Ntu Ⅱ Metabolic Nkag Siab Ntawm Cov Kev Cai Tsis Txaus Siab hauv Cov qog Microenvironment Ntawm Raum Lub Raum Clear Cell Carcinoma

Kev tshwm sim

1. Kev txheeb xyuas qhov sib txawv ntawm cov txheej txheem metabolic hauv KIRC.

Txhawm rau tshawb nrhiav cov kab mob metabolic hauv KIRC, peb tau tshawb nrhiav cov ntaub ntawv TCGA muaj kom tau txais kev nkag siab tob rau hauv cov tshuaj kho cov tshuaj metabolism hauv cov chaw kho mob. Rau lub hom phiaj no, peb tau xaiv ib txheej ntawm 1916 metabolic genes uas tau cuam tshuam los ntawm ob qhov sib txawv datasets [16, 17] thiab tshuaj xyuas 1100 qhov sib txawv ntawm cov noob hauv qog thiab cov ntaub so ntswg ib txwm muaj (Table 2). Cov txheej txheem metabolic no tau piav qhia qhov sib txawv tau npaj rau hauv cov roob hluav taws kub thiab daim ntawv qhia tshav kub (Daim duab 1(a) thiab 1(b)). Tawm ntawm 1100 qhov sib txawv qhia cov noob metabolic, 78 cov noob tau hloov kho thiab 163 cov noob tau raug txo qis. Ntxiv mus, muaj 859 cov noob tsis hloov pauv. Daim ntawv qhia tshav kub sawv cev rau tus kheej qhia qhov ntsuas ntawm cov kab mob metabolic sib txawv hauv cov qog thiab cov qauv ib txwm muaj (Daim duab 1(b)). Tom ntej no, peb txheeb xyuas cov saum toj kawg nkaus 10 qhov sib txawv ntawm cov kab mob metabolic; Ntawm lawv, ENPP3, NNMT, CYP2J2, SCD, thiab HK2 tau raug tswj xyuas thiab HSD11B2, HMGCS2, HPD, HS6ST2, thiab ALDOB raug txo qis. Cov phiaj xwm ntawm cov DEmGs no tau pom hauv daim duab 1(c). Ntawm cov noob caj noob ces, ENPP3 yog ~ 7-fold qhia hauv cov qog. Xwb, cov noob ALDOB yog ~5-fold downregulated nyob rau hauv soj ntsuam qog cov qauv.

Tsis tas li ntawd, peb tau soj ntsuam KEGG txoj hauv kev thiab GO tsom xam ntawm DEmGs. KEGG txoj kev tsom xam tau qhia tias cov noob caj noob ces tau ua kom muaj txiaj ntsig zoo hauv cov pa roj carbon metabolism, HIF1 signaling, thiab glycolysis / gluconeogenesis nrog cov noob qoob loo ntau dua (8-9 tus lej ntawm cov noob hauv txhua txoj hauv kev) (Daim duab 1(d)). Ib yam li ntawd, ntawm DEmGs downregulated, peb pom tias carbon metabolism thiab valine, leucine, thiab isoleucine degradation yog cov saum toj kawg nkaus txoj kev cuam tshuam los ntawm metabolically active noob (Daim duab 1(e)). Txoj hauv kev uas cuam tshuam nrog peroxisome organelle kuj tseem ua rau muaj txiaj ntsig zoo nyob rau hauv ib pawg downregulated ntawm cov qog qog ntshav. Qhov tsim nyog, piv nrog cov hauv cov noob caj noob ces, txoj hauv kev koom nrog hauv cov noob caj noob ces muaj qhov tseem ceeb dua p. Nws yog ib qho tsim nyog hais tias feem ntau ntawm KEGG txoj hauv kev ntxiv rau hauv cov noob caj noob ces muaj feem xyuam rau cov amino acid metabolism. Txhawm rau txiav txim siab ntxiv txog kev koom tes ntawm DEmG hauv cov qog nqaij hlav, GO kev ua haujlwm kev soj ntsuam ntawm cov noob caj noob ces tau ua tiav. Peb faib cov GO ontology rau peb pawg ua haujlwm subontology, BP (cov txheej txheem lom neeg), CC (cellular tivthaiv), thiab MF (molecular function) (Figures 1(f) thiab 1(g)). Tsis tas li ntawd, GSEA tsom xam tau nthuav tawm qhov kev nce ntxiv hauv cov noob caj noob ces cuam tshuam nrog BENPORATH_MYC_TARGETS_nrog_EBOX hauv cov qog, thaum BROWN{{11} } MYELOID{12}}CELL_Kev txhim kho_UP, KEGG_ALPHA_ LINOLENIC_ACID_METABOLISM, thiab KEGG{ {19}}ETHER_ LIPID_METABOLISM tau pom tias muaj kev nplua nuj tsis zoo. Nyob rau theem tom ntej, peb tsim cov protein-protein kev sib cuam tshuam PPI network nrog nce thiab txo qis DEmGs. Ib tus lej ntawm cov noob tau pom muaj kev cuam tshuam nrog ib leeg. Los ntawm cov noob 'kev sib cuam tshuam, peb cais cov noob hub. Txhua lub node yog discrete los ntawm lwm yam raws li tus nqi degree; Ntxiv mus, peb cais cov saum toj kawg nkaus 7 hub noob rau PPI. Peb kuj tau tshawb fawb txog kev sib raug zoo ntawm qhov hub gene qhia thiab clincopathological nta ntawm KIRC hauv TCGA datasets.

