STAT3 regulated ARF expression suppresses prostate cancer metastasis

被引：131

作者：

Pencik, Jan ^{[1
]}

Schlederer, Michaela ^{[1
,2
]}

Gruber, Wolfgang ^{[3
]}

Unger, Christine ^{[4
]}

Walker, Steven M. ^{[5
]}

Chalaris, Athena ^{[6
]}

Marie, Isabelle J. ^{[7
,8
,9
]}

Hassler, Melanie R. ^{[2
]}

Javaheri, Tahereh ^{[1
]}

Aksoy, Osman ^{[2
]}

Blayney, Jaine K. ^{[10
]}

Prutsch, Nicole ^{[2
]}

Skucha, Anna ^{[11
]}

Herac, Merima ^{[2
]}

Kraemer, Oliver H. ^{[12
]}

Mazal, Peter ^{[2
]}

Grebien, Florian ^{[1
]}

Egger, Gerda ^{[2
]}

Poli, Valeria ^{[13
]}

Mikulits, Wolfgang ^{[14
]}

Eferl, Robert ^{[14
]}

Esterbauer, Harald ^{[15
]}

Kennedy, Richard ^{[5
]}

Fend, Falko ^{[16
]}

Scharpf, Marcus ^{[16
]}

Braun, Martin ^{[17
]}

Perner, Sven ^{[17
]}

Levy, David E. ^{[7
,8
,9
]}

Malcolm, Tim ^{[18
]}

Turner, Suzanne D. ^{[18
]}

Haitel, Andrea ^{[2
]}

Susani, Martin ^{[2
]}

Moazzami, Ali ^{[19
]}

Rose-John, Stefan ^{[6
]}

Aberger, Fritz ^{[3
]}

Merkel, Olaf ^{[2
]}

Moriggl, Richard ^{[1
,20
]}

Culig, Zoran ^{[21
]}

Dolznig, Helmut ^{[4
]}

Kenner, Lukas ^{[1
,2
,22
]}

机构：

[1] Ludwig Boltzmann Inst Canc Res, A-1090 Vienna, Austria

[2] Med Univ Vienna, Clin Inst Pathol, A-1090 Vienna, Austria

[3] Paris Lodron Univ Salzburg, Dept Mol Biol, A-5020 Salzburg, Austria

[4] Med Univ Vienna, Inst Med Genet, A-1090 Vienna, Austria

[5] Queens Univ Belfast, Ctr Canc Res & Cell Biol, Belfast BT7 1NN, Antrim, North Ireland

[6] Univ Kiel, Inst Biochem, D-24098 Kiel, Germany

[7] NYU, Sch Med, Dept Pathol, New York, NY 10016 USA

[8] NYU, Sch Med, Inst Canc, New York, NY 10016 USA

[9] NYU, Sch Med, Dept Microbiol, New York, NY 10016 USA

[10] Univ Ulster, NI Stratified Med Res Grp, Londonderry BT47 6SB, North Ireland

[11] Austrian Acad Sci, CeMM Res Ctr Mol Med, A-1090 Vienna, Austria

[12] Univ Med Ctr, Dept Toxicol, D-55131 Mainz, Germany

[13] Univ Turin, Dept Genet Biol & Biochem, Ctr Mol Biotechnol, I-10126 Turin, Italy

[14] Med Univ Vienna, Ctr Comprehens Canc, Dept Med 1, Div Inst Canc Res, A-1090 Vienna, Austria

[15] Med Univ Vienna, Dept Lab Med, A-1090 Vienna, Austria

[16] Univ Hosp Tuebingen, Inst Pathol & Neuropathol, D-72076 Tubingen, Germany

[17] Univ Hosp Bonn, Ctr Integrated Oncol Cologne Bonn, Inst Pathol, D-53127 Bonn, Germany

[18] Univ Cambridge, Dept Pathol, Cambridge CB2 0QQ, England

[19] Swedish Univ Agr Sci, Dept Chem & Biotechnol, S-75007 Uppsala, Sweden

[20] Univ Vet Med Vienna, Unit Translat Methods Canc Res, A-1210 Vienna, Austria

[21] Med Univ Innsbruck, Dept Urol, A-6020 Innsbruck, Austria

[22] Univ Vet Med Vienna, Unit Pathol Lab Anim, A-1210 Vienna, Austria

来源：

NATURE COMMUNICATIONS | 2015年 / 6卷

基金：

奥地利科学基金会;

关键词：

TUMOR-SUPPRESSOR; CELLULAR SENESCENCE; PTEN; GENE; P53; ACTIVATION; INHIBITOR; CELLS; MDM2; IDENTIFICATION;

D O I：

10.1038/ncomms8736

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：

Prostate cancer (PCa) is the most prevalent cancer in men. Hyperactive STAT3 is thought to be oncogenic in PCa. However, targeting of the IL-6/STAT3 axis in PCa patients has failed to provide therapeutic benefit. Here we show that genetic inactivation of Stat3 or IL-6 signalling in a Pten-deficient PCa mouse model accelerates cancer progression leading to metastasis. Mechanistically, we identify p19(ARF) as a direct Stat3 target. Loss of Stat3 signalling disrupts the ARF-Mdm2-p53 tumour suppressor axis bypassing senescence. Strikingly, we also identify STAT3 and CDKN2A mutations in primary human PCa. STAT3 and CDKN2A deletions co-occurred with high frequency in PCa metastases. In accordance, loss of STAT3 and p14(ARF) expression in patient tumours correlates with increased risk of disease recurrence and metastatic PCa. Thus, STAT3 and ARF may be prognostic markers to stratify high from low risk PCa patients. Our findings challenge the current discussion on therapeutic benefit or risk of IL-6/STAT3 inhibition.

