PartⅠMetabolic Nkag Siab Ntawm Cov Kev Cai Tsis Txaus Siab hauv Cov Kabmob Microenvironment Ntawm Raum Lub Raum Clear Cell Carcinoma
May 08, 2023
Abstract
Metabolic dysregulation yog ib qho cim ntawm cov qog nqaij hlav nrog rau KIRC, tshwj xeeb yog tshwm sim los ntawm kev hloov pauv hauv cov noob caj noob ces. Tam sim no, tsis muaj kev pom zoo tshwm sim ntawm cov cim kos npe metabolic hauv qog microenvironment. Hauv txoj kev tshawb no, peb tau pom qhov sib txawv tseem ceeb ntawm qhov sib txawv ntawm cov kab mob metabolic (DEmGs) ntawm KIRC thiab cov piv txwv zoo sib xws. Luv luv, peb tau sau cov kab mob metabolic los ntawm RNA-seq cov ntaub ntawv ntawm KIRC thiab cov ntaub so ntswg ib txwm los ntawm TCGA, ua raws li kev txheeb xyuas KIRC ntsig txog DEmGs. Tom ntej no, cov neeg mob tau muab faib ua peb pawg, thiab siv WGCNA, peb tau txheeb xyuas cov noob metabolic koom nrog kev muaj sia nyob ntawm ntau pawg.
Tsis tas li ntawd, peb tau tshawb xyuas kev muaj sia nyob thiab kev kho mob tsis zoo nrog rau kev tiv thaiv kab mob hauv cov pawg. Nyob rau tib lub sijhawm, peb tau tsim thiab siv tau cov qauv kev twv ua ntej raws li DEmGs. Cov kev soj ntsuam no tau qhia tias cov neeg mob uas muaj kev qhia siab ntawm DEmGs pom tias muaj kev muaj sia nyob tsis zoo, thaum kev nkag mus ntawm lub cev tsis muaj zog tau cuam tshuam nrog cov metastasis ntawm KIRC. Thaum kawg, peb tau txheeb xyuas NUDT1 yog cov noob caj noob ces raws li nws pom tau hais tias muaj kev qhia ntau heev hauv KIRC cov qauv nrog rau kev cuam tshuam nrog kev ciaj sia thiab kev cia siab ntawm cov neeg mob. Kev tshuaj xyuas ntxiv tau qhia txog lub luag haujlwm oncogenic ntawm NUDT1 hauv 786-O thiab ACHN hlwb. Yog li, peb txiav txim siab tias NUDT1 tuaj yeem yog qhov muaj peev xwm kuaj mob thiab kuaj pom tus cim rau KIRC.
Ntsiab lus
Metabolic dysregulation; Sib txawv ntawm cov kab mob metabolic (DEmGs); Cov ciaj sia taus; NUDT1;Cov txiaj ntsig Cistanche.
Nyem qhov no kom paubCistanche cov teebmeem
Taw qhia
Raum lub raum ntshiab cell carcinoma (KIRC) yog ib hom mob raum cell carcinoma (RCC), suav hais tias yog ib qho ntawm cov qog nqaij hlav uas suav nrog 70-80 feem pua ntawm cov neeg mob [1], ranked li 16 feem ntau ua rau mob qog noj ntshav. thoob ntiaj teb [2]. Lub raum cell carcinoma (RCC) yog hom mob qog noj ntshav ntau tshaj plaws thiab suav txog 90 feem pua ntawm cov mob cancer raum [3]. Tsis ntev los no, bioinformatics-raws li kev txheeb xyuas ntawm cov cim muaj peev xwm hauv cov qog nqaij hlav tau siv dav tab sis tsuas yog qee qhov kev ntseeg siab biomarkers ntawm KIRC tau txheeb xyuas lossis feem ntau ntawm cov cim tseem tsis tau lees paub. Yog li, bioinformatics tsom xam ua ke nrog kev sim validation yog tsim nyog los qhia txog lub peev xwm mechanism ntawm biogenesis thiab kev loj hlob ntawm KIRC [4]. Kev tshawb nrhiav tob ntawm cov qog microenvironment thiab kev txhim kho ntawm kev tiv thaiv kab mob tau ua rau nws muaj peev xwm kawm txog kev sib cuam tshuam ntawm cov qog thiab lub cev tiv thaiv kab mob [5]. Txawm li cas los xij, ntau tus neeg txheeb xyuas biomarkers tsis tau kawm txog