Nyem qhov no kom paubCov txiaj ntsig Cistanche yog dab tsi.

2. Kev Ntsuam Xyuas Network nthuav qhia cov kev hloov pauv hauv metabolic hauv ntau yam qog nqaij hlav.

Tom ntej no, cov ntaub ntawv qhia ntawm DEmGs tau raug xaiv thiab siv los ua cov ntaub ntawv nkag rau WGCNA, uas tau txheeb xyuas 6 qhov sib txawv ntawm cov qauv sib txawv uas muaj cov noob sib txawv rau txhua qhov module (Daim duab 2(a)). Peb tau txheeb xyuas cov noob sib txawv nrog cov yam ntxwv sab nraud thiab txheeb xyuas cov qauv uas cuam tshuam nrog kev kho mob zoo (Daim duab 2(b)). Raws li kev sib txheeb coefficient, peb pom tias MEturquoise modules tsis zoo cuam tshuam nrog cov xwm txheej ciaj sia taus. GO thiab KEGG txoj kev txhim kho kev txheeb xyuas tau ua tiav siv cov noob los ntawm cov qauv no (Figures 2(c) thiab 2(d)). Txoj hauv kev zoo tshaj plaws KEGG yog valine, leucine, thiab isoleucine degradation; carbon metabolism; propanoate metabolism; fatty acid metabolism; fatty acid degradation; peroxisome thiab butanoate metabolism; glyoxylate thiab dicarboxylate metabolism; thiab tryptophan metabolism (Daim duab 2(c)). Cov noob muaj feem xyuam nrog BP cov ntsiab lus tau ua kom muaj txiaj ntsig zoo hauv cov khoom me me, carboxylic acid, thiab cov txheej txheem organic acid catabolic. Cov noob muaj feem xyuam rau cov ntsiab lus CC feem ntau yog enriched hauv mitochondrial matrix. Qhov sib txawv ntawm cov noob uas muaj feem xyuam nrog MF yog qhov tseem ceeb hauv coenzyme khi (Daim duab 2(d)). Tsis tas li ntawd, peb tau ua qhov kev soj ntsuam muaj sia nyob ntawm 8 cov noob hauv cov ciaj sia taus module. Cov neeg mob siab dua ACADSB, PANK1, SLC25A4, PCCA, HADH, AUH, ACAT1, thiab ALDH6A1 qhia tau muaj sia nyob ntev dua li cov neeg uas muaj qis dua ntawm cov noob no (p=0) (Cov duab 2(e)–2( l)).

3. Clustering ntawm KIRC Cov Neeg Mob.

Peb xaiv DEmGs saum toj kawg nkaus rau kev txheeb xyuas pawg; KIRC cov neeg mob tau muab faib ua peb pawg raws li qhov sib txawv ntawm cov kab mob metabolic. Daim duab 3(a) qhia cov duab tshav kub ntawm DEmGs hauv cov neeg mob KIRC. Cov xim teev qhia tus nqi qhia (lub teeb xiav qhia tus nqi qis dua; tsaus xiav qhia tias muaj txiaj ntsig ntau dua cov noob).

KM nkhaus tau npaj los sib piv qhov kev ciaj sia tag nrho ntawm peb pawg rau KIRC cov neeg mob. Tag nrho cov ciaj sia taus txawv qhov txawv ntawm peb pawg (p < {{0}}}:01 Daim duab 3(b)). Pawg 1 tau pom qhov muaj sia nyob tsis zoo dua piv nrog Pawg 2 thiab Pawg 3. PFS cov ciaj sia taus kuj sib txawv ntawm 3 pawg (p < 0: 001, Daim duab 3(c)), thiab pawg 1 tau nthuav tawm PFS cov ciaj sia tsis zoo dua piv rau nrog pawg 2 thiab pawg 3.

Cov xim sib txawv hauv peb cov qauv sawv cev rau cov kev kuaj mob thiab cov theem hauv qab ntawm cov kab mob (Daim duab 3(d)). Cluster 3 muaj qis Mo ratios thiab siab dua M1 tus nqi piv nrog pawg 1 thiab 2 qhia tias mob qog noj ntshav ntau dua thiab ntau theem ntawm cov qog hauv pawg 3 dua li pawg 1 thiab 2. Ib yam li, hauv pawg 3, mob qog noj ntshav tau kis mus rau cov qog nqaij hlav ntau dua. (siab dua N1) piv rau cov nyob hauv pawg 1 thiab 2. Feem ntau ntawm cov neeg mob KIRC tau kuaj pom nyob rau theem III thiab IV (Figures 3(e) thiab 3(f)), qhia cov qog loj los yog nthuav dav, nrog rau kev txav mus los. cov ntshav los yog lymphatic system mus rau thaj chaw deb ntawm lub cev.

