PRKCI promotes immune suppression in ovarian cancer

被引：73

作者：

Sarkar, Sharmistha ^{[1
]}

Bristow, Christopher A. ^{[1
,2
]}

Dey, Prasenjit ^{[3
]}

Rai, Kunal ^{[1
]}

Perets, Ruth ^{[4
]}

Ramirez-Cardenas, Alejandra ^{[5
]}

Malasi, Shruti ^{[1
]}

Huang-Hobbs, Emmet ^{[1
]}

Haemmerle, Monika ^{[6
]}

Wu, Sherry Y. ^{[6
]}

McGuire, Michael ^{[6
]}

Protopopov, Alexei ^{[7
]}

Jiang, Shan ^{[1
]}

Liu, Joyce F. ^{[8
]}

Hirsch, Michelle S. ^{[9
]}

Chang, Qing ^{[2
]}

Lazar, Alexander J. ^{[10
,11
]}

Sood, Anil K. ^{[3
,6
,12
]}

Drapkin, Ronny ^{[8
,13
]}

DePinho, Ronald ^{[3
]}

Draetta, Giulio ^{[1
,2
,14
]}

Chin, Lynda ^{[15
]}

机构：

[1] Univ Texas MD Anderson Canc Ctr, Dept Genom Med, Houston, TX 77054 USA

[2] Univ Texas MD Anderson Canc Ctr, Inst Appl Canc Sci, Houston, TX 77054 USA

[3] Univ Texas MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX 77054 USA

[4] Clin Res Inst Rambam, Div Oncol, IL-31096 Haifa, Israel

[5] Boston Univ, Dept Environm Hlth, Boston, MA 02118 USA

[6] Univ Texas MD Anderson Canc Ctr, Dept Gynecol Oncol & Reprod Med, Houston, TX 77054 USA

[7] KEW Grp, Cambridge, MA 02139 USA

[8] Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[9] Harvard Med Sch, Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA

[10] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77054 USA

[11] Univ Texas MD Anderson Canc Ctr, Dept Dermatol, Houston, TX 77054 USA

[12] Univ Texas MD Anderson Canc Ctr, Ctr RNA Interference & Noncoding RNA, Houston, TX 77054 USA

[13] Univ Penn, Dept ObGyn, Philadelphia, PA 19104 USA

[14] Univ Texas MD Anderson Canc Ctr, Dept Mol & Cellular Oncol, Houston, TX 77054 USA

[15] Univ Texas Syst, Inst Hlth Transformat, Houston, TX 77030 USA

来源：

GENES & DEVELOPMENT | 2017年 / 31卷 / 11期

基金：

美国国家卫生研究院;

关键词：

PRKCI; YAP; ovarian cancer; NECROSIS-FACTOR-ALPHA; KINASE-C-IOTA; HIPPO PATHWAY; PKC-IOTA; INFLAMMATION MARKERS; POOR-PROGNOSIS; FALLOPIAN-TUBE; BREAST-CANCER; LUNG-CANCER; T-CELLS;

D O I：

10.1101/gad.296640.117

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

A key feature of high-grade serous ovarian carcinoma (HGSOC) is frequent amplification of the 3q26 locus harboring PRKC-t (PRKCI). Here, we show that PRKCI is also expressed in early fallopian tube lesions, called serous tubal intraepithelial carcinoma. Transgenic mouse studies establish PRKCI as an ovarian cancer-specific oncogene. Mechanistically, we show that the oncogenic activity of PRKCI relates in part to the up-regulation of TNF alpha to promote an immune-suppressive tumor microenvironment characterized by an abundance of myeloid-derived suppressor cells and inhibition of cytotoxic T-cell infiltration. Furthermore, system-level and functional analyses identify YAP1 as a downstream effector in tumor progression. In human ovarian cancers, high PRKCI expression also correlates with high expression of TNF alpha and YAP1 and low infiltration of cytotoxic T cells. The PRKCI-YAP1 regulation of the tumor immunity provides a therapeutic strategy for highly lethal ovarian cancer.

引用

页码：1109 / 1121

页数：13

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