Roles of KLF6 and KLF6-SV1 in ovarian cancer progression and intraperitoneal dissemination
ABSTRACT We investigated the role of the KLF6 tumor suppressor gene and its alternatively spliced isoform KLF6-SV1 in epithelial ovarian cancer (EOC).
We first analyzed tumors from 68 females with EOC for KLF6 gene inactivation using fluorescent loss of heterozygosity (LOH) analysis and direct DNA sequencing and then defined changes in KLF6 and KLF6-SV1 expression levels by quantitative real-time PCR. We then directly tested the effect of KLF6 and KLF6-SV1 inhibition in SKOV-3 stable cell lines on cellular invasion and proliferation in culture and tumor growth, i.p. dissemination, ascites production, and angiogenesis in vivo using BALB/c nu/nu mice. All statistical tests were two sided.
LOH was present in 59% of samples in a cell type-specific manner, highest in serous (72%) and endometrioid (75%) subtypes, but absent in clear cell tumors. LOH was significantly correlated with tumor stage and grade. In addition, KLF6 expression was decreased in tumors when compared with ovarian surface epithelial cells. In contrast, KLF6-SV1 expression was increased approximately 5-fold and was associated with increased tumor grade regardless of LOH status. Consistent with these findings, KLF6 silencing increased cellular and tumor growth, angiogenesis, and vascular endothelial growth factor expression, i.p. dissemination, and ascites production. Conversely, KLF6-SV1 down-regulation decreased cell proliferation and invasion and completely suppressed in vivo tumor formation.
Our results show that KLF6 and KLF6-SV1 are associated with key clinical features of EOC and suggest that their therapeutic targeting may alter ovarian cancer growth, progression, and dissemination.
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ABSTRACT: Female reproductive tract pathologies arise largely from dysregulation of estrogen and progesterone receptor signaling leading to aberrant cell proliferation, survival and differentiation. The signaling pathways orchestrated by these nuclear receptors are complex, require the participation of many nuclear proteins serving as key binding partners or targets and involve a range of paracrine and autocrine regulatory circuits. Members of the Krüppel-like family of transcription factors are ubiquitously expressed in reproductive tissues and have been increasingly implicated as critical co-regulators and integrators of steroid hormone actions. Here we explore the involvement of KLF family members in uterine pathology, describe their currently known molecular mechanisms and discuss their potential as targets for therapeutic intervention.Journal of Molecular Endocrinology 02/2015; 54(2). DOI:10.1530/JME-14-0310 · 3.62 Impact Factor
Article: KLF6 (Kruppel like factor 6)02/2011; DOI:10.4267/2042/38449
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ABSTRACT: Alterations in the abundance or activities of alternative splicing regulators generate alternatively spliced variants that contribute to multiple aspects of tumor establishment, progression and resistance to therapeutic treatments. Notably, many cancer-associated genes are regulated through alternative splicing suggesting a significant role of this post-transcriptional regulatory mechanism in the production of oncogenes and tumor suppressors. Thus, the study of alternative splicing in cancer might provide a better understanding of the malignant transformation and identify novel pathways that are uniquely relevant to tumorigenesis. Understanding the molecular underpinnings of cancer-associated alternative splicing isoforms will not only help to explain many fundamental hallmarks of cancer, but will also offer unprecedented opportunities to improve the efficacy of anti-cancer treatments.International Journal of Cell Biology 10/2013; 2013:962038. DOI:10.1155/2013/962038