Down-Regulation of Autophagy-Related Protein 5 (ATG5) Contributes to the Pathogenesis of Early-Stage Cutaneous Melanoma

被引：153

作者：

Liu, He ^{[1
]}

He, Zhaoyue ^{[1
]}

von Ruette, Thomas ^{[1
]}

Yousefi, Shida ^{[1
]}

Hunger, Robert E. ^{[2
]}

Simon, Hans-Uwe ^{[1
]}

机构：

[1] Univ Bern, Inst Pharmacol, CH-3010 Bern, Switzerland

[2] Univ Hosp Bern, Inselspital, Dept Dermatol, CH-3010 Bern, Switzerland

来源：

SCIENCE TRANSLATIONAL MEDICINE | 2013年 / 5卷 / 202期

基金：

瑞士国家科学基金会;

关键词：

CELLS; TUMORIGENESIS; OVEREXPRESSION; INHIBITION; MUTATIONS; INDUCTION; APOPTOSIS; BECLIN-1;

D O I：

10.1126/scitranslmed.3005864

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

The role of autophagy in cancer is controversial: Both tumor-suppressing and tumor-promoting functions have been reported. We show that a key regulator of autophagy, autophagy-related protein 5 (ATG5), is often down-regulated in primary melanomas compared to benign nevi, leading to a reduction of basal autophagy as evidenced by a reduced expression of LC3. A follow-up of 158 primary melanoma patients showed that patients with low levels of ATG5 in their tumors had a reduced progression-free survival. In an in vitro model of melanoma tumorigenesis, where the BRAF oncogene was transduced into normal melanocytes, we observed that lowering ATG5 expression promoted proliferation by precluding oncogene-induced senescence. Hence, it appears that down-regulation of ATG5 contributes to tumorigenesis in early-stage cutaneous melanoma, and the expression of ATG5 and LC3 correlates with melanoma diagnosis and prognosis.

引用

页数：12

共 45 条

[1] HUMAN-SKIN FIBROBLASTS INVITRO DIFFERENTIATE ALONG A TERMINAL CELL LINEAGE [J].

BAYREUTHER, K ;

RODEMANN, HP ;

HOMMEL, R ;

DITTMANN, K ;

ALBIEZ, M ;

FRANCZ, PI .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1988, 85 (14) :5112-5116

[2] The landscape of somatic copy-number alteration across human cancers [J].

Beroukhim, Rameen ;

Mermel, Craig H. ;

Porter, Dale ;

Wei, Guo ;

Raychaudhuri, Soumya ;

Donovan, Jerry ;

Barretina, Jordi ;

Boehm, Jesse S. ;

Dobson, Jennifer ;

Urashima, Mitsuyoshi ;

Mc Henry, Kevin T. ;

Pinchback, Reid M. ;

Ligon, Azra H. ;

Cho, Yoon-Jae ;

Haery, Leila ;

Greulich, Heidi ;

Reich, Michael ;

Winckler, Wendy ;

Lawrence, Michael S. ;

Weir, Barbara A. ;

Tanaka, Kumiko E. ;

Chiang, Derek Y. ;

Bass, Adam J. ;

Loo, Alice ;

Hoffman, Carter ;

Prensner, John ;

Liefeld, Ted ;

Gao, Qing ;

Yecies, Derek ;

Signoretti, Sabina ;

Maher, Elizabeth ;

Kaye, Frederic J. ;

Sasaki, Hidefumi ;

Tepper, Joel E. ;

Fletcher, Jonathan A. ;

Tabernero, Josep ;

Baselga, Jose ;

Tsao, Ming-Sound ;

Demichelis, Francesca ;

Rubin, Mark A. ;

Janne, Pasi A. ;

Daly, Mark J. ;

Nucera, Carmelo ;

Levine, Ross L. ;

Ebert, Benjamin L. ;

Gabriel, Stacey ;

Rustgi, Anil K. ;

Antonescu, Cristina R. ;

Ladanyi, Marc ;

Letai, Anthony .

