Departments of Physiology & Biophysics, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72202, USA.
Biol Reprod. 2011 Aug;85(2):378-85. doi: 10.1095/biolreprod.110.090654. Epub 2011 May 4.
Endometrial cancer is the most commonly diagnosed female genital tract malignancy. Krüppel-like factor 9 (KLF9), a member of the evolutionarily conserved Sp family of transcription factors, is expressed in uterine stroma and glandular epithelium, where it affects cellular proliferation, differentiation, and apoptosis. Deregulated expression of a number of Sp proteins has been associated with multiple types of human tumors, but a role for KLF9 in endometrial cancer development and/or progression is unknown. Here, we evaluated KLF9 expression in endometrial tumors and adjacent uninvolved endometrium of women with endometrial carcinoma. KLF9 mRNA and protein levels were lower in endometrial tumors coincident with decreased expression of family member KLF4 and growth-regulators FBJ murine osteosarcoma viral oncogene homolog (FOS) and myelocytomatosis viral oncogene homolog (MYC) and with increased expression of telomerase reverse transcriptase (TERT) and the chromatin-modifying enzymes DNA methyltransferase 1 (DNMT1) and histone deacetylase 3 (HDAC3). Expression of estrogen receptor alpha (ESR1) and the tumor-suppressor phosphatase and tensin homolog deleted in chromosome 10 (PTEN) did not differ between tumor and normal tissue. The functional relevance of attenuated KLF9 expression in endometrial carcinogenesis was further evaluated in the human endometrial carcinoma cell line Ishikawa by siRNA targeting. KLF9 depletion resulted in loss of normal cellular response to the proliferative effects of estrogen concomitant with reductions in KLF4 and MYC and with enhancement of TERT and ESR1 gene expression. Silencing of KLF4 did not mimic the effects of silencing KLF9 in Ishikawa cells. We suggest that KLF9 loss-of-expression accompanying endometrial carcinogenesis may predispose endometrial epithelial cells to mechanisms of escape from estrogen-mediated growth regulation, leading to progression of established neoplasms.
子宫内膜癌是最常见的女性生殖道恶性肿瘤。Krüppel 样因子 9（KLF9）是进化上保守的 Sp 转录因子家族的成员之一，在子宫基质和腺体上皮中表达，影响细胞增殖、分化和凋亡。许多 Sp 蛋白的表达失调与多种人类肿瘤有关，但 KLF9 在子宫内膜癌的发生和/或进展中的作用尚不清楚。在这里，我们评估了子宫内膜癌患者子宫内膜肿瘤和相邻未受累子宫内膜中 KLF9 的表达。KLF9 mRNA 和蛋白水平在子宫内膜肿瘤中降低，同时家族成员 KLF4 以及生长调节剂 FBJ 鼠骨肉瘤病毒癌基因同源物（FOS）和髓细胞瘤病毒癌基因同源物（MYC）的表达降低，端粒酶逆转录酶（TERT）和染色质修饰酶 DNA 甲基转移酶 1（DNMT1）和组蛋白去乙酰化酶 3（HDAC3）的表达增加。肿瘤和正常组织之间雌激素受体α（ESR1）和肿瘤抑制因子磷酸酶和张力蛋白同源物缺失的 10 号染色体（PTEN）的表达没有差异。通过靶向 siRNA 在人子宫内膜癌细胞系 Ishikawa 中进一步评估了减弱的 KLF9 表达在子宫内膜癌发生中的功能相关性。KLF9 耗竭导致正常细胞对雌激素增殖作用的反应丧失，同时降低 KLF4 和 MYC，并增强 TERT 和 ESR1 基因表达。沉默 KLF4 并不能模拟 Ishikawa 细胞中沉默 KLF9 的作用。我们认为，KLF9 表达缺失伴随着子宫内膜癌的发生，可能使子宫内膜上皮细胞易发生逃避雌激素介导的生长调节的机制，导致已建立的肿瘤进展。
