBD-2 kho cov teebmeem no hauv G i dependent [89]. Nyob rau hauv cov qauv qog raws li sau qoob loo macrophages thiab qog nqaij hlav cancer mis los ntawm Swiss albino nas, hBD-2 kev kho mob ntawm macrophages tau nce qhov kev qhia ntawm inflammatory cytokines (IFN- , interleukin 1 (IL-1) thiab qog necrosis. factor (TNF- )) thiab chemokines (CXCL1, CXCL5, thiab CCL5). Hauv kev sib koom ua ke ntawm hBD-2-stimulated macrophages thiab qog hlwb, feem ntau ntawm cov qog nqaij hlav tuag tau kuaj pom piv rau cov kab lis kev cai nrog cov macrophages uas tsis muaj zog [90]. Thaum hBD-3 tau ntxiv rau tib neeg txoj hlab ntsws du leeg hlwb, qhov nce ntxiv ntawm cov tshuaj tiv thaiv kab mob proinflammatory CXCL8 tau ntsuas hauv kab lis kev cai supernatant. Qhov no tsis tau pom thaum ntxiv hBD-1. Tsis tas li ntawd, CXCL8 ntau lawm tau kho los ntawm CCR6 thiab los ntawm cov teeb liab ntxiv-tso tswj kinase 1/2 mitogen-activated protein kinase (ERK1/2 MAPK), c-Jun N-terminal kinase mitogen-activated protein kinase (JNK MAPK) thiab nuclear factor. -κB (NF-κB) kev taw qhia txoj hauv kev.
\ Tsis tas li ntawd, hBD-3 ib txhij induced apoptosis ntawm cov hlab ntsha du leeg hlwb, sib koom tswj los ntawm mitochondrial reactive oxygen hom [91]. hBD-3 kuj tau tshaj tawm los ua rau Tus Xov Tooj Zoo li receptors (TLRs) TLR1 thiab TLR2 ntawm cov tshuaj tiv thaiv kab mob tam sim no, ua rau txoj hauv kev NF-κB hauv monocytes thiab mature DCs, thaum kawg txhim kho cov noob qhia ntawm cov kab mob inflammatory [92 ]. Hauv nas Flt-3-induced dendritic cells thiab tib neeg peripheral ntshav mononuclear hlwb, hBD-3 kuj tseem tuaj yeem cuam tshuam nrog TLR9 los txhim kho cov lus teb rau cov kab mob DNA [93]. Hauv cov qauv nrog tib neeg Langerhans cell-zoo li DCs (LC-DCs), nws tau pom tias hBD-3 induced maturation, nce CCR7 qhia, thiab T pab hom 1 (Th1) skewing muaj nuj nqi hauv cov LC-DCs. Tsis tas li ntawd, hBD3- txhawb nqa LC-DCs txhawb kev loj hlob thiab IFN- tso tawm los ntawm tib neeg T hlwb. Cov teebmeem zoo sib xws tau pom nrog thawj qhov kev hloov pauv hauv DCs los ntawm tib neeg cov tawv nqaij explants, uas ntxiv dag zog rau qhov kev xav tias hBD-3 pab txhawb rau kev koom ua ke ntawm innate thiab adaptive tiv thaiv raws li endogenous adjuvant [94].