引用

页数：14

共 72 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] Constitutively Active Stat3 Enhances Neu-Mediated Migration and Metastasis in Mammary Tumors via Upregulation of Cten [J].

Barbieri, Isaia ;

Pensa, Sara ;

Pannellini, Tania ;

Quaglino, Elena ;

Maritano, Diego ;

Demaria, Marco ;

Voster, Alessandra ;

Turkson, James ;

Cavallo, Federica ;

Watson, Christine J. ;

Provero, Paolo ;

Musiani, Piero ;

Poli, Valeria .

CANCER RESEARCH, 2010, 70 (06) :2558-2567

[3] In vivo identification of novel STAT5 target genes [J].

Basham, Beth ;

Sathe, Manjiri ;

Grein, Jeffrey ;

McClanahan, Terrill ;

D'Andrea, Annalisa ;

Lees, Emma ;

Rascle, Anne .

NUCLEIC ACIDS RESEARCH, 2008, 36 (11) :3802-3818

[4] TGF-β suppresses tumor progression in colon cancer by inhibition of IL-6 trans-signaling [J].

Becker, C ;

Fantini, MC ;

Schramm, C ;

Lehr, HA ;

Wirtz, S ;

Nikolaev, A ;

Burg, J ;

Strand, S ;

Kiesslich, R ;

Huber, S ;

Ito, H ;

Nishimoto, N ;

Yoshizaki, K ;

Nishimoto, N ;

Galle, PR ;

Blessing, M ;

Rose-John, S ;

Neurath, MF .

IMMUNITY, 2004, 21 (04) :491-501

[5] Reciprocal Feedback Regulation of PI3K and Androgen Receptor Signaling in PTEN-Deficient Prostate Cancer [J].

Carver, Brett S. ;

Chapinski, Caren ;

Wongvipat, John ;

Hieronymus, Haley ;

Chen, Yu ;

Chandarlapaty, Sarat ;

Arora, Vivek K. ;

Le, Carl ;

Koutcher, Jason ;

Scher, Howard ;

Scardino, Peter T. ;

Rosen, Neal ;

Sawyers, Charles L. .

CANCER CELL, 2011, 19 (05) :575-586

[6] Apoptosis is a natural stimulus of IL6R shedding and contributes to the proinflammatory trans-signaling function of neutrophils [J].

Chalaris, Athena ;

Rabe, Bjoern ;

Paliga, Krzysztof ;

Lange, Hans ;

Laskay, Tamas ;

Fielding, Ceri A. ;

Jones, Simon A. ;

Rose-John, Stefan ;

Scheller, Juergen .

BLOOD, 2007, 110 (06) :1748-1755

[7] Stapled α-helical peptide drug development: A potent dual inhibitor of MDM2 and MDMX for p53-dependent cancer therapy [J].

Chang, Yong S. ;

Graves, Bradford ;

Guerlavais, Vincent ;

Tovar, Christian ;

Packman, Kathryn ;

To, Kwong-Him ;

Olson, Karen A. ;

Kesavan, Kamala ;

Gangurde, Pranoti ;

Mukherjee, Aditi ;

Baker, Theresa ;

Darlak, Krzysztof ;

Elkin, Carl ;

Filipovic, Zoran ;

Qureshi, Farooq Z. ;

Cai, Hongliang ;

Berry, Pamela ;

Feyfant, Eric ;

Shi, Xiangguo E. ;

Horstick, James ;

Annis, D. Allen ;

Manning, Anthony M. ;

Fotouhi, Nader ;

Nash, Huw ;

Vassilev, Lyubomir T. ;

Sawyer, Tomi K. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2013, 110 (36) :E3445-E3454

[8] ETS factors reprogram the androgen receptor cistrome and prime prostate tumorigenesis in response to PTEN loss [J].

Chen, Yu ;

Chi, Ping ;

Rockowitz, Shira ;

Iaquinta, Phillip J. ;

Shamu, Tambudzai ;

Shukla, Shipra ;

Gao, Dong ;

Sirota, Inna ;

Carver, Brett S. ;

Wongvipat, John ;

Scher, Howard I. ;

Zheng, Deyou ;

Sawyers, Charles L. .

NATURE MEDICINE, 2013, 19 (08) :1023-+

[9] Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis [J].

Chen, ZB ;

Trotman, LC ;

Shaffer, D ;

Lin, HK ;

Dotan, ZA ;

Niki, M ;

Koutcher, JA ;

Scher, HI ;

Ludwig, T ;

Gerald, W ;

Cordon-Cardo, C ;

Pandolfi, PP .

NATURE, 2005, 436 (7051) :725-730

[10] Differential p53-Independent Outcomes of p19Arf Loss in Oncogenesis [J].

Chen, Zhenbang ;

Carracedo, Arkaitz ;

Lin, Hui-Kuan ;

Koutcher, Jason A. ;

Behrendt, Nille ;

Egia, Ainara ;

Alimonti, Andrea ;

Carver, Brett S. ;

Gerald, William ;

Teruya-Feldstein, Julie ;

Loda, Massimo ;

Pandolfi, Pier Paolo .

SCIENCE SIGNALING, 2009, 2 (84) :ra44

← 1 2 3 4 5 6 7 8 →