4. Kev tiv thaiv kab mob ntawm peb pawg.

Peb siv ESTIMATE algorithm los kwv yees cov qhab nia stromal thiab kev tiv thaiv kab mob ntawm cov ntaub so ntswg KIRC raws li lawv cov metabolic transcriptional profiles (Daim duab 4(a)). Tom qab ntawd, cov qhab nia no tau raug coj mus rau hauv tus account txhawm rau txhim kho stromal-immune score-based metabolic genes kos npe rau prognosis stratification hauv KIRC. Raws li pom hauv daim duab 4(a), peb pawg pawg (C1, C2, thiab C3) tau stratified nyob rau hauv lub thawv ntawv raws li lawv cov qhab nia stromal-immune. Ntawm peb pawg, C1 tau pom qhov qhab nia siab dua hauv ob qho tib si stromal thiab kev tiv thaiv kab mob.

Tsis tas li ntawd, peb pawg tau txheeb xyuas los ntawm CIBERSORT nrog p-value < 0.1 (Daim duab 4(b)). Cov qog purity, cov qhab nia tiv thaiv kab mob, thiab cov qhab nia stromal nrog rau cov theem pathological ntawm 3 pawg tau pom nyob rau sab saum toj ntawm daim ntawv qhia tshav kub. Hauv qhov kev tshuaj ntsuam no, peb feem ntau pom tias kev tswj hwm T hlwb (Tregs) tau ua kom muaj txiaj ntsig hauv pawg C1 thiab cov neeg mob hauv C1 feem ntau yog nyob rau theem III thiab IV. Ntxiv mus, cov activated NK hlwb, CD8 ntxiv rau T hlwb, T follicular pab hlwb, thiab M0 macrophages hauv C1 pawg; CD8 ntxiv rau T hlwb thiab T follicular pab hlwb hauv C2 pawg; thiab so mast cells, M2 macrophages, so nco CD4 T hlwb, monocytes, naive B hlwb, thiab M1 macrophages hauv C3 pawg kuj tau kuaj pom (Daim duab 4(b)).

Sib nrug los ntawm CIBERSORT, peb ua hauj lwm lwm cov pob khoom algorithmic los xyuas cov xwm txheej ntawm kev tiv thaiv kab mob. Daim ntawv qhia tshav kub hierarchical ntawm MCP tsom xam muaj nyob rau hauv daim duab 4(c). Cov kev tshawb pom tseem ceeb ntawm MCP tsom xam yog neutrophil infiltration thiab endothelial cell infiltration hauv pawg C3 uas ploj lawm hauv pawg C1. Qhov kev tshuaj ntsuam no kuj tau nthuav tawm NK cell, kab mob monocytic, thiab myeloid dendritic cell infiltration hauv pawg C3. Lwm cov tshuaj tiv thaiv kab mob tau muab sib xyaw rau hauv peb pawg tshuaj ntsuam xyuas (Daim duab 4(c)).

Txhawm rau ua kom tiav CIBERSORT thiab MCP kev tshuaj ntsuam xyuas, peb tau thov ssGSEA txhawm rau txheeb xyuas qib infiltration rau hom kab mob tiv thaiv kab mob uas siv hauv R pob GSVA. Peb pawg 'cov ntaub ntawv tau muab pub rau pob ssGSEA thiab tau txais kev nplua nuj ntawm 28 lub cev tiv thaiv kab mob thiab hom hauv KIRC cov qauv. Cov txiaj ntsig tau qhia tias C1 thiab C2 muaj kev tiv thaiv kab mob ntau dua; Qee lub cev tiv thaiv kab mob hauv lub cev, suav nrog NK, neutrophils, thiab eosinophils, tau sib xyaw hauv 3 pawg (Daim duab 4(d)).

5. Kev tsim kho thiab kev lees paub ntawm tus qauv kev kwv yees raws li DEmGs.

Thaum kawg, peb tsim thiab siv tau cov qauv kev twv ua ntej raws li qhov sib txawv ntawm cov kab mob metabolic. Peb suav cov qhab nia tiv thaiv kab mob ntsig txog kev pheej hmoo ntawm DEmGs raws li kev muaj sia nyob tag nrho. Rau lub hom phiaj no, peb tsim ob pab pawg los ntsuas qhov sib txheeb ntawm cov qhab nia txaus ntshai; ib qho yog rau cov pab pawg cob qhia, thiab lwm qhov yog rau pawg xeem. Peb pom tias tag nrho cov ciaj sia taus tsawg thiab tawg mus thoob plaws qhov kev pheej hmoo (Daim duab 5(a) thiab 5(b)). Tom ntej no, raws li tus qhab nia nruab nrab ntawm qhov kev pheej hmoo, peb tau muab KIRC cov neeg mob rau cov pab pawg siab thiab tsis tshua muaj kev pheej hmoo rau kev ntsuas ntxiv. Tom qab ntawd peb tau ua qhov kev soj ntsuam ciaj sia ntawm ob pab pawg muaj kev pheej hmoo no hauv kev cob qhia thiab kev sim cov pab pawg. Raws li qhov xav tau, cov pab pawg muaj kev pheej hmoo siab tau pom tias muaj kev muaj sia nyob tsawg dua li piv nrog cov pab pawg uas muaj kev pheej hmoo tsawg (Daim duab 5(c) thiab 5(d)). Tsis tas li ntawd, ROC nkhaus tsom xam tau ua rau kev cob qhia thiab kuaj cov pab pawg. Peb tau soj ntsuam ROC cov qhab nia ntawm 0.68 ntawm 5 xyoo hauv kev sim cov pab pawg, uas qhia tau hais tias kev ua tau zoo hauv kev kwv yees qhov kev cia siab ntawm KIRC (Figures 5(e) thiab 5(f)). Ntxiv nrog rau ROC nkhaus tsom xam, peb kuj tau ua cov qauv LASSO COX regression kom siv tau peb cov qauv prognostic raws li qhia los ntawm ib feem ntawm qhov muaj feem cuam tshuam (Cov duab ntxiv 5(a)) thiab regression coefficient ntawm DEmGs (Cov duab ntxiv 5(b)). Thaum kawg, tsib lub noob (ABCG1, CRYL1, FDX1, PANK1, thiab SLC44A) tau kwv yees tias yuav muaj peev xwm prognostic yam nrog HR <1 (Cov Duab Ntxiv 5(c)).

