고찰

전사체가 minor 전사체로 전위되는 유전자는 종양 세포가 암에서 생존하는 데 이점을 줄 수 있는 것으로 사료된다. 종양 세포는 종양 형성을 위해 정상적인 세포사멸을 회피하며, 암에서 선택 접합된 전사체가 세포사멸을 비정상적으로 조절하는 사례가 많이 알려져 있다(Takehara et al., 2001). 예를 들어, 리간드 및 receptor (FasL, Fas, LARD), adaptor 단백질 및 regulator (TRAF2, TRAF3, MyDD88, MADD, Apaf-1, survivin, Smac/Diablo), Bcl-2 family (Bcl-x, Bak, Bid, Bim), caspase 및 caspase-like 단백질(caspase-2, caspase-9, caspase-10, FLIP), caspase 타겟 단백질(ICAD, CAD, Acinus) 등 세포사멸에 관여하는 많은 유전자에서 선택 접합이 일어나는

분류로 확인된 subtype 1 에 해당하는 환자들이 subtype 2 의 환자들보다 더

있으며, 4E-BP1 의 비활성화와 몇 가지 종양 유전자 및 anti-apoptotic 기능을 하는

알려진 유전자이다(Bi et al., 2014). WNT5A 는 유방암, 위암, 췌장암, al., 2011; Stefater et al., 2011; Abdelmaksoud-Dammak et al., 2014; Bi et al., 2014; Cheng et al., 2014). Wnt 신호과정은 간암에서 비정상적으로 활성화된다고 알려진 기전

간암 종양 조직에서 정상 조직과 다르게 major 전사체에서 minor 전사체로의 전위가 일어난 유전자 목록에 이미 암에서 선택 접합이 중요한 역할을 한다고 알려진 유전자인 세포 주기 check point 의 기능을 하는 BRCA1 과 암의 침습에 두 개의 단백질이 다른 기능을 한다고 알려진 ERBB3 와 세포사멸에 상반된 기능을 한다고 보고된 CASP9 (capase9)이 포함되어 있었다(Orban and Olah, 2003;

Lin et al., 2008; Shultz et al., 2010). 본 연구에서는 간암 환자들에서 다르게 선택 접합이 일어난 전사체로 인해 간암 발달에 다른 영향을 미칠 수 있음을 제시하였다.

이상의 연구 결과들은 HCC 의 환자들간의 차등 선택 접합이 일어나고 있는 유전자가 암과 관련된 생물학적 과정에 관여하고 있음을 제시하고 있으며, 선택 접합이 일어난 유전자에 대한 전사체 수준에서의 연구가 간암의 이질성과 관련한 분자 기전을 규명하는 데에 새로운 방향성을 제시할 수 있음을 시사해 주고 있다. 또한, 선택 접합 프로파일링에 기반한 간암 환자의 분류가 간암 환자간의 임상 병리학적으로 다른 특성을 지닌 subtype 을 예측하는 데 유용할 수 있음을 시사한다.

Ⅴ. 결론

본 논문에서는 RNA 서열분석을 사용하여 간암 환자의 전사체 및 선택 접합 프로파일링을 하였고, 하나의 유전자에서 선택 접합이 일어난 두 전사체간의 발현량에 대한 비율에 기반하여 환자들을 분류하는 것이 환자들의 임상적 예후 차이를 밝혀줄 수 있음을 확인하였다. 한 유전자에서 선택 접합된 두 전사체간의 발현량에 대한 비율을 기반으로 한 간암 환자의 분류 방법이 환자의 특성과 분자기전을 이해하는 데 유용할 수 있음을 제시하고, 선택 접합이 환자에 따른 간암의 발생기전 및 종양 발달에 기여하는 기전을 규명하는 데에 중요한 영향을 미칠 수 있음을 시사한다.

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- ABSTRACT -

Genomic Profiling of Alternative splicing in liver cancer

Mi-kyoung Seo

Department of Biomedical Sciences The Graduate School, Ajou University

(Supervised by professor Hyun Goo Woo)

The development of liver cancers is a multistep process, which is known to progress through diverse molecular and biological mechanisms. Recently, the next generation sequencing has allowed many advances in the characterization and quantification of transcripts in genome-wide manner. In particular, RNA-sequencing provides ability to

The development of liver cancers is a multistep process, which is known to progress through diverse molecular and biological mechanisms. Recently, the next generation sequencing has allowed many advances in the characterization and quantification of transcripts in genome-wide manner. In particular, RNA-sequencing provides ability to

문서에서 Genomic Profiling of Alternative splicing in liver cancer (페이지 49-70)