4. Cov pov thawj ntawm kev tiv thaiv kev tiv thaiv kab mob hauv (tsiaj) qauv
Ntau qhov kev tshawb fawb pom tau tias HNPs yog cov tshuaj tiv thaiv kab mob muaj zog hauv cov qauv murine. Intranasal xa ntawm cov defensins ua ke nrog ovalbumin (OVA) txhim kho cov kab mob immunoglobulin G (IgG) cov lus teb los ntawm CD4 ntxiv rau Th1- thiab Th2- hom cytokines thiab txhawb kev sib cuam tshuam ntawm B thiab T cell [95]. Hauv lwm txoj kev tshawb fawb, kev txhaj tshuaj intraperitoneal ntawm HNPs hauv cov nas tuaj yeem tswj hwm cov tshuaj tiv thaiv tshwj xeeb Ig ntau lawm, lees paub tias cov tshuaj tiv thaiv tawm los ntawm neutrophils tuaj yeem pab txhawb rau ob qho tib si hauv lub cev thiab kev tiv thaiv kab mob [96]. Hauv kev tsim CT26 nyuv qog noj ntshav thiab 4T1 tus qauv mob qog noj ntshav mis, kev qhia intratumoral ntawm ib daim ntawv zais cia ntawm HNP-1 ua rau cov tshuaj lom neeg thiab ua kom muaj zog ntawm imDCs, ua ke nrog cov qog loj hlob inhibition, nce CTL infiltration thiab nce hauv kev tiv thaiv kab mob humoral. lus teb [97]. Kev tswj hwm ntawm HNP-2 nyob rau hauv transplanted human papillomavirus-positive (HPV plus) keratinocytes uas tsim neoplastic lesions nyob rau hauv nas reverted ib tug nquag pom lub cev hloov pauv nyob rau hauv kev loj hlob mob qog noj ntshav los ntawm recruiting intravenously txhaj tib neeg DCs rau lub qog [98].
Tsis tas li ntawd, kev txhaj tshuaj DNA nrog fusion constructs uas muaj hBD-2 tuaj yeem ua rau muaj zog humoral lub cev tiv thaiv kab mob tawm tsam lwm yam uas tsis yog-immunogenic lymphoma antigen hauv cov nas, ua rau muaj kev tiv thaiv zoo thiab kho mob qog noj ntshav [62]. Thaum HNPs lossis hBDs tau koom nrog kev tswj hwm hauv lub cev nrog OVA hauv C57BL / 6 nas, HNP-1 thiab hBD-2 induced ntau dua OVA-specific IgG, qis IgM thiab qis dua IFN- , thaum HNP{{11 }} induced qis IgG thiab siab dua IgM, thiab hBD-1 ntxias siab IgG, siab dua IgM thiab siab dua IL-10 [99]. Kev tswj hwm subcutaneous ntawm hBD-2 hauv cov nas pom qhov ua tau zoo thiab hBD{16}} nkag mus rau hauv cov hlab ntsha sai sai, tso cai rau cov kev cuam tshuam hauv lub cev yog tias kev kho mob los ntawm txoj kev no puas dhau los ua kev xaiv [100].
Cov tshuaj tiv thaiv kab mob los yog tshuaj tiv thaiv qog nqaij hlav ntawm defensins tsis tsuas yog pom hauv nas. Hauv Drosophila, piv txwv li, thaum lub defensin gene (def) raug tshem tawm ntawm ob qho tag nrho los ntawm CRISPR / Cas9, tus dev qog loj hlob tsis tau txwv ntxiv lawm thiab pom cov qog cell tuag tsawg dua. Qhov no txiv hmab txiv ntoo ya defensin yog ib txwm qhia nyob rau hauv cov ntaub so ntswg tiv thaiv kab mob, thiab nws zoo nkaus li pom kev noj qab haus huv thiab qog hlwb los ntawm aberrant phosphatidylserine qhia nyob rau hauv cov qog hlwb, paub tseeb hais tias ib tug kev tshawb xav hais ua ntej. TNF yam homolog Eiger yog xav tau rau qhov no phosphatidylserine raug rau cov qog hlwb, tso cai rau kev lees paub los ntawm defensin [101]. Yang et al. speculated tias defensins tejzaum nws khi rau antigenic microbial membranes tom qab tua cov microbes, tsim defensin-antigen complexes. Complexes zoo li qhov no tuaj yeem ua rau sab hauv los ntawm imDCs, tejzaum nws nyob rau hauv txoj kev tiv thaiv-receptor-kho, txhim kho qhov kev nthuav qhia antigen ntawm cov hlwb. Xav txog qhov no, cov complexes kuj tseem tuaj yeem tsim nrog lwm yam (cov qog nqaij hlav) antigens, nrog rau cov txiaj ntsig zoo ntawm tag nrho cov immunogenicity ntawm cov qog [102]. Ntxiv mus, -defensins kuj tau tshaj tawm tias inhibit angiogenesis, piv txwv li hauv pathologic retinal neovascularization thiab cov kev ntsuam xyuas angiogenesis sib txawv xws li sprout formation assay thiab qaib chorioallantois membrane (CAM) assay [103,104].
