Wassermann Stella, Scheel Silvio K, Hiendlmeyer Elke, Palmqvist Richard, Horst David, Hlubek Falk, Haynl Angela, Kriegl Lydia, Reu Simone, Merkel Susanne, Brabletz Thomas, Kirchner Thomas, Jung Andreas
Pathologisch-Anatomisches Institut der Universität Erlangen-Nürnberg, Erlangen, Germany.
Gastroenterology. 2009 Jan;136(1):196-205.e2. doi: 10.1053/j.gastro.2008.09.019. Epub 2008 Sep 20.
BACKGROUND & AIMS: Human colorectal carcinomas display an infiltrative front of invasion where tumor cells undergo an epithelomesenchymal transition associated with low survival. Epithelomesenchymal transition is regulated by a nuclear beta-catenin accumulation, and subsequently, activation of beta-catenin/TCF4 target genes similar to CYCLIN D(1). Unexpectedly, these tumor cells are characterized by low proliferation, which correlates with the expression of the cell cycle inhibitor p16(INK4A). Therefore, we investigated the molecular mechanism of the transcriptional regulation of p16(INK4A) in colorectal cancer and its correlation with survival.
Molecular biological techniques were used for investigating the transcriptional mechanisms of the p16(INK4A) gene regulation. Moreover, p16(INK4A) expression was correlated with the 10-year survival of patients with colorectal carcinomas.
In colorectal carcinomas, expression of the p16(INK4A) gene is regulated by beta-catenin/TCF4 and correlates with low survival rates of patients with tumors displaying an infiltrative front of invasion.
beta-catenin/TCF4 regulates cell cycle promoting (c-MYC, CYCLIN D(1)) and inhibiting genes (p16(INK4A)) at the same time in the mesenchymally differentiated tumor cells at the front of invasion. The function of p16(INK4A) seems to supersede in this context thus leading to low proliferation. Moreover, these tumor cells seem to govern the outcome of colorectal cancer independently of their proliferation.
人类结肠直肠癌呈现浸润性侵袭前沿，在此处肿瘤细胞经历上皮-间质转化，且生存率较低。上皮-间质转化受核β-连环蛋白积累调控，随后激活类似于细胞周期蛋白D1的β-连环蛋白/TCF4靶基因。出乎意料的是，这些肿瘤细胞的特征是增殖率低，这与细胞周期抑制剂p16(INK4A)的表达相关。因此，我们研究了结直肠癌中p16(INK4A)转录调控的分子机制及其与生存率的相关性。
采用分子生物学技术研究p16(INK4A)基因调控的转录机制。此外，p16(INK4A)表达与结肠直肠癌患者的10年生存率相关。
在结肠直肠癌中，p16(INK4A)基因的表达受β-连环蛋白/TCF4调控，且与具有浸润性侵袭前沿的肿瘤患者的低生存率相关。
在侵袭前沿的间充质分化肿瘤细胞中，β-连环蛋白/TCF4同时调控细胞周期促进基因（c-MYC、细胞周期蛋白D1）和抑制基因（p16(INK4A)）。在这种情况下，p16(INK4A)的功能似乎占主导地位，从而导致增殖率低。此外，这些肿瘤细胞似乎独立于其增殖情况决定着结肠直肠癌的预后。
