Clinical Performance of Friend Leukemia Virus Integration 1 Methylation as a Biomarker for Colorectal Carcinoma

Abstract Objectives Accumulating evidence supports the reliability of molecular biomarkers and cancer, the current situation is lacking. This present study was aimed to investigate clinical performance of friend leukemia virus integration 1 (FLI1) methylation as a biomarker for colorectal cancer (CRC). Methods The datasets of UALCAN, GEPIA, cBioPortal, STRING, TIMER2.0, GEO, and KOBAS were utilized in this present study. In order to testify the methylation function of FLI1 in CRC, we studied 6 CRC cell lines and 20 pairs of tumor tissues. The transcriptional levels of FLI1 were tested by reverse transcription PCR quantitatively and western blot. Cell viability, transwell assays and plate clone assay were utilized to assess the cell function. Results FLI1 was up-regulated in the GBM, KIRC, LAML, etc. Meanwhile, it was down-regulated in BLCA, BRCA, CESC, etc (p<0.05). The CPTAC dataset showed higher total protein in the primary tissues of KIRC, lower protein in the BRCA, OV, LUAD, UCEC than normal tissues(p<0.05). Highly expressed FLI1 was linked to poor prognosis of overall survival (OS) in LGG, UVM (p<0.05). Low expression of FLI1 was associated with short OS in KIRC, LUAD, SKCM (p<0.05). Compared with normal tissues, the methylation level of FLI1 was increased in BRCA, CESC, CHOL, COAD, etc (p<0.05). In the contrary, it was decreased in KIRP, PCPG obviously (p<0.05). Moreover, it showed a reduced phosphorylation for selected probes (BRCA: NP_002008.2:S39, NP_002008.2:S3241; OV: NP_002008.2:S39; LUAD: NP_002008.2:S79, NP_002008.2:S3241; all p<0.05). Meanwhile, it showed an enhanced phosphorylation level of FLI1 in KIRC for selected probes (NP_002008.2:S241, p<0.05). Besides, a statistical negative correlation was found between FLI1 and Treg cells, neutrophils, monocytes, macrophages, NK cells, cancer-associated fibroblasts, and common immune checkpoint gene levels (p<0.05). Besides, in vivo experience showed that 5-Aza-2’-deoxycytidine diminished FLI1 methylation level and restored transcriptional levels (p>0.05) in CRC. In vitro experiments demonstrated that the proliferation, colony formation, invasion and migration of CRC cells were inhibited by FLI1 overexpression through FMNL1 (p<0.05). Conclusions This present study offers a comprehensive understanding of FLI1 in carcinomas with oncogenesis and immunotherapeutic implications. Moreover, FLI1 reduced the proliferation, colony formation, invasion and migration of CRC by FMNL1.

Download Full-text

What can we learn from Fli1-deficient mice, new animal models of systemic sclerosis?

Journal of Scleroderma and Related Disorders ◽

10.1177/2397198318758221 ◽

2018 ◽

Vol 3 (1) ◽

pp. 6-13 ◽

Cited By ~ 1

Author(s):

Yoshihide Asano

Keyword(s):

Systemic Sclerosis ◽

Animal Models ◽

Leukemia Virus ◽

Environmental Influences ◽

Epidemiological Studies ◽

Potential Candidate ◽

Predisposing Factor ◽

Friend Leukemia ◽

Virus Integration ◽

Friend Leukemia Virus

Systemic sclerosis is a complex multifactorial disease characterized by autoimmunity, vasculopathy, and selective organ fibrosis. A series of genetic and epidemiological studies have demonstrated that environmental influences play a central role in the onset of systemic sclerosis, while genetic factors determine the susceptibility to and the severity of this disease. Therefore, the identification of predisposing factors related to environmental influences would provide us with an informative clue to better understand the pathological process of this disease. Based on this concept, the deficiency of transcription factor Friend leukemia virus integration 1, which is epigenetically suppressed in systemic sclerosis, seems to be a potential candidate acting as the predisposing factor of this disease. Indeed, Fli1-mutated mice serve as a set of useful disease models to disclose the complex pathology of systemic sclerosis. This article overviews the recent advancement in systemic sclerosis animal models associated with Friend leukemia virus integration 1 deficiency.

Download Full-text

Abnormal Expression of Friend Leukemia Virus Integration 1 (Fli1) Protein Is An Adverse Prognostic Factor In AML.