5. Kev nthuav qhia ntawm Defensins hauv Cancer
Thaum saib ntau dua thoob ntiaj teb ntawm kev qhia ntawm defensins hauv qog noj ntshav, zoo li muaj qhov sib txawv ntawm cov nqaij mos thiab cov qog nqaij hlav rau ob leeg - thiab -defensins. Kev txheeb xyuas kev sib koom ua ke ntawm cov lej lej ntawm ntau dua 10 000 cov neeg mob thoob plaws 31 hom mob qog noj ntshav los ntawm Cancer Genome Atlas lees paub qhov sib txuas ntawm interferon (IFN) kev ua, cov tshuaj tiv thaiv kab mob, thiab kev tiv thaiv kev tiv thaiv kab mob. Hom-I IFN thiab - thiab -defensin genes tau homozygously tshem tawm hauv yuav luag 20 hom mob qog noj ntshav uas muaj ntau zaus, thiab homozygous deletion ntawm IFNs tau txuas rau lub sijhawm luv luv tag nrho thiab tsis muaj kab mob nyob hauv qee hom mob qog noj ntshav. Tshwj xeeb tshaj yog qhov piv ntawm homozygous deletion ntawm IFNs (HDI) thiab defensins (HDD) yog qhov txaus siab, raws li nyob rau hauv hom mob qog noj ntshav feem ntau cov HDI / HDD piv tau ntau dua piv rau hom mob qog noj ntshav tsawg, qhia tias HDI / HDD yog ib qho molecular. mechanism ntawm kev koom tes nyob rau hauv carcinogenesis ntawm cov qog nqaij hlav. Qhov sib piv HDI / HDD no yog qhov siab tshaj plaws hauv lub hlwb qis-qib glioma, glioblastoma, pancreatic adenocarcinoma, thiab mesothelioma.
Hauv qhov sib piv, cov qog nqaij hlav uas muaj qhov sib piv HDD / HDI siab yog prostate adenocarcinoma, colon adenocarcinoma, qhov quav adenocarcinoma, daim siab hepatocellular carcinoma, thiab zis carcinosarcoma. Ntawm ob pawg no yog cov qog nqaij hlav uas muaj qhov sib npaug ntawm HDI thiab HDD, thiab cov no muaj xws li zais zis urothelial carcinoma, ntsws adenocarcinoma, ntsws squamous cell carcinoma, mis invasive carcinoma, zes qe menyuam cystadenocarcinoma, lub taub hau thiab caj dab squamous cell carcinoma, daim tawv nqaij cutaneous melanoma. , esophageal carcinoma, sarcoma thiab plab adenocarcinoma [105]. Gene qhia kev txheeb xyuas pom cov cim qhia ntawm kev ua kom muaj oncogenic thiab cell-cycle txoj hauv kev thiab kev tawm tsam ntawm cov noob koom nrog hauv txoj kev tiv thaiv kab mob thaum muaj homozygous deletion ntawm IFN thiab defensin noob, qhia txog qee yam qog-tawm cov nyhuv ntawm defensins uas raug tshem tawm thaum deletion tshwm sim. [105]. Cov tshuaj tiv thaiv kab mob no sib txawv ntawm cov tsev neeg defensin (thiab ), tab sis qhov sib txawv kuj pom hauv tsev neeg.
