Oncogene database

1316

KLF6

Kruppel-like factor 6;KLF6;Kruppel-like factor 6

B-cell-derived protein 1|GC-rich binding factor|GC-rich sites-binding factor GBF|Krueppel-like factor 6|Kruppel-like zinc finger protein Zf9|core promoter element binding protein|core promoter element-binding protein|proto-oncogene BCD1|protooncogene B-ce

10p15

protein-coding

BACKGROUND: Gliomas constitute the vast majority of primary central nervous system tumors in adults. Glioblastoma multiforme (GBM) is the most aggressive form of these primary brain tumors. There is a need to define diagnostic and prognostic markers that may help to distinguish GBM from non-GBM tumors. The Kruppel-like factor 6 (KLF6) gene has recently emerged as a promising candidate. The goal of our study was to determine if there is a link between KLF6 splice variants expression and different grades of gliomas. METHODS: Fifty-three primary gliomas tumor samples were analyzed using quantitative real-time PCR for the total KLF6, wild-type and alternatively spliced (SV1) KLF6 mRNA. RESULTS: Compared to the non-GBM group, the GBM group had a 2.2-fold increase in the mean level of total KLF6 mRNA expression. GBM showed a 2.1-fold increase in the KLF6 splicing ratio. In addition, KLF6-SV1 mRNA expression levels were also 2.2-fold higher in the GBM group, suggesting that the increase in the KLF6 splicing ratio was due to increased expression of the KLF6-SV1 oncogenic splice variant. CONCLUSIONS: Our study demonstrates that quantification of total and spliced forms of KLF6 may provide a new and useful supplementary molecular tool for grading glioma.

Breast cancer cells preferentially home to the bone microenvironment, which provides a unique niche with a network of multiple bidirectional communications between host and tumor, promoting survival and growth of bone metastases. In the bone microenvironment, the c-fms proto-oncogene that encodes for the CSF-1 receptor, along with CSF-1, serves as one critical cytokine/receptor pair, functioning in paracrine and autocrine fashion. Previous studies concentrated on the effect of inhibition of host (mouse) c-fms on bone metastasis, with resulting decrease in osteolysis and bone metastases as a paracrine effect. In this report, we assessed the role of c-fms inhibition within the tumor cells (autocrine effect) in the early establishment of breast cancer cells in bone and the effects of this early c-fms inhibition on subsequent bone metastases and destruction. This study exploited a multidisciplinary approach by employing two non-invasive, in vivo imaging methods to assess the progression of bone metastases and bone destruction, in addition to ex vivo analyses using RT-PCR and histopathology. Using a mouse model of bone homing human breast cancer cells, we showed that an early one-time application of anti-human c-fms antibody delayed growth of bone metastases and bone destruction for at least 31 days as quantitatively measured by bioluminescence imaging and computed tomography, compared to controls. Thus, neutralizing human c-fms in the breast cancer cell alone decreases extent of subsequent bone metastasis formation and osteolysis. Furthermore, we are the first to show that anti-c-fms antibodies can impact early establishment of breast cancer cells in bone.

The Kruppel like factor 6 (KLF6) gene encodes multiple protein isoforms derived from alternative mRNA splicing, most of which are intimately involved in hepatocarcinogenesis and tumor progression. Recent bioinformatics analysis shows that alternative mRNA splicing of the KLF6 gene produces around 16 alternatively spliced variants with divergent or even opposing functions. Intriguingly, the full-length KLF6 (KLF6-FL) is a tumor suppressor gene frequently inactivated in liver cancer, whereas KLF6 splice variant 1 (KLF6-SV1) is an oncogenic isoform with antagonistic function against KLF6-FL. Compelling evidence indicates that miRNA, the small endogenous non-coding RNA (ncRNA), acts as a vital player in modulating a variety of cellular biological processes through targeting different mRNA regions of protein-coding genes. To identify the potential miRNAs specifically targeting KLF6-FL, we utilized bioinformatics analysis in combination with the luciferase reporter assays and screened out two miRNAs, namely miR-210 and miR-1301, specifically targeted the tumor suppressive KLF6-FL rather than the oncogenic KLF6-SV1. Our in vitro experiments demonstrated that stable expression of KLF6-FL inhibited cell proliferation, migration and angiogenesis while overexpression of miR-1301 promoted cell migration and angiogenesis. Further experiments demonstrated that miR-1301 was highly expressed in liver cancer cell lines as well as clinical specimens and we also identified the potential methylation and histone acetylation for miR-1301 gene. To sum up, our findings unveiled a novel molecular mechanism that specific miRNAs promoted tumorigenesis by targeting the tumor suppressive isoform KLF6-FL rather than its oncogenic isoform KLF6-SV1.

