Ptpn11/Shp2 Acts as a Tumor Suppressor in Hepatocellular Carcinogenesis

被引：305

作者：

Bard-Chapeau, Emilie A. ^{[1
,2
,3
]}

Li, Shuangwei ^{[1
,2
]}

Ding, Jin ^{[4
]}

Zhang, Sharon S. ^{[1
,2
]}

Zhu, Helen H. ^{[1
,2
]}

Princen, Frederic ^{[3
]}

Fang, Diane D. ^{[1
,2
]}

Han, Tao ^{[4
]}

Bailly-Maitre, Beatrice ^{[3
]}

Poli, Valeria ^{[5
]}

Varki, Nissi M. ^{[1
,2
]}

Wang, Hongyang ^{[4
]}

Feng, Gen-Sheng ^{[1
,2
,4
]}

机构：

[1] Univ Calif San Diego, Dept Pathol, La Jolla, CA 92093 USA

[2] Univ Calif San Diego, Div Biol Sci, La Jolla, CA 92093 USA

[3] Sanford Burnham Med Res Inst, La Jolla, CA 92037 USA

[4] Second Mil Med Univ, Eastern Hepatobiliary Surg Hosp, Lab Signal Transduct, Shanghai 200433, Peoples R China

[5] Univ Turin, Dept Genet Biol & Biochem, I-10126 Turin, Italy

来源：

CANCER CELL | 2011年 / 19卷 / 05期

关键词：

SHP-2 TYROSINE PHOSPHATASE; BREAST-CANCER; CELLS; INFLAMMATION; MUTATIONS; STAT3; DIFFERENTIATION; ACTIVATION; EXPRESSION; ONCOGENES;

D O I：

10.1016/j.ccr.2011.03.023

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

The human gene Ptpn11, which encodes the tyrosine phosphatase Shp2, may act as a proto-oncogene because dominantly activating mutations have been detected in several types of leukemia. Herein we report a tumor-suppressor function of Shp2. Hepatocyte-specific deletion of Shp2 promotes inflammatory signaling through the Stat3 pathway and hepatic inflammation/necrosis, resulting in regenerative hyperplasia and development of tumors in aged mice. Furthermore, Shp2 ablation dramatically enhanced diethylnitrosamine (DEN)-induced hepatocellular carcinoma (HCC) development, which was abolished by concurrent deletion of Shp2 and Stat3 in hepatocytes. Decreased Shp2 expression was detected in a subfraction of human HCC specimens. Thus, in contrast to the leukemogenic effect of dominant-active mutants, Ptpn11/Shp2 has a tumor-suppressor function in liver.

引用

页码：629 / 639

页数：11

共 33 条

[1] Essential role of STAT3 in the control of the acute-phase response as revealed by inducible gene activation in the liver [J].

Alonzi, T ;

Maritano, D ;

Gorgoni, B ;

Rizzuto, G ;

Libert, C ;

Poli, V .

MOLECULAR AND CELLULAR BIOLOGY, 2001, 21 (05) :1621-1632

[2] Concerted functions of Gab1 and Shp2 in liver regeneration and hepatoprotection [J].

Bard-Chapeau, Emilie A. ;

Yuan, Jing ;

Droin, Nathalie ;

Long, Shinong ;

Zhang, Eric E. ;

Nguyen, Thanh V. ;

Feng, Gen-Sheng .

MOLECULAR AND CELLULAR BIOLOGY, 2006, 26 (12) :4664-4674

[3] MOLECULAR THEMES IN ONCOGENESIS [J].

BISHOP, JM .

CELL, 1991, 64 (02) :235-248

[4] Oncogenic kinase signalling [J].

Blume-Jensen, P ;

Hunter, T .

NATURE, 2001, 411 (6835) :355-365

[5] PTPN11 is the first identified proto-oncogene that encodes a tyrosine phosphatase [J].

Chan, Rebecca J. ;

Feng, Gen-Sheng .

BLOOD, 2007, 109 (03) :862-867

[6] A definitive role of Shp-2 tyrosine phosphatase in mediating embryonic stem cell differentiation and hematopoiesis [J].

Chan, RJ ;

Johnson, SA ;

Li, YJ ;

Yoder, MC ;

Feng, GS .

BLOOD, 2003, 102 (06) :2074-2080

[7] Inflammation and cancer [J].

Coussens, LM ;

Werb, Z .

NATURE, 2002, 420 (6917) :860-867

[8] Type 1 T Helper Cells Induce the Accumulation of Myeloid-Derived Suppressor Cells in the Inflamed Tgfb1 Knockout Mouse Liver [J].

Cripps, James G. ;

Wang, Jing ;

Maria, Ann ;

Blumenthal, Ian ;

Gorham, James D. .

HEPATOLOGY, 2010, 52 (04) :1350-1359

[9] SH2-CONTAINING PHOSPHOTYROSINE PHOSPHATASE AS A TARGET OF PROTEIN-TYROSINE KINASES [J].

FENG, GS ;

HUI, CC ;

PAWSON, T .

SCIENCE, 1993, 259 (5101) :1607-1611

[10] IKKβ links inflammation and tumorigenesis in a mouse model of colitis-associated cancer [J].

Greten, FR ;

Eckmann, L ;

Greten, TF ;

Park, JM ;

Li, ZW ;

Egan, LJ ;

Kagnoff, MF ;

Karin, M .

CELL, 2004, 118 (03) :285-296

← 1 2 3 4 →