6. Cov Mechanisms hauv qab ntawm KIRC Progression.

Txhawm rau tshawb xyuas ntxiv cov txheej txheem hauv qab no rau KIRC kev nce qib, peb tau ua qhov sib txawv ntawm kev qhia ntawm txhua pawg thiab siv cov phiaj xwm cua sov kom pom cov txiaj ntsig (Daim duab 6(a)). Txhawm rau txheeb xyuas cov kev taw qhia ntawm DEmGs, peb tau ua KEGG thiab GO enrichment tsom xam ntawm DEGs hauv peb pawg. Nyob rau hauv luv luv, cov txiaj ntsig no tau qhia tias DEGs ntawm peb pawg tau txais txiaj ntsig ntau hauv focal adhesion, Foxo signaling pathway, thiab Apelin signaling pathway rau pawg C3 thiab ntxhia nqus, neutrophil extracellular trap tsim, thiab staphylococcus aureus kab mob rau pawg C2 (Daim duab 6. (b)). Tsis tas li ntawd, GO functional analysis of DEGs uncovered MF-, CC-, and BP-related ontologies show in Figure 6(c). Interestingly, qhov sib txawv qhia kev tsom xam tau nthuav tawm cov cwj pwm txawv txav ntawm cov noob kev tswj hwm hauv peb pawg. Feem ntau, NUDT1 tau qhia ntau heev hauv C1, uas muaj kev ciaj sia tsis zoo. Kev tshawb nrhiav ntxiv tau qhia tias NUDT1 kev qhia tau raug txo qis los ntawm kev nce qib ntawm C1 mus rau C3 (Daim duab 6(d)). Tsis tas li ntawd, NUDT1 tau pom tias yuav raug kho hauv KIRC cov qog nqaij hlav (Daim duab 6(e)). Tom ntej no, peb tau hais txog NUDT1 qhia hauv txhua theem qog (Daim duab 6(f)). Kev soj ntsuam kev ciaj sia tag nrho kuj tau ua los ntawm Kaplan-Meier plotter, thiab peb pom tias cov neeg mob uas muaj kev qhia ntau dua ntawm NUDT1 muaj kev ciaj sia tsis zoo (HR=1:82 (1.34–2.48), log-rank p=0 }:00012) (Daim duab 6(g)).

Thaum kawg, peb tau ua KEGG thiab GO kev ua kom muaj txiaj ntsig zoo rau cov noob cuam tshuam nrog NUDT1. Cov noob tau muab faib ua ob pawg - muaj txiaj ntsig zoo nrog NUDT1 thiab tsis zoo cuam tshuam nrog NUDT1. KEGG txoj kev tsom xam pom tau tias cov noob muaj txiaj ntsig zoo feem ntau ua rau cov kab mob ribosomal, Huntington's disease, amyotrophic lateral sclerosis, thiab Alzheimer's disease. Ntawm qhov tod tes, cov noob tsis zoo sib xws tau ua kom muaj txiaj ntsig ntau hauv kab mob siab B thiab Foxo signaling (Daim duab 6(h)). Ntxiv mus, GO ontology ntawm peb pawg sib txawv MF, CC, thiab BP rau ob qho tib si zoo thiab tsis zoo sib cuam tshuam cov noob tau pom hauv daim duab 6(i). Tsis tas li ntawd, peb pom tias qhov kev qhia ntawm NUDT1 muaj feem cuam tshuam nrog kev nkag mus ntawm lub cev tiv thaiv kab mob (Cov duab ntxiv 6) thiab cov yam ntxwv sib txawv ntawm cov neeg mob KIRC (Table 1).

