Alternative splicing promotes tumour aggressiveness and drug resistance in African American prostate cancer

被引：80

作者：

Wang, Bi-Dar ^{[1
,2
]}

Ceniccola, Kristin ^{[1
]}

Hwang, Sujin ^{[3
]}

Andrawis, Ramez ^{[4
]}

Horvath, Anelia ^{[1
]}

Freedman, Jennifer A. ^{[5
,6
]}

Olender, Jacqueline ^{[1
]}

Knapp, Stefan ^{[7
,8
]}

Ching, Travers ^{[9
]}

Garmire, Lana ^{[9
]}

Patel, Vyomesh ^{[10
]}

Garcia-Blanco, Mariano A. ^{[11
]}

Patierno, Steven R. ^{[5
,6
]}

Lee, Norman H. ^{[1
]}

机构：

[1] George Washington Univ, Dept Pharmacol & Physiol, Sch Med & Hlth Sci, Washington, DC 20037 USA

[2] Univ Maryland Eastern Shore, Dept Pharmaceut Sci, Sch Pharm & Hlth Profess, Princess Anne, MD 21853 USA

[3] George Washington Univ, Dept Microbiol Immunol & Trop Med, Sch Med & Hlth Sci, Washington, DC 20037 USA

[4] George Washington Univ, Dept Urol, Sch Med & Hlth Sci, Washington, DC 20037 USA

[5] Duke Univ, Med Ctr, Duke Canc Inst, Durham, NC 27710 USA

[6] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA

[7] Univ Oxford, Dept Clin Pharmacol, Oxford OX3 7BN, England

[8] Univ Oxford, Nuffield Dept Clin Med, Struct Genom Consortium, Oxford OX3 7BN, England

[9] Univ Hawaii, Canc Ctr, Canc Epidemiol Program, Honolulu, HI 96813 USA

[10] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA

[11] Univ Texas Med Branch, Dept Biochem & Mol Biol, Galveston, TX 77555 USA

来源：

NATURE COMMUNICATIONS | 2017年 / 8卷

关键词：

PHOSPHATIDYLINOSITOL; 3-KINASE; ANDROGEN RECEPTOR; SOMATIC MUTATIONS; PI3K PATHWAY; P110-DELTA; INHIBITOR; EXPRESSION; IDELALISIB; CAL-101; GROWTH;

D O I：

10.1038/ncomms15921

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Clinical challenges exist in reducing prostate cancer (PCa) disparities. The RNA splicing landscape of PCa across racial populations has not been fully explored as a potential molecular mechanism contributing to race-related tumour aggressiveness. Here, we identify novel genome-wide, race-specific RNA splicing events as critical drivers of PCa aggressiveness and therapeutic resistance in African American (AA) men. AA-enriched splice variants of PIK3CD, FGFR3, TSC2 and RASGRP2 contribute to greater oncogenic potential compared with corresponding European American (EA)-expressing variants. Ectopic overexpression of the newly cloned AA-enriched variant, PIK3CD-S, in EA PCa cell lines enhances AKT/mTOR signalling and increases proliferative and invasive capacity in vitro and confers resistance to selective PI3Kd inhibitor, CAL-101 (idelalisib), in mouse xenograft models. High PIK3CD-S expression in PCa specimens associates with poor survival. These results highlight the potential of RNA splice variants to serve as novel biomarkers and molecular targets for developmental therapeutics in aggressive PCa.

引用

页数：14

共 69 条

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