lncRNA FEZF1-AS1 Research Articles

LncRNA FEZF1-AS1 Is Associated With Prognosis in Lung Adenocarcinoma and Promotes Cell Proliferation, Migration, and Invasion

Long noncoding RNAs (lncRNAs) have been reported to play important roles in tumorigenesis. In the present study, we demonstrated that lncRNA forebrain embryonic zinc finger protein 1 (FEZF1) antisense RNA1 (FEZF1-AS1) is markedly upregulated in human lung adenocarcinoma (LAD) tissues and cell lines and is associated with poor prognosis. Loss of function revealed that deletion of FEZF1-AS1 expression significantly inhibited the LAD cell proliferation, invasion, and migration. Further studies revealed that downregulation of FEZF1-AS1 reduced mRNA and protein expression of its sense-cognate gene FEZF1 in LAD cells, and vice versa. Correlation analysis indicated that there was a positive correlation between FEZF1-AS1 and FEZF1 expression in LAD tissues. Additionally, rescue assay confirmed that the function of FEZF1-AS1 in LAD was mediated by FEZF1. Our findings suggested that dysregulation of FEZF1-AS1 contributed to the progression of LAD, which might be a potential target for LAD therapy.

Long Noncoding RNA FEZF1-AS1 Promotes Osteosarcoma Progression by Regulating the miR-4443/NUPR1 Axis.

Long noncoding RNA (lncRNA) FEZF1-AS1 was demonstrated to facilitate cell proliferation and migration in some cancers. However, the functions of FEZF1-AS1 and its molecular mechanism in osteosarcoma remain to be elucidated. In our study, we found that the expression of FEZF1-AS1 was upregulated in osteosarcoma samples and cell lines compared with normal tissues or cells. Besides, we showed that the expression levels of FEZF1-AS1 in osteosarcoma patients were positively correlated with tumor metastasis and TNM stage. Additionally, FEZF1-AS1 knockdown inhibited cell proliferation, migration, and invasion in U2OS and MG63 cells, while upregulation had the opposite effects in vitro. Moreover, FEZF1-AS1 depletion inhibited tumor growth and metastasis in vivo. We found that FEZF1-AS1 sponged miR-4443 to promote NUPR1 expression in U2OS and MG63 cells. Furthermore, knockdown of miR-4443 abrogated FEZF1-AS1 silencing-induced inhibition of cell proliferation, migration, and invasion in osteosarcoma. Finally, we found that restoration of NUPR1 rescued the proliferation, migration, and invasion abilities of FEZF1-AS1-depleted U2OS and MG63 cells. Our study indicated that FEZF1-AS1 could promote osteosarcoma progression by sponging miR-4443 to promote NUPR1 expression. The FEZF1-AS1/miR-4443/NUPR1 axis may act as a novel therapeutic strategy for osteosarcoma treatment.

Highlights of This Issue

Sipuleucel-T is an FDA-approved autologous cellular immunotherapy with established efficacy in metastatic castration-resistant prostate cancer (mCRPC); elucidation of its mechanism of action continues to evolve. Peripheral cellular and humoral immune responses to PAP and the immunogen PA2024 demonstrated long-lived, antigen-specific immune responses to sipuleucel-T that correlate with overall survival (OS). The current study shows persistent antigen-specific peripheral CD4+ T-cell responses and the induction of antigen specific CD8+ T cells with potential lytic function following sipuleucel-T. Moreover, a positive correlation between OS and PAP- as well as PA2024-specific cytotoxic T lymphocytes (CTLs) phenotype was found. Sipuleucel-T–induced antigen-specific CTL activity could provide a biologic basis for the OS benefit observed in mCRPC.Radiotherapy is an integral component in the adjuvant treatment of breast cancer, but reliable biomarkers predictive of radiotherapy benefit have been lacking. In this work, Cui and colleagues developed gene expression signatures reflecting two distinct biological processes: intrinsic radiosensitivity and antitumor immunity. Both radiosensitivity and immunological signatures were shown to be predictive of radiotherapy benefit, and integration of the two further improved patient stratification. The integrated gene signatures may be used to select patients who are most likely to benefit from radiotherapy, or to identify patients who may not respond well to standard radiotherapy and will need alternative therapies.LncRNAs are promising diagnostic markers, prognostic factors and therapeutic targets in tumorigenesis. Bian and colleagues revealed that LncRNA—FEZF1-AS1 is frequently upregulated in colorectal cancer (CRC) and was associated with poor prognosis. The in vitro and in vivo functional assays demonstrated that FEZF1-AS1 promotes CRC cell growth and metastasis. Mechanistically, FEZF1-AS1 could bind and increase the stability of PKM2 protein, resulting in the activating of STAT3 signaling and the increasing of aerobic glycolysis. Targeting FEZF1-AS1/PKM2 signaling appears to be a promising treatment for CRC.The glycosaminoglycan hyaluronan (HA) accumulates in the tumor microenvironment (TME) of many solid tumors, with HA accumulation linked to aggressive malignancy. To further elucidate the biological and physical changes associated with tumor HA accumulation, Li and colleagues used two different methods to modulate HA in mouse tumor models. Experiments compared xenografts from parental cells with cells engineered to overexpress hyaluronan synthase. Additionally, a PEGylated hyaluronidase (PEGPH20) was used to enzymatically degrade HA. Higher tumor HA was accompanied by increased collagen, reduced perfusion, increased hypoxia, and increased α-SMA. PEGPH20 treatment reversed these changes and depleted tumor-associated VEGF-A165. Data support continued investigation of strategies to target HA in the TME.