lawv cov txiaj ntsig ntawm cellular phenotype thiab cov txheej txheem hauv qab molecular hauv KIRC [6]. Txawm li cas los xij, qhov kev cia siab ntawm cov neeg mob KIRC tsis to taub thiab tag nrho 5-xyoo muaj sia nyob tsawg dua 10 feem pua tom qab kuaj thawj zaug [7, 8]. Feem ntau, cov ntaub so ntswg ib txwm muaj feem ntau muaj cov tshuaj antiangiogenic siab. Qhov kev cuam tshuam ntawm cov theem ntawm cov xwm txheej no tuaj yeem ua rau cov yam ntxwv proangiogenic uas ua rau muaj kev faib tawm ntawm cov hlwb ntxiv ntawm qhov txawv txav uas ua rau cov qog tsim tawm [9]. Hauv cov txheej txheem no, cov qog hlwb qhia txog qib siab ntawm kev loj hlob ntawm proangiogenic thiab cov nyhuv no txhawb kev tsim cov hlab ntsha tshiab hauv cov qog nqaij hlav [10]; Yog li, kev loj hlob ntawm cov qog pib. Yog li ntawd, ntau lwm yam tseem ceeb tau koom nrog hauv cov qog nqaij hlav, nrog rau kev nkag mus ntawm lub cev tiv thaiv kab mob thiab kev qhia ntawm ntau yam metabolic genes. Nws tau paub zoo tias muaj ntau hom kev tiv thaiv kab mob hauv cov qog microenvironment feem ntau cuam tshuam rau cov qog nqaij hlav thiab kev tiv thaiv kab mob; Yog li, kev hloov pauv ntawm cov tshuaj tiv thaiv kab mob tseem cuam tshuam rau kev faib ua feem thiab kev ua haujlwm ntawm lub cev tiv thaiv kab mob hauv cov qog microenvironment [11]. Piv txwv li, infiltration ntawm lub cev tiv thaiv kab mob hauv cov qog microenvironment cuam tshuam rau kev loj hlob ntawm glioma [12]. Txawm hais tias tsis muaj kev txaus siab rau cov noob metabolic uas cuam tshuam rau cov qog nqaij hlav, cov kev tshawb fawb tam sim no tau rov ua dua qhov kev paub txog kev mob qog noj ntshav raws li kev mob metabolic [13, 14]. Cov kev tshawb fawb no muab lub hauv paus rau suav nrog metabolic reprogramming raws li lub cim tshiab ntawm malignant transformation [15]. Txawm li cas los xij, kev nthuav qhia ntawm tag nrho cov kab mob metabolic lossis txoj hauv kev ntawm cov ntaub so ntswg sib txawv nrog rau cov qog thiab cov ntaub so ntswg ib txwm txawv ntawm ib leeg thiab nws tsis tau tshawb nrhiav ntau, tshwj xeeb tshaj yog hauv KIRC.
Zuag qhia tag nrho, muaj tsawg dua ntawm cov biomarkers txhim khu kev qha muaj rau kev kwv yees ntawm kev kuaj mob thiab cov tshuaj tiv thaiv kab mob hauv KIRC; yog li ntawd, nws yog ib qho nyuaj kom ua tiav kev kho mob. Yog li ntawd, kev tshawb fawb txog bioinformatics ua ke nrog kev sim validation tuaj yeem qhia txog cov txheej txheem ntawm biogenesis thiab kev loj hlob ntawm KIRC. Yog li, txoj kev tshawb fawb tam sim no yog tsom rau kev ntsuam xyuas qhov cuam tshuam ntawm cov txheej txheem metabolic ntawm cov metabolic transcriptional profiles hauv KIRC piv nrog lawv cov ntaub so ntswg zoo sib xws. Ntawm no, peb ua tiav tsis yog tsuas yog cais cov kab mob sib txawv lossis sib txawv molecular subtypes ntawm tib tus kab mob tab sis kuj tau kwv yees cov lus teb rau kev kho cov metabolism. Qhov no sawv cev rau txoj hauv kev tshiab ntawm kev txheeb xyuas cov txheej txheem uas cov txheej txheem metabolic cuam tshuam rau hauv kev mob hnyav thiab muaj cov hom phiaj tshiab rau kev kho mob.
