Reduced expression of Krüppel-like factor 17 is related to tumor growth and poor prognosis in lung adenocarcinoma

Cai, Xingdong; Zhou, Yan; Huang, Lixia; Zeng, Qingli; Zhang, Longjuan; Wang, Qinqin; Li, Shaoli; Feng, Jianqiang; Han, Anjia

doi:10.1016/j.bbrc.2011.12.129

Cited by 24 publications

(29 citation statements)

References 22 publications

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“…Compared with spheroid-forming glioma-DACH1-low cells, glioma-DACH1-high cells also displayed lower tumorigenicity, indicating that DACH1 decreases the number of tumor-initiating cells. KLF17 is a negative regulator of EMT and metastasis in breast cancer and a TS in lung, liver, and esophageal cancer (43)(44)(45)(46), whereas GATA3 is a regulator of mammary gland morphogenesis and luminal differentiation in breast tissue (47,48). In pathological settings, GATA3 is a marker of estrogen receptor (ER)-positive breast cancer in which high levels of GATA3 correlate with high ER expression, whereas low levels are strongly associated with ERnegative, higher histologic grade, lymph node positivity, and a higher propensity for metastasis (49).…”

Section: Discussionmentioning

confidence: 99%

Identification of New Tumor Suppressor Genes in Triple-Negative Breast Cancer

et al. 2017

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Although genomic sequencing has provided a better understating of the genetic landmarks in triple-negative breast cancer (TNBC), functional validation of candidate cancer genes (CCG) remains unsolved. In this study, we used a transposon mutagenesis strategy based on a two-step sleeping beauty (SB) forward genetic screen to identify and validate new tumor suppressors (TS) in this disease. We generated 120 siRNAs targeting 40 SB-identified candidate breast cancer TS genes and used them to downregulate expression of these genes in four human TNBC cell lines. Among CCG, whose SB-mediated genetic mutation resulted in increased cellular proliferation in all cell lines tested, the genes ADNP, AP2B1, TOMM70A, and ZNF326 showed TS activity in tumor xenograft studies. Subsequent studies showed that ZNF326 regulated expression of multiple epithelial-mesenchymal transition and cancer stem cell (CSC) pathway genes. It also modulated expression of TS genes involved in the regulation of migration and cellular invasion and was a direct transcriptional activator of genes that regulate CSC self-renewal. ZNF326 expression associated with TNBC patient survival, with ZNF326 protein levels showing a marked reduction in TNBC. Our validation of several new TS genes in TNBC demonstrate the utility of two-step forward genetic screens in mice and offer an invaluable tool to identify novel candidate therapeutic pathways and targets.

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Section: Discussionmentioning

confidence: 99%

Identification of New Tumor Suppressor Genes in Triple-Negative Breast Cancer

et al. 2017

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“…In breast cancer, KLF17 protein acts as a negative regulator of epithelial-mesenchymal transition and metastasis (Gumireddy et al, 2009), by binding its 5'-CACCC-3' sequence to the ID1 promoter, a key metastasis regulator in breast cancer, and repressing its expression. Similarly reduced KLF17 levels correlates with tumor growth, distant metastasis and poor prognosis in lung carcinoma, hepatocellular carcinoma, gastric cancer, and papillary thyroid carcinoma (Cai et al, 2012; Liu et al, 2013; Peng et al, 2014; Ye et al, 2014). In endometrioid-type uterine cancer, KLF17 was implicated in epithelial to mesenchymal transition via direct activation of TWIST1 and its overexpression was associated with high tumor grade and loss of hormone receptors (Dong et al, 2014).…”