LncRNA-FEZF1-AS1 Promotes Tumor Proliferation and Metastasis in Colorectal Cancer by Regulating PKM2 Signaling.

Purpose: Long non-coding RNAs (lncRNAs) play key roles in human cancers. Here, FEZF1-AS1, a highly overexpressed lncRNA in colorectal cancer, was identified by lncRNA microarrays. We aimed to explore the roles and possible molecular mechanisms of FEZF1-AS1 in colorectal cancer.Experimental Design: LncRNA expression in colorectal cancer tissues was measured by lncRNA microarray and qRT-PCR. The functional roles of FEZF1-AS1 in colorectal cancer were demonstrated by a series of in vitro and in vivo experiments. RNA pull-down, RNA immunoprecipitation and luciferase analyses were used to demonstrate the potential mechanisms of FEZF1-AS1.Results: We identified a series of differentially expressed lncRNAs in colorectal cancer using lncRNA microarrays, and revealed that FEZF1-AS1 is one of the most overexpressed. Further validation in two expanded colorectal cancer cohorts confirmed the upregulation of FEZF1-AS1 in colorectal cancer, and revealed that increased FEZF1-AS1 expression is associated with poor survival. Functional assays revealed that FEZF1-AS1 promotes colorectal cancer cell proliferation and metastasis. Mechanistically, FEZF1-AS1 could bind and increase the stability of the pyruvate kinase 2 (PKM2) protein, resulting in increased cytoplasmic and nuclear PKM2 levels. Increased cytoplasmic PKM2 promoted pyruvate kinase activity and lactate production (aerobic glycolysis), whereas FEZF1-AS1-induced nuclear PKM2 upregulation further activated STAT3 signaling. In addition, PKM2 was upregulated in colorectal cancer tissues and correlated with FEZF1-AS1 expression and patient survival.Conclusions: Together, these data provide mechanistic insights into the regulation of FEZF1-AS1 on both STAT3 signaling and glycolysis by binding PKM2 and increasing its stability. Clin Cancer Res; 24(19); 4808-19. ©2018 AACR.

Long non-coding RNA FEZF1-AS1 promotes cell invasion and epithelial-mesenchymal transition through JAK2/STAT3 signaling pathway in human hepatocellular carcinoma

Long non-coding RNAs (lncRNAs) have emerged as key regulators in the development of hepatocellular carcinoma (HCC). In the present study, we explored the expression profile and biological role of lncRNA FEZF1-AS1 in HCC. We observed remarkable upregulation of FEZF1-AS1 in HCC tissues and cell lines, and high FEZF1-AS1 expression was correlated with aggressive phenotypes and poor prognosis of HCC patients. Furthermore, we found that FEZF1-AS1 knockdown markedly inhibited the proliferation of HCC cells by inducing cell cycle arrest. In addition, FEZF1-AS1 knockdown suppressed HCC tumor growth in vivo. Moreover, FEZF1-AS1 knockdown inhibited the migration and invasion of HCC cells through suppression of JAK2/STAT3 signaling-mediated epithelial-mesenchymal transition (EMT). In conclusion, the present study for the first time demonstrated that FEZF1-AS1 serves as an oncogenic lncRNA in human HCC and implicated FEZF1-AS1 as a valuable therapeutic target for HCC treatment.

Long non-coding RNA FEZF1-AS1 promotes breast cancer stemness and tumorigenesis via targeting miR-30a/Nanog axis.