Standardized Cistanche
Khoom siv thiab cov txheej txheem
1. Cov ntaub ntawv tau txais.
Cov ntaub ntawv RNA sequencing (FPKM) cuam tshuam rau KIRC tau ncaj qha rub tawm los ntawm Cancer Genome Atlas (TCGA). Tom qab ntawd, cov ntaub ntawv tau ua tiav raws li qhov xav tau hauv cov ntawv sau cia. Tsis tas li ntawd, cov ntaub ntawv kho mob rau cov neeg mob KIRC sib xws, suav nrog poj niam txiv neej, haiv neeg, hnub nyoog, qhov chaw qog nqaij hlav, kev faib tawm histology, qib sib txawv, qog theem, thiab cov ntaub ntawv muaj sia nyob, tau txais los ntawm UCSC Cancer Browser. Txhawm rau kom tau txais kev nkag siab rau hauv metabolic heterogeneity ntawm KIRC cov neeg mob, cov txheej txheem metabolic tau raug coj los ntawm cov ntawv tshaj tawm yav dhau los [16, 17]. Lub graphical abstract ntawm txoj kev tshawb no yog qhia nyob rau hauv Ntxiv daim duab 1, thiab cov ncauj lus kom ntxaws workflow ntawm cov ntaub ntawv nrhiav thiab downstream txheej txheem kev kawm yog qhia nyob rau hauv Ntxiv daim duab 2.
2. Kev txheeb xyuas qhov sib txawv ntawm cov txheej txheem metabolic (DEmGs).
Cov txheej txheem metabolic tau txheeb xyuas los ntawm kev sib tshuam ntawm ob cov ntaub ntawv thiab siv rau DEG tsom xam ntawm qog thiab cov qauv ib txwm. Tom qab ntawd, peb kuj tau txheeb xyuas DEmGs siv WGCNA, thiab raws li cov kev muaj sia nyob, cov neeg mob tau muab faib ua peb pawg. Hauv luv luv, cov neeg mob tau muab faib ua peb pawg, xws li pawg C1, pawg C2, thiab pawg C3. Txhawm rau txheeb xyuas DEGs, cov qauv linear tau siv los ntawm kev ua haujlwm R pob limma. Qhov kev tshawb pom tsis tseeb (FDR) hloov kho p-tus nqi < 0.05 ua ke nrog tus nqi tag nrho ntawm kev hloov pauv log2, logFC> 1, thiab logFC < −1 tau teeb tsa raws li qhov pib rau DEG kev txheeb xyuas. Cov phiaj xwm hluav taws xob tau tsim los siv ggplot2. Cov noob uas muaj logFC> 1 tau suav tias yog kev tswj hwm, thiab cov noob uas muaj logFC < −1 raug muab tso ua cov noob tsis raug cai.
3. Kev Tshawb Fawb Kev Ua Haujlwm Zoo Tshaj Plaws thiab Kev Sib Raug Zoo ntawm cov protein-Protein.
Cov kev ntsuam xyuas ntxiv los ntawm GO thiab KEGG cov ntsiab lus tau ua los ntawm R pob Cluster profile. Cov ntsiab lus GO tau muab faib ua peb pawg xws li molecular functions (MF), cellular Cheebtsam (CC), thiab cov txheej txheem lom neeg (BP). Txhawm rau txiav txim siab qhov sib txawv tseem ceeb thiab kev sib raug zoo ntawm DEmGs ntawm cov qog thiab cov ntaub so ntswg ib txwm, peb siv cov software suav nrog GSEA (gene set enrichment analysis). KEGG thiab GO (Gene Ontology) kev txheeb xyuas qhov zoo ntawm DEGs tau ua los txheeb xyuas txoj hauv kev thiab kev ua haujlwm. Tsis tas li ntawd, daim ntawv thov cystoscope tau siv los tsim cov protein-protein interaction (PPI) network ntawm DEmGs. Thawj PPI tau txais los ntawm STRING database. Qhov kev ntseeg siab tshaj plaws tau teem rau 0.9.
4. Kev soj ntsuam ciaj sia taus.
Cov noob sib txawv hauv cov neeg mob qog noj ntshav tau txheeb xyuas los ntawm pob limma, thiab cov noob sib txawv tau txheeb xyuas los ntawm kev siv WGCNA pob los ua coexpression, tsim kom muaj kev sib koom tes sib tham uas tau txheeb xyuas tag nrho ntawm 6 modules.=5 thiab lub network yog lub network tsis muaj nplai. Lub prognostic tseem ceeb ntawm DEmGs txheeb xyuas los ntawm WGCNA nyob rau hauv txoj kev ciaj sia taus yog txiav txim los ntawm Kaplan-Meier (KM) cov phiaj xwm nrog rau qhov kev xeem-qib xeem.
