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Biology of Reproduction (1)
Brain pathology (Zurich, Switzerland) (1)
Friedman, Theodore M. (2)
Brat, Daniel J. (1)
Burnett, Alexander F. (1)
Godley, Amy L. (1)
Heard, Melissa E. (1)
Olson, Jeffrey J. (1)
Pabona, John Mark P. (1)
Simmen, Frank A. (1)
Simmen, Rosalia C.M. (1)
Simmons, Christian D. (1)
Spataro, Michael T. (1)
Tehrani, Mahtab (1)
Year of Publication
Krüppel-Like Factor 9 Loss-of-Expression in Human Endometrial Carcinoma Links Altered Expression of Growth-Regulatory Genes with Aberrant Proliferative Response to Estrogen1
Simmons, Christian D.
Pabona, John Mark P.
Heard, Melissa E.
Spataro, Michael T.
Godley, Amy L.
Simmen, Frank A.
Burnett, Alexander F.
Simmen, Rosalia C.M.
Biology of Reproduction
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.
The loss of expression of transcription factor Krüppel-like factor 9 in human endometrial cells leads to aberrant growth regulation and underlies the progression of endometrial carcinoma.
endometrial carcinoma; endometrium; estradiol/estradiol receptor; Ishikawa cells; Krüppel-like factor 9; telomerase; uterine cancer; uterus
Intravascular Thrombosis in Central Nervous System Malignancies: A Potential Role in Astrocytoma Progression to Glioblastoma
Olson, Jeffrey J.
Brat, Daniel J.
Brain pathology (Zurich, Switzerland)
The presence of necrosis within a diffuse glioma is a powerful predictor of poor prognosis, yet little is known of its origins. Intravascular thrombosis is a frequent finding in glioblastoma [GBM; World Health Organization (WHO) grade IV] specimens and could potentially be involved in astrocytoma progression to GBM or represent a surrogate marker of GBM histology. We investigated whether intravascular thrombosis was more frequent or prominent in GBM than other central nervous system (CNS) malignancies and considered its prognostic significance in anaplastic astrocytoma (AA; WHO grade III), which lacks necrosis. Histologic sections were examined for thrombosis, necrosis and microvascular hyperplasia from each of 297 CNS tumors, including 103 GBMs, 46 AAs, 20 diffuse astrocytoma (DAs; WHO grade II), eight anaplastic oligodendrogliomas (AOs; WHO grade III), 20 oligodendrogliomas (ODs; WHO grade II), 49 metastatic carcinomas (METs), 31 primary central nervous system lymphomas (PCNSLs) and 20 medulloblastomas (MBs). Among newly diagnosed tumors, thrombosis was present in 92% of GBM resections, significantly greater than other types of CNS malignancies. Of tumors with thrombosis, GBMs had a higher frequency of affected vessels than AAs, DAs, AOs, ODs and MBs, but had a frequency similar to METs and PCNSLs. The sensitivity of thrombosis for the diagnosis of GBM in this set of tumors was 92% and the specificity was 91%. Intravascular thrombosis was uncommon in AAs and was only noted in stereotactic biopsies. This subset of patients had shorter survivals than those AAs without thrombosis. Thus, intravascular thrombosis is more frequent in GBM than other CNS malignancies. When present in AAs, it appears to indicate aggressive clinical behavior.
astrocytoma; brain tumor; glioblastoma; hypoxia; necrosis; thrombosis
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