Genetické a epigenetické základy radiorezistence nádorových buněk prostaty

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Authors: Denis Kutilin
Authors‘ workplace: National Medical Research Oncology Center, Rostov-on-Don, Russian Federation
Published in: Klin Onkol 2021; 34(3): 220-234
Category: Original Article
doi: https://doi.org/10.48095/ccko2021220

Overview

Východiska: Radiační terapie hraje hlavní roli v léčbě karcinomu prostaty, ale výskyt radiorezistentních forem tohoto onemocnění diktuje potřebu personalizovaného přístupu založeného na údajích z genetických a epigenetických markerů. Takové markery zahrnují změnu počtu kopií, expresi genů a mikroRNA. Cíl: Cílem studie bylo ověřit seznam potenciálních prediktorů radiorezistence nádorových buněk prostaty v modelovém experimentu založeném na stanovení variací počtu genových kopií, genové transkripční aktivity a exprese mikroRNA. Materiál a metody: Ve studii byla použita buněčná kultura karcinomu prostaty PC-3. Stanovení relativního počtu kopií a exprese 32 genů (BRCA1, BRCA2, PTEN, CASP3, CASP8, BAX, BCL2, CASP9, P53, MDM2, AKT1, ATM, BRIP1, CDK1, CDKN1B, CCND1, CCND3, FGFRAD250, RUAP80, Rif1, RNF168, TopBP1, HIST, H2AX, EXO1, XRCC4, RBBP8, EP300, LIG4, C-FLIP) a 15 mikroRNA (let-7, miR-7, miR15a/16, miR-17-92, miR-18a, miR-21, miR-24, miR-26b, miR-34s, miR-99a, miR-100, miR-101, miR-106, miR-663) bylo provedeno pomocí metody kvantitativní polymerázové řetězové reakce v reálném čase. Bylo zjištěno, že denní ozáření buněk PC-3 na lineárním urychlovači Novalis TX při dávkách 6 a 7 Gy po dobu 5 dnů vede k významnému snížení celkového počtu buněk a počtu životaschopných buněk. Nicméně po 5 dnech ozáření si asi 15 % původního počtu nádorových buněk prostaty zachovalo svou životaschopnost, což je způsobeno jejich zvláštními genetickými a epigenetickými vlastnostmi: zvýšený počet kopií a exprese BRCA2, CDK1, CDKN1B, H2AX, RAD50, XRCC4, RBBP8 a EP300 a snížený počet kopií a exprese genů CCND3, TP53 a BCL2, jakož i diferenciální exprese šesti mikroRNA (hsa-miR-18a-5p, hsa-miR-24-1-5p, hsa-miR- 99a-5p, hsa-miR-100-5p, hsa-miR-145-5p3, hsa-let-7a-2-3p). Závěr: Tato studie umožnila identifikovat genetické a epigenetické markery rezistence nádorových buněk prostaty na radiační terapii.

Klíčová slova:

radioterapie – karcinom prostaty – buněčná kultura – počet kopií genů – transkripční aktivita genů – mikro-RNA – apoptóza – oprava DNA

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