Cistanche ntxiv

7. Poob NUDT1 inhibits lub raum Cancer Cell Proliferation thiab tsiv teb tsaws.

Tom ntej no, peb muab piv rau qib qhia ntawm NUDTI hauv KIRC cov ntaub so ntswg thiab lawv cov ntaub so ntswg uas muaj feem cuam tshuam, uas tau qhia tias NUDT1 tau qhia ntau heev hauv KIRC cov ntaub so ntswg (Daim duab 7(a)). Tsis tas li ntawd, peb txiav txim siab qhov cuam tshuam ntawm NUDT1 poob ntawm lub raum mob qog noj ntshav los ntawm kev siv siRNA-mediated inhibition. NUDT1 tau tsom rau siRNA knockdown hauv ob kab ntawm tes 786-O thiab ACHN thiab NUDT1 mRNA qib tau ua tiav inhibited raws li pov thawj los ntawm qPCR tsom xam (Daim duab 7(b)). Ua raws li siRNA-mediated knockdown ntawm NUDT1, qhov kev ntsuam xyuas ntawm tes tau pom tias txo qis ntawm cell viability nyob rau hauv ob kab ntawm tes (Figures 7(c) thiab 7(d)). Tom qab ntawd, kev soj ntsuam kev tsiv teb tsaws ntawm tes ntawm qhov kev sib tw ntawm NUDT1 pom tau tias txo qis ntawm cov cell tsiv teb tsaws hauv NUDT1- depleted 786-O thiab ACHN hlwb (Figures 7(e) thiab 7(f)). Lub peev xwm tsiv teb tsaws ntawm 786-O hlwb raug txo kom txog li 50 feem pua, thiab 70 feem pua ​​​​txo tau pom hauv ACHN hlwb thaum NUDT1 knockdown (Daim duab 7(f)). Kev cuam tshuam ntawm tes kuj tseem cuam tshuam rau hauv ob lub xovtooj ntawm tes thaum NUDT1 noob raug tsoo (Figures 7(g) thiab 7(h)). Txhawm rau txhawb kev tsiv teb tsaws chaw, peb kuj tau ua qhov kev ntsuam xyuas qhov txhab zoo thaum NUDT1 raug tshem tawm los ntawm 786-O thiab ACHN kab ntawm tes thiab peb tau pom cov txiaj ntsig zoo sib xws ntawm kev txo lub qhov txhab kho lub peev xwm ntawm ob kab ntawm tes uas tsis muaj NUDT1 (Figures 7(l)– 7 (n) ib. Raws li cov txiaj ntsig no, peb xav tias kev poob ntawm NUDT1 tuaj yeem ua rau apoptosis hauv cov qog nqaij hlav raum. Yog li, peb ntsuas qhov feem pua ​​​​ntawm cov hlwb apoptotic thaum ntsiag to ntawm NUDT1. Qhov zoo siab, peb pom tias feem pua ​​​​ntawm cov hlwb apoptotic tau nce ntau hauv NUDT1-cov hlwb tsis txaus (Figures 7(i)–7(k)).

Kev sib tham

Raum lub raum ntshiab cell carcinoma (KIRC) yog ib qho ntawm cov kab mob loj tshaj plaws uas tshwm sim thoob ntiaj teb, feem ntau tsis pom cov tsos mob ntxov txog thaum cov qog loj txaus; yog li ntawd, qhov kev tuag tus nqi kuj yog siab [18–20]. Yog li, nws yog ib qho tsim nyog los tshawb xyuas cov carcinogenesis ntawm KIRC thiab txheeb xyuas cov biomarkers muaj txiaj ntsig rau nws qhov kev kuaj mob ntxov. Txawm li cas los xij, kev paub tsawg dhau los txog tam sim no tau tsim los ntawm pathogenesis thiab carcinogenesis ntawm KIRC. Tsis tas li ntawd, tsis muaj ntau cov cim molecular rau kev kho mob tau raug lees paub. Advanced high-throughput sequencing thiab bioinformatics technology ua rau nws muaj peev xwm xaiv biomarkers zoo [21]. RNA sequencing cov ntaub ntawv thiab cov ntaub ntawv kho mob ntawm ntau tshaj tsib puas KIRC cov ntaub ntawv muaj pub dawb rau ntawm TCGA database. Ua kom zoo dua ntawm cov ntaub ntawv pub dawb no los ntawm TCGA, peb tau txheeb xyuas cov ntaub ntawv RNA ua ntu zus rau qhov sib txawv ntawm cov kab mob metabolic hauv qog thiab cov qauv ntaub so ntswg. Ntawm cov genes upregulated thiab downregulated, peb tau txheeb xyuas cov saum toj kawg nkaus 10 qhov sib txawv qhia metabolic genes (DEmGs). Peb ntseeg tias cov noob metabolic muaj ntau yam haujlwm hauv KIRC; Txawm li cas los xij, nrhiav kev kuaj pom zoo thiab kho cov cim yuav yog ib qho kev sib tw los ntawm lub pas dej ntawm cov noob nrog ntau lub zog.

Yav dhau los, cov kev tshawb fawb tau kwv yees kev tiv thaiv kab mob hauv lub cev hauv cov qog microenvironment ntawm ntau cov qog nqaij hlav. Ib qho kev sib raug zoo ntawm cov qog nqaij hlav hauv lub cev thiab angiogenesis hauv KIRC cov qauv 'cov ntaub ntawv tau txais los ntawm TCGA tau kawm, thiab RFX2, SOX13, thiab THRA tau txheeb pom tias yog peb lub MTFs saum toj kawg nkaus hauv kev tswj cov npe angiogenesis hauv KIRC cov neeg mob [4]. Ntxiv mus, ob qho kev hloov kho m6A ywj siab tswj cov kev ua haujlwm lom neeg, cov yam ntxwv ntawm kev tiv thaiv kab mob, thiab kev kwv yees ntawm KIRC [22]. Autophagy-related protein 5 (ATG5) tau txuas nrog kev loj hlob ntawm ntau cov qog nqaij hlav nrog rau KIRC [23]. Hauv kev tshuaj xyuas tam sim no, qee qhov sib txawv ntawm cov noob suav nrog PBRM1, SET2, VHL, thiab BAP1 tau pom muaj kev sib raug zoo nrog cov txheej txheem metabolic hauv KIRC cov ntaub ntawv. Rau kev tshawb nrhiav tob ntxiv, peb tau txheeb xyuas cov neeg mob raws li DEmGs; pawg 1 tau pom tias qhov kev ciaj sia tsis zoo tag nrho raws li piv nrog rau lwm pawg; Txawm li cas los xij, cov neeg mob KIRC hauv pawg 3 muaj cov qog qog ntshav siab thiab muaj cov qog ntshav siab (n1 siab dua) piv nrog cov neeg hauv pawg 1 thiab 2, qhia txog kev mob qog noj ntshav thiab nthuav cov qog hauv pawg 3. Nws qhia tau tias muaj pes tsawg tus ntawm cov kab mob metabolic. nyob rau hauv pawg txuam nrog mob cancer metastasis.

