Rimkus C, Martini M, Friederichs J, Rosenberg R, Doll D, Siewert J R, Holzmann B, Janssen K P
Department of Surgery, Klinikum Rechts der Isar, Technische Universität München, Ismaninger Str 22, Munich, Germany.
Br J Cancer. 2006 Nov 20;95(10):1419-23. doi: 10.1038/sj.bjc.6603452. Epub 2006 Oct 31.
The gene SASH1 (SAM- and SH3-domain containing 1) has originally been identified as a candidate tumour suppressor gene in breast cancer. SASH1 is a member of the SH3-domain containing expressed in lymphocytes (SLY1) gene family that encodes signal adapter proteins composed of several protein-protein interaction domains. The other members of this family are expressed mainly in haematopoietic cells, whereas SASH1 shows ubiquitous expression. We have used quantitative real-time PCR to investigate the expression of SASH1 in tissue samples from 113 patients with colon carcinoma, and compared the expression with 15 normal colon tissue samples. Moreover, nine benign adenomas and 10 liver metastases were analysed. Expression levels of SASH1 were strongly and significantly reduced in colon cancer of UICC stage II, III, and IV, as well as in liver metastases. Moreover, SASH1 was also found to be downregulated on protein levels by immunoblot analysis. However, SASH1 expression was not significantly deregulated in precancerous adenomas and in earlier stage lesions (UICC I). Overall, 48 out of 113 primary colon tumours showed SASH1 expression that was at least 10-fold lower than the levels found in normal colon tissue. Downregulation of SASH1 expression was correlated with the formation of metachronous distant metastasis, and multivariate analysis identified SASH1 downregulation as an independent negative prognostic parameter for patient survival. This study demonstrates for the first time that expression of a member of the SLY1-gene family has prognostic significance in human cancer.
基因SASH1（含SAM和SH3结构域1）最初被鉴定为乳腺癌中的候选肿瘤抑制基因。SASH1是淋巴细胞中表达的含SH3结构域（SLY1）基因家族的成员，该家族编码由几个蛋白质-蛋白质相互作用结构域组成的信号衔接蛋白。该家族的其他成员主要在造血细胞中表达，而SASH1表现出普遍表达。我们使用定量实时PCR研究了113例结肠癌患者组织样本中SASH1的表达，并与15个正常结肠组织样本的表达进行了比较。此外，还分析了9个良性腺瘤和10个肝转移灶。SASH1的表达水平在UICC II、III和IV期结肠癌以及肝转移灶中显著降低。此外，通过免疫印迹分析发现SASH1在蛋白质水平上也下调。然而，SASH1在癌前腺瘤和早期病变（UICC I）中的表达没有明显失调。总体而言，113例原发性结肠肿瘤中有48例显示SASH1表达至少比正常结肠组织中的水平低10倍。SASH1表达下调与异时远处转移的形成相关，多变量分析确定SASH1下调是患者生存的独立负性预后参数。这项研究首次证明SLY1基因家族成员的表达在人类癌症中具有预后意义。
