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Signalna pot retinojske kisline pri raku sečnega mehurja
ID Mišmaš Zrimšek, Maruša (Avtor), ID Zupančič, Daša (Mentor) Več o mentorju... Povezava se odpre v novem oknu

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Izvleček
Rak sečnega mehurja je deseti najpogostejši rak na svetu z visoko stopnjo ponovljivosti. Epidemiološke študije so pokazale, da povišan vnos vitamina A s prehrano zmanjša tveganje za razvoj raka mehurja. Glavne biološko aktivne oblike vitamina A so retinol, retinaldehid in retinojska kislina. Za prevzem retinola v celico je odgovoren transmembranski receptor STRA6 (angl. stimulated by retinoic acid 6). V celici se retinol pretvori v založni retinil ester z encimom LRAT (angl. lecithin retinol acyltransferase) ali pa se pretvori v retinaldehid, ki ga encim ALDH1/2 (angl. aldehyde dehydrogenase) ireverzibilno oksidira v retinojsko kislino. Ta se veže na celični vezavni protein CRABP1 (angl. cellular retinoic acid binding protein), ki le to transportira v jedro. Jedrni receptor za retinojsko kislino RXR (angl. retinoid X receptor) po vezavi retinojske kisline sproži transkripcijo tarčnih genov. Nenormalna signalna pot retinojske kisline je povezana s karcinogenezo pri različnih oblikah raka, vključno z rakom mehurja. V magistrski nalogi smo z imunooznačevanjem in prenosom western preučevali izražanje in lokalizacijo STRA6, LRAT, ALDH1/2, CRABP1 in RXR v človeških in podganjih vzorcih normalnega in rakavega urotelija. Pokazali smo razlike v izražanju proteinov med normalnim in rakavim urotelijem. STRA6 se je v normalnem človeškem uroteliju izražal predvsem v površinskih celicah, v rakavem uroteliju pa se je izražal v vseh skladih urotelija. Statistično značilno povišano količino STRA6 glede na normalen vzorec smo dokazali na podganjem vzorcu z najbolj napredovana obliko raka. LRAT se je izražal v vseh urotelijskih skladih tako pri normalnih kot rakavih človeških in podganjih vzorcih. Kvantifikacija je pokazala povišano količino LRAT v rakavih vzorcih. ALDH je v normalnem in rakavem človeškem uroteliju prevladoval v bazalnih in vmesnih celicah, razen pri vzorcu z mišično invazivnim papilarnim urotelijskim karcinomom (pT2), kjer je bila reakcija negativna. V normalnih podganjih vzorcih se je ALDH1/2 močno izražal v bazalnih in vmesnih celicah, v rakavih vzorcih pa se je izražal heterogeno. CRABP1 se je izražal v vseh skladih normalnega in rakavega človeškega urotelija, razen pri stadiju pT2, kjer se je izražal le v površinskih celicah. V normalnih podganjih vzorcih je bila reakcija na CRABP1 negativna, v rakavih podganjih vzorcih pa heterogena. Kvantifikacija je pokazala povišano količino CRABP1 v človeških in podganjih rakavih vzorcih, ki pa ni bila statistično značilna. Poskuse z RXR smo izvedli le na človeških vzorcih, pri katerih se je le ta izražal v jedrih vseh skladov celic, tako v normalnih kot rakavih vzorcih. V naši nalogi smo pokazali razlike v lokalizaciji in količini proteinov STRA6, LRAT, ALDH1/2, CRABP1 in RXR v normalnem in rakavem človeškem in podganjem uroteliju.

Jezik:Slovenski jezik
Ključne besede:sečni mehur, urotelij, rak, retinojska kislina, vitamin A
Vrsta gradiva:Magistrsko delo/naloga
Tipologija:2.09 - Magistrsko delo
Organizacija:FKKT - Fakulteta za kemijo in kemijsko tehnologijo
Leto izida:2022
PID:20.500.12556/RUL-141041 Povezava se odpre v novem oknu
COBISS.SI-ID:122671875 Povezava se odpre v novem oknu
Datum objave v RUL:22.09.2022
Število ogledov:638
Število prenosov:139
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Sekundarni jezik

Jezik:Angleški jezik
Naslov:Retinoic acid signalling in urinary bladder cancer
Izvleček:
Bladder cancer is the tenth most common cancer in the world with a high recurrence rate. Epidemiological studies have shown that increased dietary intake of vitamin A reduces the risk of developing bladder cancer. The most important bioactive forms of vitamin A are retinol, retinaldehyde and retinoic acid. The transmembrane receptor STRA6 (stimulated by retinoic acid 6) is responsible for cellular retinol uptake. In the cell, retinol can be converted into retinyl ester for storage by the enzyme LRAT (lecithin retinol acyltransferase) or it can be converted into retinaldehyde, which is irreversibly oxidised to retinoic acid by the enzyme ALDH1/2 (aldehyde dehydrogenase). Retinoic acid binds to the protein CRABP1 (cellular retinoic acid binding protein), which transports it into the cell nucleus. The nuclear receptor for retinoic acid RXR (retinoid X receptor) activates the transcription of the target genes after the retinoic acid binds. Abnormal retinoic acid signalling is associated with carcinogenesis in several cancers, including bladder cancer. In our thesis, we investigated the expression and localisation of STRA6, LRAT, ALDH1/2, CRABP1 and RXR in samples of normal and cancerous human and rat urothelium using immunostaining and Western blot. We found differences in the expression of the proteins between normal and cancerous urothelium. STRA6 was expressed mainly in the surface cells in normal human, whereas it was expressed in all cell layers in cancerous urothelium. We detected a statistically significant increase in the amount of STRA6 in rat samples with the most advanced bladder cancer compared to normal rat urothelium. LRAT was expressed in all cell layers in both normal and cancerous human and rat samples. Quantification showed increased amount of LRAT in cancerous samples. ALDH in normal and cancerous human urothelium was predominantly present in basal and intermediate cells, except in one sample with muscle-invasive papillary urothelial carcinoma (pT2), in which the reaction was negative. In normal rat urothelium, it was strongly expressed in basal and intermediate cells, whereas it was heterogeneously expressed in cancerous rat urothelium. CRABP1 was expressed in all cell layers in normal and cancerous human urothelium, except at stage pT2, where CRABP1 was expressed only in surface cells. In the normal rat urothelium, the reaction to CRABP1 was negative, whereas it was heterogeneously expressed in the cancerous rat urothelium. Quantification showed increased amount of CRABP1 in human and rat cancerous samples, but this was not statistically significant. Experiments with RXR were only performed on human samples. RXR was expressed in the nuclei of all cell layers in both normal and cancerous urothelium. In our study, we showed differences in localisation and amount of the proteins STRA6, LRAT, ALDH1/2, CRABP1 and RXR in human and rat urothelium.

Ključne besede:urinary bladder, urothelium, cancer, retinoic acid, vitamin A

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