Cistanche ntsiav tshuaj
5. Kev tshuaj ntsuam xyuas lub cev tiv thaiv kab mob.
Cov kab mob tiv thaiv kab mob thiab stromal tau suav nrog siv pob R, "xCELL;" cov qauv nrog p < 0:05 raug xaiv rau kev tshuaj xyuas ntxiv. Tsis tas li ntawd, cov tshuaj tiv thaiv kab mob uas muaj cov cim kab mob lom tau raug tshuaj xyuas los ntawm R pob GSVA. Ntxiv mus, txhawm rau txheeb xyuas qhov purity ntawm cov qog, peb siv ESTIMATE algorithm los kwv yees cov qhab nia stromal thiab kev tiv thaiv kab mob ntawm cov ntaub so ntswg KIRC.
6. Kev tsim kho ntawm tus qauv kev twv ua ntej.
Qhov sib txawv ntawm cov kab mob metabolic tau txais los ntawm RNA sequencing cov ntaub ntawv ntawm KIRC cov qog nrog cov ntaub ntawv muaj sia nyob, thiab cov neeg mob tau muab faib rau hauv kev cob qhia thiab kuaj cov pab pawg siv R pob "caret;" Tom qab ntawd, kev txheeb xyuas kev muaj sia nyob tsis muaj sia nyob tau ua tiav ntawm DEmGs. Tsis tas li ntawd, LASSO tsom xam tau ua los ntawm R pob "glmnet;" thiab rau kev ua kom zoo dua ntawm cov qauv kev twv ua ntej, ib qho kev ua piv txwv ntawm cov qauv kev phom sij tau raug siv.
7. Cell Culture.
Tib neeg lub raum kab mob qog noj ntshav 786-O thiab ACHN tau yuav los ntawm American Type Culture Collection (ATCC) (Manassas, VA, USA). Cov 786-O cell kab yog kab lis kev cai hauv RPMI 1640 nruab nrab (cat. no. 11875093, Invitrogen, Carlsbad, CA, United States) ntxiv nrog 10 feem pua fetal bovine serum (cat. no. 04-001- 1ACS, Biological Industries, Israel). Cov kab ACHN ntawm tes tau raug coj los ua hauv MEM nruab nrab (cat. No. 41500034, Invitrogen, Carlsbad, CA, United States) ntxiv nrog 10 feem pua fetal bovine serum. Tag nrho cov kab lis kev cai tau tsim nyob rau ntawm 37 ° C thiab 5% CO2nyob rau hauv ib tug humidified incubator.
8. Real-Time Quantitative PCR.
Tag nrho RNA los ntawm KIRC kab thiab cov ntaub so ntswg raug cais los ntawm kev siv TRIzol (cat. no. 9109; TaKaRa, Tokyo, Nyiv) raws li cov chaw tsim khoom cov txheej txheem. RT-qPCR tau ua tiav siv QuantiNova SYBR Green PCR Cov Khoom Siv (cat. no. 208054, QIAGEN, Duesseldorf, Lub teb chaws Yelemees). kwv tij gene qhia tau xam los ntawm 2- Δ Δ Cttxoj kev. Cov txheej txheem primer tau teev nyob rau hauv Cov Lus Qhia Ntxiv 1.
9. Cell Viability Assay.
Lub cytotoxicity tom qab NUDT1 siRNA transfection hauv 786-O thiab ACHN tau txiav txim siab siv Cell Counting Kit-8 (CCK-8) assay (cat. no. C0038, Beyotime Biotechnology Co. Ltd., Tuam Tshoj). Cov NUDT1 siRNA sequences muaj nyob rau hauv Cov Lus Qhia Ntxiv 1. Lawv tau muab los ntawm GenePharma (Shanghai, Suav). Luv luv, ob lub xovtooj ntawm tes 786-O thiab ACHN nyob rau theem kev loj hlob ntawm logarithmic (24 teev tom qab siRNA hloov pauv) tau sau thiab xa mus rau hauv 96-zoo cell kab lis kev cai daim hlau (1000 hlwb/zoo). Hnub tom qab, 10 ul ntawm CCK-8 tau ntxiv rau txhua qhov dej. Tom qab incubation ntawm 37 degree C rau ib tug ntxiv 2 h, optical density (OD) ntawm 450 nm ntawm hlwb raug kuaj los ntawm ib tug microplate nyeem ntawv (Bio-Rad Laboratories, Richmond, CA, USA).