A novel B-cell derived (Bcd) oncogene has been isolated from the peripheral blood lymphocytes of one B-cell chronic lymphocytic leukemia (B-CLL) patient using DNA transfer and a mouse tumorigenicity assay. The Bcd proto-oncogene was activated by a truncation in the 5 UTR. It predicts for two open reading frames (ORFs). ORF1 consists of 240 bp that would encode 80 amino acids, while the major ORF2 consists of 648 bp capable of coding for 216 amino acids. Predicted peptide sequence of ORF2 contained a zinc finger domain which showed significant homology to GC box binding proteins BTEB2 and SP1. Transfection of an expression vector containing ORF2 but not full length cDNA was able to transform NIH3T3 cells and induce tumors in nude mice. Bcd mRNA transcripts of < or = 2.6 kb were selectively expressed in PBL and testis of healthy individuals. Within the PBL, Bcd gene expression was restricted to CD19+ B-cells and absent from CD14+ monocytes and T-cells. Bcd transcripts were detected in ALL normal PBL samples tested but not in several malignant human B-cell lines and not in 50% of B-cells from B-CLL patients. However, stimulation of B-cells from B-CLL patients under conditions which induced differentiation into plasma cells was associated with induction of Bcd gene expression. The Bcd gene may therefore play an important role in B-cell growth and development.

The expression of c-met proto-oncogene product (c-MET) has been reported to be related to invasive growth or tumor stage in some tumors, but little is known concerning the significance of c-MET expression in bone tumors. With use of formalin-fixed, paraffin-embedded tissue specimens and polyclonal antibody for c-MET, we studied the expression of c-MET in 122 cases of malignant bone tumors (43 osteosarcomas, 24 chondrosarcomas, 21 malignant fibrous histiocytomas of bone, 16 Ewing s sarcoma versus primitive neuroectodermal tumors, 18 chordomas), 65 cases of benign tumors and tumor-like lesions (including 8 giant cell tumors of bone, 8 chondroblastomas, 12 enchondromas, 7 osteochondromas, 10 fibrous dysplasias), 7 cases of articular cartilaginous tissue, and 10 cases of fetal vertebral tissue consisting of foci of enchondral ossification and notochordal tissue. In malignant tumors, c-MET expression was most frequently detected in chordoma (94.4%), followed by chondrosarcoma (54.2%) and osteosarcoma (23.3%). Among the osteosarcoma specimens, c-MET expression was frequently detected in the chondroblastic subtype (66.7%), but the incidence was low in the cases with other subtypes of osteosarcoma. We found no significant correlation between the c-MET expression and the histologic grade of malignancy in either osteosarcoma or chondrosarcoma. c-MET expression was either rarely observed or completely negative in malignant fibrous histiocytomas of bone (4.8%) and primitive neuroectodermal tumors (0%). In benign tumors and tumor-like lesions, c-MET expression was frequently detected in cartilaginous tumors, such as chondroblastoma (62.5%), enchondroma (66.7%), and osteochondroma (71.4%), but no expression was observed in giant cell tumors of bone or any other benign tumors or tumor-like lesions. In normal tissue, c-MET expression was frequently detected in the articular cartilage (100%) and notochord (70.0%) specimens examined. We conclude that c-MET expression as frequent as that observed in the notochordal tissue, chordomas, articular cartilage, and cartilaginous tumors is related to the development of both normal tissue and chondroid tumors.