Bmi1 is required for the initiation of pancreatic cancer through an Ink4a-independent mechanism

被引：20

作者：

Bednar, Filip ^{[1
]}

Schofield, Heather K. ^{[2
,3
]}

Collins, Meredith A. ^{[2
]}

Yan, Wei ^{[4
,5
]}

Zhang, Yaqing ^{[1
]}

Shyam, Nikhil ^{[3
]}

Eberle, Jaime A. ^{[6
,7
]}

Almada, Luciana L. ^{[8
]}

Olive, Kenneth P. ^{[6
,7
]}

Bardeesy, Nabeel ^{[9
]}

Fernandez-Zapico, Martin E. ^{[8
]}

Nakada, Daisuke ^{[10
]}

Simeone, Diane M. ^{[1
,11
,12
]}

Morrison, Sean J. ^{[13
,14
]}

di Magliano, Marina Pasca ^{[1
,2
,12
,15
]}

机构：

[1] Univ Michigan, Dept Surg, Ann Arbor, MI 48109 USA

[2] Univ Michigan, Program Cell & Mol Biol, Ann Arbor, MI 48109 USA

[3] Univ Michigan, Med Scientist Training Program, Ann Arbor, MI 48109 USA

[4] Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA

[5] Univ Michigan, Michigan Ctr Translat Pathol, Ann Arbor, MI 48109 USA

[6] Columbia Univ, Herbert Irving Comprehens Canc Ctr, Dept Med, New York, NY 10032 USA

[7] Columbia Univ, Herbert Irving Comprehens Canc Ctr, Dept Pathol, New York, NY 10032 USA

[8] Mayo Clin, Div Oncol Res, Schulze Ctr Novel Therapeut, Rochester, MN 55905 USA

[9] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Boston, MA 02114 USA

[10] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA

[11] Univ Michigan, Dept Mol & Integrat Physiol, Ann Arbor, MI 48109 USA

[12] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA

[13] Univ Texas SW Med Ctr Dallas, Childrens Res Inst, Dept Pediat, Dallas, TX 75390 USA

[14] Univ Texas SW Med Ctr Dallas, Howard Hughes Med Inst, Dallas, TX 75390 USA

[15] Univ Michigan, Dept Cell & Dev Biol, Ann Arbor, MI 48109 USA

来源：

CARCINOGENESIS | 2015年 / 36卷 / 07期

基金：

美国国家卫生研究院;

关键词：

CELL SELF-RENEWAL; ONCOGENIC KRAS; POLYCOMB; PROLIFERATION; SENESCENCE; REGENERATION; EXPRESSION; COOPERATE; SURVIVAL; INK4A;

D O I：

10.1093/carcin/bgv058

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Bmi1, a Polycomb repressive complex member, is required for the initiation of pancreatic cancer, independently of its known ability to repress the p16 and p19 tumor suppressor genes. Additionally, we show that Bmi1 regulates reactive oxygen species accumulation in pancreatic cancer cells.Epigenetic dysregulation is involved in the initiation and progression of many epithelial cancers. BMI1, a component of the polycomb protein family, plays a key role in these processes by controlling the histone ubiquitination and long-term repression of multiple genomic loci. BMI1 has previously been implicated in pancreatic homeostasis and the function of pancreatic cancer stem cells. However, no work has yet addressed its role in the early stages of pancreatic cancer development. Here, we show that BMI1 is required for the initiation of murine pancreatic neoplasia using a novel conditional knockout of Bmi1 in combination with a Kras(G12D)-driven pancreatic cancer mouse model. We also demonstrate that the requirement for Bmi1 in pancreatic carcinogenesis is independent of the Ink4a/Arf locus and at least partially mediated by dysregulation of reactive oxygen species. Our data provide new evidence of the importance of this epigenetic regulator in the genesis of pancreatic cancer.

引用

页码：730 / 738

页数：9

共 38 条

[1] Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma [J].