Induction of EMT by twist proteins as a collateral effect of tumor-promoting inactivation of premature senescence (Cancer Cell, 2008, 14:79-89)

報告日期: 2008/11/07
報告時間: 16:00/16:50
報告學生: 蔡漢霓
講評老師: 張 玲
附件下載:

http://basicmed.med.ncku.edu.tw/admin/up_img/971107-2.pdf

Induction of EMT by Twist Proteins as a Collateral Effect of Tumor-Promoting Inactivation of Premature Senescence

 

Ste´ phane Ansieau,Jeremy Bastid, Agne` s Doreau, Anne-Pierre Morel, Benjamin P. Bouchet, Cle´mence Thomas, Fre´ de´ rique Fauvet, Isabelle Puisieux, Claudio Doglioni, Sara Piccinin, Roberta Maestro, Thibault Voeltzel, Abdelkader Selmi, Sandrine Valsesia-Wittmann, Claude Caron de Fromentel, and Alain Puisieux

Cancer Cell 14,79-89 (2008)

Speaker:蔡漢霓 

Commentator: 張玲 老師

Time: 2008/11/07 PM 4:00

Place: Room 602

Abstract

Twist1 and Twis2 are important regulators of embryogenesis. Twist1 is required for neural tube development. Twist2 is required for inflammatory cytokine expressions. Twist1 has been shown to play a major role in promoting epithelial-mesenchymal transition (EMT) and favoring the metastatic process. Although Twist1 and Twist2 have high structure homology, the function of Twist2 in malignant tumors remains largely unknown. Oncogene-induced senescence (OIS) is a cellular response that is crucial for protection against cancer development. The authors aimed to know whether Twist1 and Twist2 inhibit premature senescence in cancer cells. They found that expression levels of Twist2 were mostly higher than those of Twist1 in 20 analyzed spontaneous mammary tumors in MMTV-ErbB2/Neu transgenic mice. This finding suggested that Twist2 is involved in tumor progression. In addition, Twist1 and Twist2 mRNA levels were increased in various types of human malignant tumors (n=148) and cancerous cell lines (n=64). Knockdown of Twist1 and Twist2 in cancer cell lines by RNA interference resulted in characteristics of senescence: flattened cytoplasm, G1 growth arrest, senescence-associated β-galactosidase activation and overexpression of differentiated embryonic chondrocyte-1(DEC1), an important marker for cellular senescence. Overexpression of both Twist1/2 and H-RasV12, a strong inducer of OIS, exhibited characteristics of malignant transformation such as loss of contact inhibition and growth in soft agar in MEF cells. These transformed MEFs were then subcutaneously grafted into athymic nude mice and tumors were seen in all 10 recipient mice. And p16INK4A and p21CIP1 downregulations were observed in these transformed MEFs and tumor cells. Also the expressions of both Twist1/2 and OIS inducer H-RasV12 or ErbB2 triggered a total loss of E-cadherin epithelial marker and overexpression of viementin mesenchymal marker in epithelial cells, indicating that Twist1/2 are crucial players for EMT. In conclusion, Twist1 and Twist2 cooperate with Ras/ErbB2 to allow cancer cell to override premature senescence and promote EMT to facilitate invasion and metastasis.

 

Reference:

1. Yang, J., et al.,2004. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell. 117, 927–939.

2. Collado, M., Gil, J., et al., 2005. Tumour biology: senescence in premalignant tumours. Nature 436, 642.