NATURE, 2010, 463 (7283) :899-905

[3] Mutations of the BRAF gene in human cancer [J].

Davies, H ;

Bignell, GR ;

Cox, C ;

Stephens, P ;

Edkins, S ;

Clegg, S ;

Teague, J ;

Woffendin, H ;

Garnett, MJ ;

Bottomley, W ;

Davis, N ;

Dicks, N ;

Ewing, R ;

Floyd, Y ;

Gray, K ;

Hall, S ;

Hawes, R ;

Hughes, J ;

Kosmidou, V ;

Menzies, A ;

Mould, C ;

Parker, A ;

Stevens, C ;

Watt, S ;

Hooper, S ;

Wilson, R ;

Jayatilake, H ;

Gusterson, BA ;

Cooper, C ;

Shipley, J ;

Hargrave, D ;

Pritchard-Jones, K ;

Maitland, N ;

Chenevix-Trench, G ;

Riggins, GJ ;

Bigner, DD ;

Palmieri, G ;

Cossu, A ;

Flanagan, A ;

Nicholson, A ;

Ho, JWC ;

Leung, SY ;

Yuen, ST ;

Weber, BL ;

Siegler, HF ;

Darrow, TL ;

Paterson, H ;

Marais, R ;

Marshall, CJ ;

Wooster, R .

NATURE, 2002, 417 (6892) :949-954

[4] The role of apoptosis in creating and maintaining luminal space with normal and oncogene-expressing mammary acini [J].

Debnath, J ;

Mills, KR ;

Collins, NL ;

Reginato, MJ ;

Muthuswamy, SK ;

Brugge, JS .

CELL, 2002, 111 (01) :29-40

[5] Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis [J].

Degenhardt, Kurt ;

Mathew, Robin ;

Beaudoin, Brian ;

Bray, Kevin ;

Anderson, Diana ;

Chen, Guanghua ;

Mukherjee, Chandreyee ;

Shi, Yufang ;

Gelinas, Celine ;

Fan, Yongjun ;

Nelson, Deirdre A. ;

Jin, Shengkan ;

White, Eileen .

CANCER CELL, 2006, 10 (01) :51-64

[6] The MAPK pathway in melanoma [J].

Fecher, Leslie A. ;

Arnaravadi, Ravi K. ;

Flaherty, Keith T. .

CURRENT OPINION IN ONCOLOGY, 2008, 20 (02) :183-189

[7] Induction of autophagy during extracellular matrix detachment promotes cell survival [J].

Fung, Christopher ;

Lock, Rebecca ;

Gao, Sizhen ;

Salas, Eduardo ;

Debnath, Jayanta .

MOLECULAR BIOLOGY OF THE CELL, 2008, 19 (03) :797-806

[8] Overexpression of Microtubule-Associated Protein-1 Light Chain 3 Is Associated with Melanoma Metastasis and Vasculogenic Mimicry [J].

Han, Chunrong ;

Sun, Baocun ;

Wang, Wei ;

Cai, Wenjuan ;

Lou, Dan ;

Sun, Yan ;

Zhao, Xiulan .

TOHOKU JOURNAL OF EXPERIMENTAL MEDICINE, 2011, 223 (04) :243-251

[9] Overexpression of autophagy-related beclin-1 in advanced malignant melanoma and its low expression in melanoma-in-situ [J].

Hara, Yoko ;

Nakamura, Motonobu .

EUROPEAN JOURNAL OF DERMATOLOGY, 2012, 22 (01) :128-129

[10] Recent trends in cutaneous melanoma incidence and death rates in the United States, 1992-2006 [J].

Jemal, Ahmedin ;

Saraiya, Mona ;

Patel, Pragna ;

Cherala, Sai S. ;

Barnholtz-Sloan, Jill ;

Kim, Julian ;

Wiggins, Charles L. ;

Wingo, Phyllis A. .

JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY, 2011, 65 (05) :S17-S25

← 1 2 3 4 5 →