Txij li HNP-1 mus rau 3 tau nce hauv ntau hom qog nqaij hlav (lub ntsws, qhov ncauj squamous cell, ntau epidermoid, zais zis, lub raum pob zeb, lub mis, lub taub hau, thiab caj dab mob cancer) [106], nws yog qhov nthuav kom nthuav tawm. lawv cov haujlwm immunological hauv cov cheeb tsam no. Hauv kev kho mob qog nqaij hlav qog nqaij hlav ntawm cov neeg mob qog nqaij hlav qog nqaij hlav tsis me me, kev kuaj pom dav dav pom tau tias HNP-1 mus rau 3 tuaj yeem muaj lub luag haujlwm ntxiv rau yav tom ntej biomarkers rau anti-PD-(L)1 immunotherapy teb, raws li qhov sib ntxiv ntawm cov biomarkers tau kwv yees cov lus teb kho tau zoo dua li PD-L1 qhia ib leeg [82].
Txawm li cas los xij, lwm yam -defensins kuj tseem cuam tshuam txog kev mob qog noj ntshav. Kev qhia theem ntawm -defensin 5 (DEFA5) tau raug txo qis hauv tib neeg mob qog noj ntshav. Thaum overexpressing DEFA5 dua nyob rau hauv kab mob qog noj ntshav hauv plab, qhov no ua rau txo qis cell proliferation thiab muaj peev xwm tsim cov cheeb tsam. Qhov kev tawm tsam ntawm cov qog loj hlob tuaj yeem paub tseeb hauv tus qauv hauv vivo qog nrog cov nas liab qab. Mechanistically, DEFA5 ncaj qha khi BMI1, txo nws txoj kev khi ntawm CDKN2a locus, tom qab ntawd txhim kho kev qhia ntawm p16 thiab p19, ob lub cyclin-dependent kinase inhibitors [107]. Hauv qhov sib piv rau qhov no, DEFA5 thiab DEFA6 qhia tau nce ntau hauv cov qog nqaij hlav hauv plab piv rau cov ntaub so ntswg noj qab haus huv. Ntxiv mus, DEFA5 tuaj yeem cuam tshuam nrog kev pom zoo ntawm kev mob qog nqaij hlav hauv plab, thaum DEFA6 tuaj yeem txuas rau qhov kev mob hnyav dua. DEFA6 qhia kuj zoo li yuav nce ntxiv hauv adenoma piv rau cov mucosa ib txwm muaj thiab nce me ntsis hauv carcinoma. Xav tau cov ntaub ntawv ntau ntxiv, tab sis DEFA5 thiab DEFA6 zoo li muaj qhov kev cog lus ntawm qhov tshwj xeeb thiab rhiab heev rau kev kwv yees qhov kev mob qog nqaij hlav hauv plab [108].
Rau -defensins, feem ntau, hBD-1 zoo li yuav txo qis hauv feem ntau cov qog nqaij hlav, qhia tias nws muaj qee hom kev tiv thaiv qog. Cov ntaub ntawv los ntawm cov neeg mob pab pawg qhia tau hais tias hBD-1 kev hloov pauv tau txo qis hauv kev mob qog nqaij hlav hauv plab [109]. Hauv tib neeg txoj hnyuv kab mob qog noj ntshav thiab organoids ntawm tib neeg cov kab mob colonic thawj cov hlwb, inhibiting epidermal growth factor receptor (EGFR) nce qhov kev qhia ntawm hBD-1, thaum ua kom EGFR los ntawm MAPK kinase 1/2 (MEKK1/2)- ERK1/2 txoj hauv kev muaj qhov cuam tshuam rov qab [109]. Ib yam li ntawd, thaum cov ntaub ntawv mob qog noj ntshav tau tshawb xyuas rau -defensin qhia, hBD-1 tau raug txo qis, nrog E-cadherin yog qhov zoo tshaj plaws correlated gene thiab hepatocyte loj hlob zoo-tswj tyrosine kinase substrate raws li cov noob tsis zoo sab saum toj, tawm tswv yim. kev tiv thaiv lub luag haujlwm ntawm no peptide hauv kev txhim kho mob qog noj ntshav siab [110]. hBD-1 qib kuj tseem qis dua piv rau cov ntaub so ntswg noj qab haus huv hauv basal cell carcinoma, squamous cell carcinoma, raum cell carcinoma (txhim kho apoptosis), mob qog noj ntshav, thiab prostatic carcinoma [111–117].