Section: Discussionmentioning

confidence: 97%

Novel FUS‐KLF17 and EWSR1‐KLF17 fusions in myoepithelial tumors

Huang

Chen

Zhang

et al. 2015

Genes Chromosomes & Cancer

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Myoepithelial (ME) tumors of soft tissue and bone display a heterogeneous histologic spectrum and in about half of the cases harbor EWSR1 gene rearrangements. Despite rare case reports, the prevalence of FUS gene abnormalities and its related fusion partners remains undetermined among ME tumors. Therefore, we screened 66 EWSR1-negative ME tumors for FUS abnormalities by fluorescence in situ hybridization (FISH). In an index FUS-rearranged case, 3'-Rapid Amplification of cDNA Ends (RACE) was applied to identify the fusion partner. Results were further confirmed by RT-PCR, followed by FISH screening the entire cohort of FUS-rearranged and EWSR1-positive ME lesions lacking a known fusion partner. The correlation between genotype and clinicopathological features was also investigated. As a result, six (9%) FUS-rearranged cases were identified, spanning divergent age groups, tumor locations, and morphologic features. A novel FUS-KLF17 fusion was identified by 3’RACE in an 11 year-old girl with a foot lesion associated with locoregional metastases. Three additional cases with FUS-KLF17 fusions were identified and one KLF17 rearrangement (6.3%) was found among the 16 EWSR1-positive cases tested. The KLF17-related ME tumors affected younger patients and often exhibited trabecular growth in a myxohyaline stroma, but this genotype did not correlate with a malignant phenotype. In conclusion, a small subset of ME tumors harbor FUS rearrangements, two thirds of them being associated with KLF17 fusion. FUS FISH analysis is recommended in EWSR1-negative lesions in which a ME diagnosis is suspected. KLF17 is also a rare gene fusion partner to EWSR1-rearranged ME tumors.

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“…ZNF444 appears to promote the transcription of SCARF2 which codes for a protein in lipoprotein metabolism, however the functional consequences of its fusion with EWSR1 and how this relates to oncogenesis has yet to be resolved 50 . Reduced KLF17 levels have been implicated in tumor growth and progression at various sites, including lung adenocarcinoma, and it has been hypothesized that the FUS-KLF17 chimeric transcript may disrupt translation of the protein 8,51 . Thus, while there is some insight into EWSR1 and FUS partner gene function, the precise mechanism by which each of these genes promote oncogenesis remains to be delineated.…”

Section: Discussionmentioning

confidence: 99%

Thoracic Myoepithelial Tumors

Leduc

Zhang

Öz

et al. 2016

American Journal of Surgical Pathology

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Thoracic myoepithelial tumors (MTs) are a rare group of tumors showing predominant or exclusive myoepithelial differentiation. They are poorly characterized from both a morphologic and genetic standpoint, in particular features that separate benign from malignant behavior. We examined the histologic and immunohistochemical features of 8 primary thoracic MTs and performed fluorescence in situ hybridization for EWSR1, FUS, PLAG1, and HMGA2, as well as several partner genes. Half (4/8) of the MTs occurred in large airways and 3 had infiltrative borders. All cases showed immunoreactivity for epithelial markers, in conjunction with S-100 protein or myogenic markers. MTs showed morphologic characteristics analogous to MTs at other sites, with no tumors having ductal differentiation. Necrosis and/or lymphovascular invasion was present in 5 cases, with mitotic activity ranging from 0–6 mitoses/2 mm2 (mean 1). Metastases occurred in 2 cases, and no patients died of disease. Gene rearrangements were identified in half of the cases, with EWSR1-PBX1, EWSR1-ZNF444, and FUS-KLF17 fusions identified in one case each, and one case having EWSR1 rearrangement with no partner identified. No cases were found to have HMGA2 or PLAG1 abnormalities. Compared to fusion negative tumors, fusion positive tumors tended to occur in patients who were younger (50 vs 58 yrs), female (1:3 vs 3:1 male:female ratio), and demonstrated predominantly spindle and clear cell morphology. Using a combined dataset of our case series with 16 cases from the literature, poor prognosis was significantly correlated with metastases (p=0.003), necrosis (p=0.027), and ≥ 5 mitoses per 2mm2/10 HPF (p=0.005). In summary, we identify a subset of thoracic MTs harboring rearrangements in EWSR1 or FUS, and our data suggests that necrosis and increased mitotic activity correlate with aggressive clinical behavior.

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Reduced expression of Krüppel-like factor 17 is related to tumor growth and poor prognosis in lung adenocarcinoma

Cited by 24 publications

References 22 publications

Identification of New Tumor Suppressor Genes in Triple-Negative Breast Cancer

Identification of New Tumor Suppressor Genes in Triple-Negative Breast Cancer

Novel FUS‐KLF17 and EWSR1‐KLF17 fusions in myoepithelial tumors

Thoracic Myoepithelial Tumors

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