Tsis tas li ntawd, cov qhab nia tiv thaiv kab mob hauv cov pawg sib txawv qhia C1 nrog cov qhab nia siab hauv stromal thiab kev tiv thaiv kab mob. Qhov tseem ceeb, cov neeg mob C1 nyob rau theem pathological III thiab IV muaj kev nkag siab siab ntawm T hlwb nrog rau CD8 ntxiv rau T hlwb, T follicular pab hlwb, thiab macrophages. Thaum tseem muaj ntau Tregs. Tregs muaj lub luag haujlwm tseem ceeb hauv kev tiv thaiv kab mob thiab homeostasis [24]. Hauv ntau cov qog nqaij hlav xws li mob qog noj ntshav, mob qog noj ntshav, thiab mob qog noj ntshav, qhov feem pua ​​​​ntawm Tregs muaj feem cuam tshuam nrog kev mob qog noj ntshav tsis zoo [25, 26]. M0 macrophage induces invasion thiab proliferation ntawm hlwb [27], thiab nce qib ntawm cov macrophages yog txuam nrog rau cov tsis zoo prognosis nyob rau hauv RCC [28]. Ib yam li ntawd, CD8 ntxiv rau T hlwb yog lub npe hu ua cov tshuaj tiv thaiv kab mob tseem ceeb thiab cov kev xaiv saum toj kawg nkaus rau kev kho lub cev tiv thaiv kab mob rau cov qog nqaij hlav [29]. Txawm hais tias C1 muaj qhov nkag siab tshaj plaws ntawm CD8 ntxiv rau T hlwb dua li lwm pawg, nws muaj qhov tsis zoo tag nrho.

Herba Cistanche

Peb siv peb txoj kev CIBERSORT, MCP, thiab ssGSEA los kawm txog kev tiv thaiv kab mob hauv lub cev hauv KIRC qog microenvironment. Ib txoj hauv kev los ntsuas cov qog tiv thaiv kab mob yog los ntawm histology ntawm cov ntaub so ntswg thiab cov kab mob tiv thaiv kab mob inferred los ntawm immunohistochemistry ntawm ib tus neeg cov cim. Txawm li cas los xij, muaj ntau qhov kev txwv uas immunohistochemistry tsis tuaj yeem txheeb xyuas ntau tus neeg tiv thaiv kab mob thiab ua tsis zoo ntawm kev ntes cov phenotypes (piv txwv li, activated vs. so lymphocytes). Yog li ntawd, peb tau siv CIBERSORT, ib txoj hauv kev suav tsim los ntawm [30] uas hais txog cov teeb meem uas tau ntsib los ntawm immunohistochemistry. Sib nrug los ntawm CIBERSORT, peb ua hauj lwm lwm cov pob khoom algorithmic los xyuas cov xwm txheej ntawm kev tiv thaiv kab mob. Qhov no yog vim hais tias CIBERSORT ntsuas tsuas yog intrasample proportions ntawm lub cev tiv thaiv kab mob uas tuaj yeem daws tau los ntawm lwm pob xws li MCP-counter uas tuaj yeem kwv yees cov hlwb cov neeg nyob hauv kev nplua mias uas ua rau muaj kev sib piv sib piv ntawm cov hlwb infiltrating hauv cov qog microenvironment [31]. Txhawm rau ua kom tiav CIBERSORT thiab MCP kev tshuaj ntsuam xyuas, peb tau thov ssGSEA txhawm rau txheeb xyuas cov qib infiltration rau cov kab mob tiv thaiv kab mob uas siv hauv R pob GSVA [32, 33]. GSA yog ib txoj hauv kev zoo tshaj plaws uas suav cov lus tshaj tawm rau cov gene cov npe ntawm kev txaus siab rau tag nrho lwm cov noob hauv genome. CIBERSORT tau pom cov txiaj ntsig zoo dua piv rau lwm txoj hauv kev; Yog li, kev soj ntsuam ntxiv tau ua los ntawm cov ntaub ntawv tau los ntawm CIBERSORT.