Blood ◽

10.1182/blood.v116.21.1674.1674 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1674-1674

Author(s):

Steven M. Kornblau ◽

Yi Hua Qiu ◽

Nianxiang Zhang ◽

Kevin R Coombes ◽

Dennis K. Watson

Keyword(s):

Prognostic Factor ◽

Target Genes ◽

Conflicts Of Interest ◽

Leukemia Virus ◽

Univariate Analysis ◽

Npm1 Mutation ◽

Friend Leukemia ◽

Hematological Tumors ◽

Virus Integration ◽

Friend Leukemia Virus

Abstract Abstract 1674 Background. Friend leukemia virus integration 1 (Fli1), a member of the Ets transcription factor family, is expressed in hematopoietic cells and tissues and aberrantly expressed in cancer. Specifically, it is aberrantly-expressed in retrovirus-induced hematological tumors in mice, and is found to be rearranged in human Ewing's sarcoma and related primitive neuroectodermal tumors characterized by a t(11;22)(q24;q12) translocation. Our ongoing studies have shown that Fli1 is essential for embryonic development: Loss of Fli1 results in embryonic lethality due in part to absence of megakaryocytes and aberrant vasculogenesis. Loss of Fli1 also negatively impacts HSC differentiation, consistent with its role in the regulation of important stem cell regulatory genes. To date, limited attention has been directed towards elucidating the potential role of Fli1 in human hematological tumors cancers, including AML. Methodology. We therefore evaluated the level of Fli1 expression in AML using Reverse Phase Protein Array (RPPA) technology to measure Fli1 expression (along with 195 other antibodies) in marrow and blood samples from 511 newly diagnosed AML patients and 21 APL patients. Results. Compared to Fli1 protein levels in normal bone marrow CD34+ cells (n=11), expression was above normal in 32% of patients and below normal in 5%. Elevated Fli1 was not associated with any WHO classification, but was more common in FAB M1. Fli1 levels did not correlate with age, gender, performance status, or any single cytogenetic abnormality, but was negatively correlated with an antecedent hematologic disorder (p=0.002) and positively correlated with infection at the time of diagnosis (p=0.008). Levels were higher in patients with a NPM1 mutation (p=0.0005) or a FLT3-ITD abnormality (p< 0.00001). Expression was significantly lower at relapse compared to diagnosis in 49 paired samples (p= .02). Expression levels were similar in blood and marrow in 140 paired specimens (p=.65). Fli1levels were negatively correlated with 10 proteins (R >0.3) (integrinβ3, SRC, SRCp416, SRCp527, FAK, BCLXL AKTp308, FOXO3A, IGFBP2 and Fibronectin) and positively correlated (R >0.3) with 19 proteins (SMAD4, CREB, CREBp133, MTOR, ELKp383, TSC2, SSPB2, GAB2, PTEN and PTENp, HSP90, AKT, NPM1, NURR77, PRKR, TNK1, TAZp, BAX and DLX1). Fli1levels were not associated with remission attainment (p=.44), but remission duration (p=0.02) and overall survival (p=0.03) were significantly shorter for those with low (RemDur 22.6 and OS 45.2, weeks) or high Fli1(RemDur 40.3 and OS 35.4 weeks) compared to patients with normal levels of Fli1(RemDur 51.1 and OS 59.4 weeks). High Fli1 levels were prognostic in univariate analysis and was an independent prognostic factor in multivariate analysis along with age, unfavorable cytogenetics, favorable cytogenetics, gender, serum creatinine and FLT3mutation. Conclusions. Both low and high expression of Fli1 protein are associated with poor outcome. While low levels of Fli1 may fail to properly regulate Fli1 target genes, elevated levels of Fli1 may not only affect expression of Fli1 target genes, but also aberrantly affect the expression of additional genes not normally responsive to Fli1. The correlation between high levels of FLi1 and high levels of AKT, mTOR, TSC2 and inactivated pPTEN suggest that targeting this signaling pathway might interfere with Fli1 expression. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

Putative tumor suppressor miR-145 inhibits colon cancer cell growth by targeting oncogene friend leukemia virus integration 1 gene

Cancer ◽

10.1002/cncr.25522 ◽

2010 ◽

Vol 117 (1) ◽

pp. 86-95 ◽

Cited By ~ 108

Author(s):

Jianjun Zhang ◽

Haiyan Guo ◽

He Zhang ◽

Haibo Wang ◽

Guanxiang Qian ◽

...