Qhov no coj mus rau qhov kev xav tias hBD-1 yog cov qog qog nqaij hlav, thiab qhov ua rau ntawm nws cov lus qhia hauv cov kab mob qog nqaij hlav qog nqaij hlav ntawm tes tiag tiag ua rau txo qis kev loj hlob ntawm tes [118]. Hauv qhov ncauj squamous cell carcinoma, hBD-1 tuaj yeem cuam tshuam cov qog migration thiab ntxeem tau thiab tuaj yeem ua raws li qhov muaj peev xwm prognostic biomarker [119]. Downregulation ntawm DEFB1 noob qhia nyob rau hauv lub qhov ncauj squamous cell carcinoma correlates nrog phem prognosis, thiab raws li ib tug gene teem enrichment tsom xam, nws cov kev tiv thaiv qog nqaij hlav yog txuam nrog rau txoj kev cuam tshuam rau extracellular matrix remodeling, receptor tyrosine kinase (RTK) / phosphoinositide {{6} }kinase (PI3K)/Akt/mechanistic phiaj ntawm rapamycin (mTOR) signaling, keratinization, thiab cytokine signaling [120]. Qhov zoo siab, cov khoom tiv thaiv qog nqaij hlav tsis tuaj yeem raug xaiv rau hBD-3, vim tias nws cov lus qhia tau raug tswj hwm hauv tsev kho mob carcinoma thiab hBD{11}} txawm tias zoo li txhawb kev loj hlob ntawm qog nqaij hlav qog noj ntshav los ntawm NF-κB signaling [121]. hBD-3 kuj tseem cuam tshuam nrog kev txhawb nqa cov qog-txhim kho ib puag ncig hauv tib neeg papillomavirus-mob qog nqaij hlav taub hau thiab caj dab [122].
Rau hBD{{0}}, nws lub peev xwm los kwv yees qhov muaj ntawm prostate adenocarcinoma nyob rau hauv morphologically ib txwm prostate qog tau tshawb xyuas, hauv kev sim txo qis qhov tsis zoo-tsis zoo biopsy. Hauv 95.6 feem pua thiab 90.0 feem pua ntawm cov neeg mob prostate adenocarcinoma nrog, raws li Gleason Patterns 3 thiab 4, qhov poob ntawm hBD-1 qhia tau pom. Hauv pab pawg neeg tsis zoo, kev poob ntawm hBD-1 qhia hauv cov hlwb basal yog ib qho biomarker zoo rau kev txheeb xyuas cov neeg mob uas muaj kev pheej hmoo siab nrog qhov pib tsis zoo biopsy [123]. Qhov kev qhia ntawm hBD-1 rau 4 yog hloov pauv los ntawm cytostatic agents thiab. Feem ntau, thaum ntxiv rau cov kab mob qog noj ntshav sib txawv, cov tshuaj cytostatic kuaj tau cuam tshuam qhov kev qhia ntawm nws, tshwj tsis yog rau vincristine uas ua rau muaj kev cuam tshuam loj ntawm hBD-1 thiab hBD-4 hauv kab mob qog noj ntshav mis. (MCF7) thiab doxorubicin uas cuam tshuam qhov kev qhia ntawm hBD-3 thiab hBD{19}} hauv kab mob qog noj ntshav epidermoid carcinoma cell kab (A431) [124].