Ntxiv mus, peb tsom mus rau lub hauv paus txheej txheem ntawm KIRC kev nce qib los ntawm kev txheeb xyuas qhov sib txawv raws li cov ntaub ntawv RNA-seq. Zuag qhia tag nrho, peb tsom qhov txawv txav txawv txav ntawm cov noob caj noob ces ntawm peb pawg. Feem ntau ntawm cov noob tau raug txo qis tshwj tsis yog NUDT1 hauv C1; Txawm li cas los xij, nws txoj kev qhia tau raug txo qis los ntawm kev nce qib ntawm C1 mus rau C3. Yog li, NUDT1 tau raug lees paub ntxiv rau nws lub luag haujlwm hauv KIRC kev nce qib. SiRNA-mediated inhibition ntawm NUDTI noob qhia nyob rau hauv ob KIRC kab ntawm tes (786-O thiab ACHN) txo cov cell viability thiab cell migration thiab nce apoptosis, uas paub meej tias nws lub luag hauj lwm nyob rau hauv cov qog nqaij hlav. Yav dhau los, nws tau raug tshaj tawm tias qib ntawm NUDT1 qhia muaj feem cuam tshuam nrog qib qog, theem, qhov loj, qhov sib txawv, qib ntawm vascular invasion, tag nrho cov ciaj sia taus (OS), thiab kab mob tsis muaj sia nyob (DFS) hauv cov neeg mob HCC, kuj tau kwv yees li. ib tug prognostic marker nrog kev kho mob muaj peev xwm nyob rau hauv HCC cov neeg mob [34]. Overexpressing NUDT1 nyob rau hauv pulmonary arterial hypertension txo oxidative kev nyuaj siab thiab DNA puas, li no txhawb cell proliferation thiab txo apoptosis [35]. Nws tau pom tias cov neeg mob ntawm qhov ncauj squamous cell carcinoma (OSCC) muaj kev qhia siab ntawm NUDT1 tau pom tias muaj kev ciaj sia tsis zoo [36]. Raws li qhov tseeb tias cov ntaub ntawv tsis txaus muaj txog NUDTI lub luag haujlwm hauv kev mob qog noj ntshav thiab, txog tam sim no, tsis muaj kev tshawb fawb tau tshaj tawm nws lub luag haujlwm hauv KIRC, yog li ntawd, peb tau tshaj tawm thawj zaug lub luag haujlwm ntawm NUDTI hauv KIRC kev nce qib. Txoj kev tshawb fawb tam sim no muaj qee qhov kev txwv; Txawm hais tias peb cov kev tshawb fawb pom tias daim ntawv kos npe tuaj yeem cuam tshuam nrog kev tiv thaiv kab mob ntawm KIRC, qhov ua tau zoo ntawm kev kos npe tsis tuaj yeem raug lees paub vim tsis muaj cov ntaub ntawv, cov peev txheej hauv qab, thiab lub luag haujlwm ua haujlwm ntawm NUDT1 hauv KIRC thiab kev kho mob yuav tsum tau tshawb nrhiav ntxiv.

Cistanche tubulosa

Cov lus xaus

Peb soj ntsuam dysregulated metabolic noob ntawm ib txwm thiab qog nqaij hlav thiab tshawb nrhiav lawv txoj haujlwm. WGCNA tsom xam tau txheeb xyuas ib pawg ntawm cov noob muaj feem cuam tshuam nrog kev muaj sia nyob ntawm KIRC. Kev pom zoo ua pawg raws li cov noob caj noob ces muaj sia nyob tau pom peb pawg nrog cov kev ciaj sia sib txawv thiab cov qauv tiv thaiv kab mob. NUDT1 cuam tshuam tsis zoo nrog kev ciaj sia, thiab kev soj ntsuam ntxiv tau qhia tias qhov kev poob qis ntawm NUDT1 inhibits kev loj hlob thiab kev tsiv teb tsaws ntawm cov qog hlwb. Ntawm qhov kev ceeb toom, tus qauv kwv yees tau tsim los ntawm cov noob caj noob ces, uas tau pom tias muaj txiaj ntsig zoo hauv kev kwv yees kev ciaj sia ntawm KIRC. Hauv kev xaus, peb tau ua ib qho kev soj ntsuam tag nrho ntawm cov noob metabolic hauv KIRC thiab txheeb xyuas NUDT1 ua ib qho oncogene uas tuaj yeem siv los ua cov phiaj xwm kho mob thiab kev soj ntsuam.

Cov nyhuv ntawm Cistanche Extract ntawm lub raum pob tshab

Muaj qee cov pov thawj tshawb fawb txog cov txiaj ntsig ntawm Cistanche ntawm lub raum pob tshab. Txawm li cas los xij, qee qhov kev tshawb fawb qhia tias Cistanche extract yuav muaj txiaj ntsig zoo rau lub raum noj qab haus huv.

Lub raum yog lub luag haujlwm rau lim cov khib nyiab thiab co toxins los ntawm lub cev, thiab lawv txoj kev noj qab haus huv yog qhov tseem ceeb rau kev noj qab haus huv tag nrho. Cov kev tshawb fawb tau pom tias Cistanche extract muaj lub zog antioxidant thiab tiv thaiv kab mob, uas tuaj yeem pab tiv thaiv oxidative kev nyuaj siab thiab mob raum.

Hauv cov tshuaj suav tshuaj, Cistanche kuj tseem siv los ua kom lub raum ua kom zoo dua qub thiab txhim kho lawv txoj haujlwm. Qee cov kws kho mob ntseeg hais tias kev noj cov Cistanche extract tsis tu ncua tuaj yeem pab txhim kho lub raum pob tshab, txawm hais tias qhov kev thov no tsis tau rov qab los ntawm kev tshawb fawb soj ntsuam zoo.