Long non-coding RNAs (lncRNAs) have been verified to modulate the tumorigenesis of breast cancer at multiple levels. In present study, we aim to investigate the role of lncRNA FEZF1-AS1 on breast cancer-stem like cells (BCSC) and the potential regulatory mechanism. In breast cancer tissue, lncRNA FEZF1-AS1 was up-regulated compared with controls and indicated poor prognosis of breast cancer patients. In vitro experiments, FEZF1-AS1 was significantly over-expressed in breast cancer cells, especially in sphere subpopulation compared with parental subpopulation. Loss-of-functional indicated that, in BCSC cells (MDA-MB-231 CSC, MCF-7 CSC), FEZF1-AS1 knockdown reduced the CD44+ /CD24- rate, the mammosphere-forming ability, stem factors (Nanog, Oct4, SOX2), and inhibited the proliferation, migration and invasion. In vivo, FEZF1-AS1 knockdown inhibited the breast cancer cells growth. Bioinformatics analysis tools and series of validation experiments confirmed that FEZF1-AS1 modulated BCSC and Nanog expression through sponging miR-30a, suggesting the regulation of FEZF1-AS1/miR-30a/Nanog. In summary, our study validate the important role of FEZF1-AS1/miR-30a/Nanog in breast cancer stemness and tumorigenesis, providing a novel insight and treatment strategy for breast cancer.

FEZF1-AS1/miR-107/ZNF312B axis facilitates progression and Warburg effect in pancreatic ductal adenocarcinoma

Long non-coding RNAs (lncRNAs) play a pivotal role in pathological processes. However, little information has been published regarding the underlying functions and mechanisms of lncRNAs in pancreatic ductal adenocarcinoma (PDAC). A novel lncRNA FEZF1-AS1 and its sense-cognate gene ZNF312B were found to be highly expressed in human PDAC tissues and cell lines, which is associated with disease progression and predicts clinical outcome in PDAC patients. Of note, bioinformatics analysis, luciferase assays and RNA immunoprecipitation assays indicated that FEZF1-AS1 may act as an endogenous sponge by competing for miR-107, thereby modulating the derepression of ZNF312B. Downregulation of FEZF1-AS1 or ZNF312B significantly inhibited proliferation, colony formation, migration, and invasion of PDAC cells in vitro, whereas the miR-107 inhibitor abrogated the effect of dow-regulation of FEZF1-AS1 or ZNF312B in reducing oncogenic capacities of PDAC cells. In addition, FEZF1-AS1/miR-107/ZNF312B axis-induced promotion of PDAC cells proliferation appeared to be mediated by modulation of the apoptosis and the G1-S checkpoint. Furthermore, downregulation of FEZF1-AS1 repressed tumor growth in mouse xenograft models. In particular, our results highlight the contribution of FEZF1-AS1/miR-107/ZNF312B axis to Warburg effect maintenance of PDAC cells. Collectively, our findings demonstrate that the FEZF1-AS1/miR-107/ZNF312B axis regulatory network might provide a potential new therapeutic strategy for PDAC.

Long noncoding RNA FEZF1-AS1 indicates a poor prognosis of gastric cancer and promotes tumorigenesis via activation of Wnt signaling pathway

Long non-coding RNAs (lncRNAs) have been demonstrated that it plays very important role in development and progression of carcinomas. LncRNA FEZF1 antisense RNA 1 (FEZF1-AS1) has been proved to be implicated in tumor initiation and progression of various cancers, recently. Nevertheless, the biological function and clinical significance of lncRNA FEZF1-AS1 in gastric cancer (GC) are not clear enough. Here, we concentrated on the association of FEZF1-AS1 expression and clinicopathological factors in GC tissues and cells. Moreover, we explored the potential regulatory mechanisms. The results showed that lncRNA FEZF1-AS1 was observably upregulated in human GC tissues and GC cell lines, compared with the adjacent non-tumor tissues and human gastric epithelial cell line (GES-1). Moreover, high expression of lncRNA FEZF1-AS1 was significantly associated with later stage and higher grade. Furthermore, Kaplan-Meier survival analysis was conducted, indicating that lncRNA FEZF1-AS1 may be an independent prognostic factor in GC. Additionally, the area under the receiver operating characteristic (ROC) curve of lncRNA FEZF1-AS1 exhibited its diagnostic value in GC. Notably, whenever the lncRNA FEZF1-AS1 was silenced, the proliferation of GC cells were significantly inhibited and the cell cycle was arrested at a G0/G1 stage in GC cells. Furthermore, downregulation of lncRNA FEZF1-AS1 could suppress the activation of the Wnt/β-catenin signaling pathway. Conclusively, our findings indicated that lncRNA FEZF1-AS1 could be considered as a novel biomarker for the treatment of GC.