10. Cell Migration, Invasion, and Apoptosis Assay.
KIRC hlwb {{0}}O thiab ACHN tau hloov pauv rau siRNA-mediated knockdown ntawm NUDT1. Tom qab 24 teev ntawm kev hloov pauv, cov hlwb tau muab cog rau hauv 6- cov phiaj xwm zoo rau kev tshuaj xyuas qhov txhab. Tom qab cov hlwb tau txais 100 feem pua ntawm cov qhov txhab, cov qhov txhab tau tsim nyob rau hauv cov hlwb ua monolayer siv cov yas pipette taub hau. Cov hlwb tau muab yaug nrog PBS thiab coj mus rau lwm 48 teev. Qhov kev ncua deb ntawm qhov raug kaw tau pom los ntawm lub tshuab tsom iav thiab thaij duab rau kev ntsuas qhov cuam tshuam ntawm NUDT1 knockdown ntawm KIRC 786-O thiab ACHN hlwb. Cell tsiv teb tsaws & ntxeem tau tau ua los ntawm transwell 24-cov phiaj zoo (Corning, New York, NY). Nyob rau hauv luv luv, ib tug sib npaug ntawm cov hlwb tau coj mus rau hauv lub FBS-dawb xov xwm nyob rau hauv lub sab sauv chamber, thiab kev tsiv teb tsaws ntawm cov hlwb raug soj ntsuam nyob rau hauv lub qis chamber ntawm lub transwell qhov twg xov xwm yog supplemented nrog 10 feem pua FBS. Transwell chambers tau ua tib zoo ntxuav thiab stained nrog 0.2 feem pua pob zeb siv lead ua violet, pom, thiab yees duab; Tom qab ntawd, qhov sib txawv ntawm cov cell tsiv teb tsaws ntawm kev tswj tsis zoo thiab NUDT1 knockdown tau txiav txim siab los ntawm kev suav cov xov tooj ntawm tes. Apoptosis assay tau ua tiav tom qab 72 teev ntawm kev hloov pauv, cov hlwb raug sau, ntxuav, thiab rov muab tso rau hauv dej txias PBS. Cells tau kuaj pom los ntawm Apoptosis Detection Kit (cat. No. KGA1013, KeyGen BioTech, Nanjing, Tuam Tshoj) raws li cov chaw tsim khoom cov lus qhia thiab tshuaj xyuas los ntawm cytometry ntws (FACScan; BD Biosciences). Txhua qhov kev sim tau ua hauv triplicate.
11. Kev Tshawb Fawb Txog Kev Tshawb Fawb.
Tag nrho cov kev txheeb xyuas txheeb cais tau ua nyob rau ntawm GraphPad prism (V7.0) thiab R (3.6.4), Wilcox test tau siv los sib piv cov kab mob ntawm lub cev tiv thaiv kab mob hauv cov nqaij mos thiab cov qog nqaij hlav, thiab kev sim chi-square. tau ua rau kev kawm txog kev sib raug zoo ntawm lub cev tiv thaiv kab mob hauv lub cev thiab cov kab mob pathological. Kev tshuaj xyuas qhov sib txawv yog siv los sib piv cov qhab nia tiv thaiv kab mob, stromal qhab nia, thiab qog purity ntawm peb pawg. Rau kev soj ntsuam ciaj sia taus, p-value tau suav nrog siv qhov ntsuas ntsuas ntsuas. Ib p-value<0.05 was considered statistically significant.
Cistanche ntxiv
Cov ntaub ntawv
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Junwei Xie, 1,2,3,4,5 Lingang Cui, 6 Shaokang Pan, 1,2,3,4,5 Dongwei Liu, 1,2,3,4,5 Fengxun Liu,1,2,3,4 ,5 and Zhangsuo Liu 1,2,3,4,5
1 Department of Nephrology, Thawj Tsev Kho Mob ntawm Zhengzhou University, Zhengzhou 450052, Suav
2 Kev tshawb fawb lub koom haum ntawm Nephrology, Zhengzhou University, Zhengzhou 450052, Tuam Tshoj
3 Chaw Tshawb Fawb Txog Kab Mob Raum, Zhengzhou, 450052 Henan, Suav
4 Lub Tuam Txhab Tseem Ceeb ntawm Precision Diagnosis thiab Kev Kho Mob raum Kab Mob hauv Henan Xeev, Zhengzhou 450052, Tuam Tshoj
5 Core Unit ntawm National Clinical Medical Research Center of Kidney Disease, Zhengzhou 450052, Suav teb
6 Department of Urology, Thawj Tsev Kho Mob ntawm Zhengzhou University, Zhengzhou 450052, Suav