Keyword(s):

Colon Cancer ◽

Cell Growth ◽

Tumor Suppressor ◽

Leukemia Virus ◽

Colon Cancer Cell ◽

Cancer Cell Growth ◽

Friend Leukemia ◽

Putative Tumor Suppressor ◽

Virus Integration ◽

Friend Leukemia Virus

Download Full-text

Abnormal expression of FLI1 protein is an adverse prognostic factor in acute myeloid leukemia

Blood ◽

10.1182/blood-2011-04-348052 ◽

2011 ◽

Vol 118 (20) ◽

pp. 5604-5612 ◽

Cited By ~ 33

Author(s):

Steven M. Kornblau ◽

Yi Hua Qiu ◽

Nianxiang Zhang ◽

Neera Singh ◽

Stefan Faderl ◽

...

Keyword(s):

Cell Biology ◽

Leukemia Virus ◽

Myelogenous Leukemia ◽

Hematologic Disorder ◽

Friend Leukemia ◽

Cd34 Cells ◽

Acute Myelogenous ◽

Ets Transcription Factor ◽

Virus Integration ◽

Friend Leukemia Virus

Abstract Friend leukemia virus integration 1 (FLI1), an Ets transcription factor family member, is linked to acute myelogenous leukemia (AML) by chromosomal events at the FLI1 locus, but the biologic impact of FLI1 expression on AML is unknown. FLI1 protein expression was measured in 511 newly diagnosed AML patients. Expression was similar in peripheral blood (PB) and BM and higher at diagnosis than at relapse (P = .02). Compared with normal CD34+ cells, expression in AML was above or below normal in 32% and 5% of patients, respectively. Levels were negatively correlated with an antecedent hematologic disorder (P = .002) but not with age or cytogenetics. Mutated NPM1 (P = .0007) or FLT3-ITD (P < .02) had higher expression. FLI1 levels were negatively correlated with 10 of 195 proteins associated with proliferation and stromal interaction, and positively correlated (R > 0.3) with 19 others. The FLI1 level was not predictive of remission attainment, but patients with low or high FLI1 expression had shorter remission duration (22.6 and 40.3 vs 51.1 weeks, respectively; P = .01) and overall survival (45.2 and 35.4 vs 59.4 weeks, respectively; P = .03). High FLI1 levels were adverse in univariate and multivariate analysis. FLI1 expression is frequently abnormal and prognostically adverse in AML. FLI1 and/or its response genes may be therapeutically targetable to interfere with AML cell biology.

Download Full-text

Friend leukemia virus integration 1 activates the Rho GTPase pathway and is associated with metastasis in breast cancer

Oncotarget ◽

10.18632/oncotarget.4350 ◽

2015 ◽

Vol 6 (27) ◽

pp. 23764-23775 ◽

Cited By ~ 13

Author(s):

Wei Song ◽

Wei Li ◽

Lingyu Li ◽

Shilin Zhang ◽

Xu Yan ◽

...

Keyword(s):

Breast Cancer ◽

Rho Gtpase ◽

Leukemia Virus ◽

Friend Leukemia ◽

Virus Integration ◽

Friend Leukemia Virus

Download Full-text

Successful Radical Pneumonectomy for a Primitive Neuroendodermal Tumor in the Lung: A Case Report and Review of the Literature

Frontiers in Surgery ◽

10.3389/fsurg.2021.667467 ◽

2021 ◽

Vol 8 ◽

Author(s):

Bingqing Yue ◽

Peng Chen ◽

Pan Yin ◽

Jiankai Wang ◽

Fanying Liu ◽

...

Keyword(s):

Leukemia Virus ◽

Neuron Specific Enolase ◽

Lung Parenchyma ◽

Malignant Neoplasms ◽

Round Cell ◽

Small Round Cell ◽

Friend Leukemia ◽

Virus Integration ◽

Friend Leukemia Virus ◽

Ewing Family Of Tumors

Peripheral primitive neuroendodermal tumors (PNETs) and Ewing's sarcoma belong to the Ewing family of tumors and are small round-cell malignancies originating from spinal cord cells. These tumors account for 5% of all small round-cell malignant neoplasms. PNETs that arise from the lung parenchyma without pleural or chest wall involvement are very rare. We report a case of an adult female with a large pulmonary PNET who had given birth just 1 month prior to the diagnosis. She had cough and expectoration for 6 months, and the preoperative examination showed no metastases. Thus, we performed radical pneumonectomy and lymph node dissection. The patient recovered well without surgical complications and was discharged 7 days after the surgery. Postoperative pathology confirmed that the tumor was a small round-cell malignancy, and the tumor cells were positive for CD99, Friend leukemia virus integration 1 (FLI-1), and neuron-specific enolase (NSE), which was consistent with the diagnosis of a PNET. For primary large pulmonary PNETs, radical pneumonectomy may be a safe surgical method, worthy of further application in clinical practice.

Download Full-text