Yog li ntawd, kev tshawb fawb nruj dua yuav tsum tau nkag siab txog cov txiaj ntsig zoo ntawm Cistanche extract ntawm lub raum pob tshab. Txawm li cas los xij, ib yam li kev noj zaub mov ntxiv lossis lwm txoj kev kho mob, nws yog ib qho tseem ceeb uas yuav tau sab laj nrog tus kws kho mob ua ntej muab cov khoom tshiab ntxiv rau hauv koj cov zaub mov, tshwj xeeb yog tias koj muaj mob ua ntej.

Cov ntaub ntawv

[18] RL Siegel, KD Miller, thiab A. Jemal, "Cancer statistics, 2019," CA: A Cancer Journal for Clinicians, vol. 6 9, nr. 1, p.m. 7–34, 2019.

[19] RL Siegel, KD Miller, HE Fuchs, thiab A. Jemal, "Cancer statistics, 2021," CA: A Cancer Journal for Clinicians, vol. 7 1, nr. 1, pp. 7–33, 2021.

[20] JC Angulo thiab O. Shapiro, "Kev hloov kho toj roob hauv pes ntawm metastatic lub raum mob cancer," Cancers, vol. 11, nr. 9 ib,p. 1227 Peb 2019.

[21] AK Sharma, "Tshwj xeeb tshaj tawm hauv kev tshawb pom biomarker: yooj yim ntawm kev kuaj mob thiab kev kwv yees hauv kev mob qog noj ntshav," Kev Sib Tham hauv Cancer Biology, vol. 52, Part 1, p. iii–iv, 2018.

[22] H. Li, J. Hu, A. Yu et al., "RNA modification of N6- methyladenosine predicts immune phenotypes and therapeutic chance in the raum clear cell carcinoma," Frontiers in Oncology, vol. 11, xov 642159, 2021.

[23] C. Xu, Y. Zang, Y. Zhao, et al., "Kev tshuaj ntsuam xyuas kab mob qog noj ntshav tau lees paub tias ATG5 txhawb kev saib xyuas cov qog nqaij hlav metabolism thiab qhov tshwm sim ntawm qog tiv thaiv kab mob tawm," Frontiers in Oncology, vol. 11, xov 652211, 2021.

[24] Y. Takeuchi thiab H. Nishikawa, "Lub luag haujlwm ntawm kev tswj hwm T hlwb hauv kev tiv thaiv kab mob qog noj ntshav," International Immunology, vol. 28, nr. 8, pp. 401–409, 2016.

[25] C. Zhuo, Y. Xu, M. Ying, et al., "FOXP3 ntxiv rau Tregs: heterogeneous phenotypes thiab tsis sib haum xeeb cuam tshuam rau kev ciaj sia nyob rau hauv cov neeg mob qog noj ntshav," Immunologic Research, vol. 61, Nr. 3, pp. 338–347, 2015.

[26] H. Wang, F. Franco, thiab PC Ho, "Metabolic regulation of Tregs in cancer: lub sij hawm rau immunotherapy," Trends Cancer, vol. 3, nre. 8, pp. 583–592, 2017.

[27] BZ Qian thiab JW Pollard, "Macrophage ntau haiv neeg txhim kho qog nqaij hlav thiab metastasis," Cell, vol. 141, Nr. 1, pp. 39–51, 2010.

[28] A. Hajiran, N. Chakiryan, AM Aydin, et al., "Reconnaissance of qog immune microenvironment spatial heterogeneity in metastatic renal cell carcinoma and correlation with immunotherapy response," Clinical and Experimental Immunology, vol. 204, Nr. 1, nr 96–106, 2021.

[29] B. Farhood, M. Najafi, thiab K. Mortezaee, "CD8(plus) cytotoxic T lymphocytes hauv kev kho mob qog noj ntshav: kev tshuaj xyuas," Journal of Cellular Physiology, vol. 234, Nr. 6, nr 8509–8521, 2019.

[30] AM Newman, CL Liu, MR Green, et al., "Robust enumeration of cell subsets from tissue expression profiles," Nature Methods, vol. 12, nr. 5, pp. 453–457, 2015.

[31] E. Becht, NA Giraldo, L. Lacroix, et al., "Kev kwv yees cov pej xeem abundance ntawm cov ntaub so ntswg-infiltrating tiv thaiv kab mob thiab stromal cell pej xeem siv gene qhia," Genome Biology, vol. 17, nr. 1 ib,p. Peb Hlis 218, 2016.

[32] DA Barbie, P. Tamayo, JS Boehm, et al., "Systematic RNA cuam tshuam qhia tias oncogenic KRAS-driven cancers xav tau TBK1," Xwm, vol. 462, Nr. 7269, pp. 108–112, 2009.

[33] S. Hanzelmann, R. Castelo, and J. Guinney, "GSVA: gene set variation analysis for microarray and RNA-seq data," BMC Bioinformatics, vol. 14, nr. 1, 2013.

[34] Q. Ou, N. Ma, Z. Yu et al., "Nudix hydrolase 1 is a prognostic biomarker in hepatocellular carcinoma," Aging, vol. 12, nr. 8 Ib., 7363–7379, 2020.

[35] G. Vitry, R. Paulin, Y. Grobs, et al., "Oxidized DNA precursors cleanup by NUDT1 contributes to vascular remodeling in pulmonary arterial hypertension," American Journal of Respiratory and Critical Care Medicine, vol. 203, Nr. 5, nr 614–627, 2021.

[36] Y. Shen, X. 4 9, nr. 3, pp. 210–218, 2020.

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