Thaum kawg, thaum kev npaj ntawm ob qho tib si / -defensins tau muab rau cov neeg mob qog noj ntshav ntawm qhov ncauj thiab oropharyngeal uas tau txais kev kho hluav taws xob lossis kws khomob, cov tshuaj tiv thaiv tau muaj cov nyhuv adjuvant, nrog rau cov txiaj ntsig zoo ntawm kev kho hluav taws xob. Cov kws tshawb fawb tau thov tias kev siv cov tshuaj tiv thaiv kab mob ua rau muaj kev tiv thaiv kab mob tso cai rau lawv kom ua tiav cov txiaj ntsig zoo dua ntawm cov txheej txheem tiv thaiv qog nqaij hlav no [125]. Hais txog kev tiv thaiv kab mob, kev tawm dag zog lub cev tau paub tias muaj txiaj ntsig zoo rau koj txoj kev noj qab haus huv thiab kev tiv thaiv kab mob, thiab cov pov thawj ua ntej txhawb kev xav tias kev tawm dag zog yuav txhim kho kev tiv thaiv kab mob ntawm cov neeg mob uas tau txais kev tiv thaiv kab mob tiv thaiv kab mob [126]. Ua raws li qhov no rau hauv tus account, nws yog qhov nthuav kom nco ntsoov tias hauv cov neeg ncaws pob ntaus pob ncaws pob, HNP-1 thiab HBD-1 tau nce zuj zus nrog kev cob qhia hnyav, thaum qhov kev tawm dag zog no nce ntxiv tsis hloov cov qib ntawm lub cev tiv thaiv kab mob [127 ].
6. Cov lus xaus
Hauv kev xaus, defensins muaj ntau tshaj li cov tshuaj tua kab mob peptides xwb. Lawv tuaj yeem muaj lub luag haujlwm tseem ceeb hauv cov qog microenvironment nyob rau hauv ob txoj kev sib txawv. Ua ntej, lawv muaj cov nyhuv cytotoxic ncaj qha rau cov qog hlwb, uas yog nrog los ntawm kev tso tawm cov qog antigens. Qhov thib ob, lawv lub luag haujlwm ua cov neeg tiv thaiv kab mob yuav tsum tsis txhob raug ignored, raws li lawv chemoattract ntau hom ntawm lub cev tiv thaiv kab mob, ua rau chemokine thiab cytokine tso tawm nyob rau hauv cov qog microenvironment, thiab tejzaum nws kho ntau yam kev tiv thaiv qog nqaij hlav los ntawm IFN- ntau lawm, tsim ib tug choj. nruab nrab ntawm lub innate thiab lub adaptive tiv thaiv.
Tus sau kev koom tes:
Kev Sau Ntawv—kev npaj ua ntej, tshuaj xyuas, thiab kho, LA; conceptualization thiab kev saib xyuas, SS thiab PP Txhua tus kws sau ntawv tau nyeem thiab pom zoo rau cov ntawv luam tawm ntawm cov ntawv sau.
Nyiaj txiag:
Qhov kev tshawb fawb no tau txais kev txhawb nqa los ntawm C1 nyiaj pab (Grant C16/17/010) los ntawm KU Leuven. Tsis tas li ntawd, LA tau txais kev txhawb nqa los ntawm SB Ph.D. Kev sib raug zoo ntawm FWO-Vlaanderen (Grant nr. 1S40823N).
Institutional Review Board Statement:
Tsis tau.
Cov Lus Qhia Txog Kev Pom Zoo:
Tsis tau.
Cov ntaub ntawv muaj nyob:
Tsis muaj cov ntaub ntawv tshiab raug tsim lossis tshuaj xyuas hauv qhov kev tshawb fawb no. Kev sib faib cov ntaub ntawv tsis siv rau kab lus no.
Kev tsis sib haum xeeb ntawm kev txaus siab:
Cov kws sau ntawv tshaj tawm tsis muaj kev sib cav txog kev txaus siab.
Cov ntaub ntawv
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