Center of Human Genetics, University of Bremen, Leobener Strasse ZHG, 28359 Bremen, Germany.
Genes Chromosomes Cancer. 2010 Aug;49(8):661-8. doi: 10.1002/gcc.20777.
Pathogenetically, uterine leiomyomas (ULs) can be interpreted as the result of a monoclonal abnormal proliferation of myometrial cells. Oncogene-induced senescence (OIS) is a frequent phenomenon in premalignant lesions that leads to a growth arrest mainly by the activation of two potent growth-inhibitory pathways as represented by p16(Ink4a) and p19(Arf). The relevance of OIS for the development of UL has not been addressed, but HMGA2, encoded by a major target gene of recurrent chromosomal abnormalities in UL, has been implicated in the repression of the Ink4a/Arf (CDKN2A) locus. This prompted us to examine if HMGA2 contributes to the growth of leiomyomas by repressing this locus. Contrary to the expectations, we were able to show that generally ULs express significantly higher levels of p19(Arf) mRNA than myometrium and that UL with 12q14 approximately 15 rearrangements showed higher expression levels than UL with other cytogenetic aberrations. Furthermore, the finding of a significant correlation between the expressions of p19(Arf) and CDKN1A shows that p19(Arf) triggers senescence rather than apoptosis in UL. Furthermore, the expression levels of HMGA2, p19(Arf), and CDKN1A were found to be correlated with the size of the tumors, indicating that an enhanced growth potential is counterbalanced by the p19(Arf) pathway. Mechanistically, the UL may thus execute a program already present in their cell of origin, where it is activated to protect the genome, for example, in the case of enhanced proliferation. In summary, the results identify the p19(Arf)-TP53-CDKN1A pathway as a major player in the growth control and genomic stability of uterine fibroids.
从发病机制上讲，子宫平滑肌瘤（UL）可以被解释为子宫平滑肌细胞单克隆异常增殖的结果。癌基因诱导的衰老（OIS）是癌前病变中的一种常见现象，主要通过两条强有力的生长抑制途径的激活导致生长停滞，这两条途径分别由 p16(Ink4a)和 p19(Arf)代表。OIS 与 UL 的发展之间的关系尚未得到解决，但 UL 中反复出现的染色体异常的主要靶基因编码的 HMGA2 已被牵涉到抑制 Ink4a/Arf（CDKN2A）基因座。这促使我们研究 HMGA2 是否通过抑制该基因座来促进平滑肌瘤的生长。与预期相反，我们能够证明 UL 通常表达明显高于子宫肌层的 p19(Arf)mRNA，并且 12q14 大约 15 重排的 UL 表达水平高于具有其他细胞遗传学异常的 UL。此外，p19(Arf)和 CDKN1A 表达之间的显著相关性表明，p19(Arf)在 UL 中引发衰老而不是细胞凋亡。此外，还发现 HMGA2、p19(Arf)和 CDKN1A 的表达水平与肿瘤的大小相关，表明增强的生长潜力被 p19(Arf)途径所平衡。从机制上讲，UL 可能会执行其起源细胞中已经存在的程序，例如在增殖增强的情况下，该程序被激活以保护基因组。总之，这些结果确定了 p19(Arf)-TP53-CDKN1A 途径是控制子宫纤维瘤生长和基因组稳定性的主要因素。