LncRNA FEZF1-AS1 enhances epithelial-mesenchymal transition (EMT) through suppressing E-cadherin and regulating WNT pathway in non-small cell lung cancer (NSCLC)

ObjectiveRecent discoveries verify that long non-coding RNAs (lncRNAs) are important functional regulators involved in non-small cell lung cancer (NSCLC) progression. However, long non-coding RNA FEZF1-AS1 was not been investigated in NSCLC so for. MethodsWe applied the quantitative real time polymerase chain reaction (qRT-PCR) assays to detect the expression of lncRNA FEZF1-AS1 in NSCLC tissues and adjacent normal tissues. Cell proliferation and invasion capacities were evaluated by MTT, colony formation, and cell invasion assays. Chromatin immunoprecipitation (ChIP) and RNA immunoprecipitation (RIP) methods demonstrated the association between lncRNA FEZF1-AS1 expression and E-cadherin. The relative protein expression levels were analyzed by western blot analysis. ResultsLncRNA FEZF1-AS1 was significantly up-regulated in NSCLC tissues compared with adjacent normal tissues. Higher lncRNA FEZF1-AS1 expression levels associated with lymph node metastasis, poor differentiation grade and advanced TNM stage. In vitro, we revealed that down-regulation of lncRNA FEZF1-AS1 inhibited cell proliferation and cell invasion capacities in NSCLC. Moreover, down-regulation of lncRNA FEZF1-AS1 suppressed cell epithelial-mesenchymal transition (EMT) process by increasing the expression of E-cadherin and ZO-1, whereas, decreasing the expression of Slug, Twist and Vimentin in NSCLC cells. Furthermore, we demonstrated lncRNA FEZF1-AS1 could epigenetically repress the expression of E-cadherin via binding with LSD1 and EZH2 in NSCLC cells. We also revealed that knockdown of lncRNA FEZF1-AS1 suppressed Wnt/β-catenin signaling in NSCLC. ConclusionThese results demonstrated that lncRNA FEZF1-AS1 could function as a tumor promoting regulator in NSCLC, which may provide a target of treatment in NSCLC.

LincRNAFEZF1-AS1 represses p21 expression to promote gastric cancer proliferation through LSD1-Mediated H3K4me2 demethylation

BackgroundAlthough the prognosis of gastric cancer patients have a favorable progression, there are some patients with unusual patterns of locoregional and systemic recurrence. Therefore, a better understanding of early molecular events of the disease is needed. Current evidences demonstrate that long noncoding RNAs (lncRNAs) may be an important class of functional regulators involved in human gastric cancers development. Our previous studies suggest that HOTAIR contributes to gastric cancer development, and the overexpression of HOTAIR predicts a poor prognosis. In this study, we investigated the characteristic of the LncRNA FEZF1-AS1 in gastric cancer.MethodsQRT-PCR was used to detect the expression of FEZF1-AS1 in gastric cancer tissues and cells. MTT assays, clonogenic survival assays and nude mouse xenograft model were used to examine the tumorigenesis function of FEZF1-AS1 in vitro and in vivo. Bioinformatics analysis were used to select downstream target genes of FEZF1-AS1. Cell cycle analysis, ChIP, RIP,RNA Pulldown assays were examined to dissect molecular mechanisms.ResultsIn this study, we reported that FEZF1-AS1, a 2564 bp RNA, was overexpressed in gastric cancer, and upregulated FEZF1-AS1 expression indicated larger tumor size and higher clinical stage; additional higher expression of FEZF1-AS1 predicted poor prognosis. Further experiments revealed that knockdown FEZF1-AS1 significantly inhibited gastric cancer cells proliferation by inducing G1 arrest and apoptosis, whereas endogenous expression FEZF1-AS1 promoted cell growth. Additionally, RIP assay and RNA-pulldown assay evidenced that FEZF1-AS1 could epigenetically repress the expression of P21 via binding with LSD1, the first discovered demethylase. ChIP assays demonstrated that LSD1 could directly bind to the promoter of P21, inducing H3K4me2 demethylation.ConclusionIn summary, these data demonstrated that FEZF1-AS1 could act as an “oncogene” for gastric cancer partly through suppressing P21 expression; FEZF1-AS1 may be served as a candidate prognostic biomarker and target for new therapies of gastric cancer patients.