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Vrednotenje signalnih poti, ki vključujejo katepsina B in X, v tumorskih matičnih celicah raka dojke = Evaluation of signalling pathways which include cathepsins B and X in breast cancer stem cells : magistrska naloga : magistrski študijski program Laboratorijska biomedicinaFrlic, TjašaRak dojke je drugi najpogostejši vzrok smrti zaradi raka pri ženskah na svetu. Smrtnost zaradi raka dojke se je zaradi napredka pri diagnosticiranju in zdravljenju bolezni v zadnjih desetletjih ... značilno zmanjšala. Kljub temu pri številnih bolnicah ostajata problem neodzivnost na zdravljenje in ponovni pojav bolezni, za kar je odgovorna majhna populacija rakavih celic – tumorske matične celice (TMC). Zato potrebujemo nove terapevtske pristope, ki bi bili učinkoviti tudi proti tej populaciji celic. Poleg obstoječih protitumornih terapij, ki ciljajo diferencirane tumorske celice, bi s ciljanjem TMC lahko dosegli daljše obdobje brez bolezni ali popolno okrevanje bolnic z rakom dojke. Kot obetavni terapevtski tarči sta se izkazali cisteinski lizosomski peptidazi, katepsina B in X, ki sta udeležena v ključnih procesih nastanka in napredovanja raka. Za njihovo uspešno uvedbo v nove terapevtske pristope zdravljenja raka je ključnega pomena tudi razumevanje njihovih molekularnih mehanizmov in učinkov na ključne signalne poti v TMC. TMC smo izolirali iz celičnih linij MDA-MB-231, MCF-10A neoT in MCF7 na podlagi njihove sposobnosti tvorbe tumorskih sfer. Najprej smo po detekciji s specifičnimi protitelesi na membrani po prenosu western pokazali, da je izražanje katepsinov B in X v TMC, izoliranih s tvorbo tumorskih sfer, povečano v primerjavi z diferenciranimi tumorskimi celicami pred izolacijo TMC. Z zaviranjem katepsinov B in X smo nato ovrednotili vpliv na celično signalizacijo v TMC. Pri tem smo določili izražanje izbranih proteinov, ki so udeleženi v ključih signalnih poteh TMC; pGSK3β, ciklin D1, β-katenin, TGFβ in NF-κB. Pokazali smo, da z zaviranjem katepsinov B in X pomembno vplivamo na signalni poti Wnt in TGFβ, medtem ko zaviranje katepsinov B in X nima večjega vpliva na signalno pot NF-κB. Nazadnje smo z zaviranjem signalnih kinaz določili vlogo katepsinov B in X v signalnih poteh TMC raka dojke. S prenosom western in določanjem aktivnosti z encimsko kinetiko smo pokazali, da imata katepsina B in X pomembno vlogo v signalnih poteh JAK/STAT, Wnt, MAPK in PI3K ter sta vključena v signalizacijo preko Trk in integrinskih receptorjev. Pokazali smo, da sta katepsina B in X udeležena v številnih signalnih poteh TMC raka dojke. S tem smo prispevali k razumevanju učinka zaviranja katepsinov B in X na ključne signalne poti v TMC, kar je pomembno za razumevanje njihovih molekularnih mehanizmov in možnost uporabe pri protitumorni terapiji.Type of material - master's thesis ; adult, seriousPublication and manufacture - Ljubljana : [T. Frlic], 2023Language - slovenianCOBISS.SI-ID - 163636483
Author
Frlic, Tjaša
Other authors
Kos, Janko, 1959- |
Mitrović, Ana
Topics
Rak (medicina) |
Dojke |
Zdravljenje |
tumorske matične celice |
signalne poti |
katepsin B |
katepsin X |
rak dojke
Library/institution |
City | Acronym | For loan | Other holdings |
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Faculty of Pharmacy, Ljubljana | Ljubljana | FFALJ |
reading room 1 cop.
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Database name | Field | Year |
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Links to authors' personal bibliographies | Links to information on researchers in the SICRIS system |
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Frlic, Tjaša | |
Kos, Janko, 1959- | 04648 |
Mitrović, Ana | 36440 |
Source: Personal bibliographies
and: SICRIS
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