FOXC1 induces cancer stem cell-like properties through upregulation of beta-catenin in NSCLC

Cao, Sisi; Wang, Zhuo; Gao, Xiujuan; Wang, He; Cai, Yue; Chen, Hui; Xu, Rong

doi:10.1186/s13046-018-0894-0

Cited by 71 publications

(57 citation statements)

References 56 publications

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“…Recent studies have demonstrated that FOXC1 is highly expressed in various cancers, including NSCLC, and is postulated to be a marker of poor prognosis In the present study, we identified that high FOXC1 expression in NSCLC patients was more frequently associated with adverse clinical parameters and poor OS independent of other clinicopathological prognostic factors, including lymph node status in NSCLC patients. This result was consistent with the conclusion of the study of Cao et al, in which FOXC1 expression was found to be elevated in NSCLC tissues and negatively correlated with patient survival . In addition, FOXC1 was expressed in the membrane and cytoplasm, as well as in the cell nucleus.…”

Section: Discussionsupporting

confidence: 93%

Forkhead box C1 promotes metastasis and invasion of non–small cell lung cancer by binding directly to the lysyl oxidase promoter

et al. 2019

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Increasing evidence indicates that human forkhead box C1 (FOXC1) plays important roles in tumor development and metastasis. However, the underlying molecular mechanism of FOXC1 in non–small cell lung cancer (NSCLC) metastasis remains unclear. Here, we identified FOXC1 as an independent prognostic factor in NSCLC and showed clear biological implications in invasion and metastasis. FOXC1 overexpression enhanced the proliferation, migration and invasion of NSCLC cells, whereas FOXC1 silencing impaired the effects both in vitro and in vivo. Importantly, we found a positive correlation between FOXC1 expression and lysyl oxidase (LOX) expression in NSCLC cells and patient samples. Downregulation of LOX or LOX activity inhibition in NSCLC cells inhibited the FOXC1‐driven effects on cellular migration and invasion. Xenograft models showed that inhibition of LOX activity by β‐aminopropionitrile monofumarate decreased the number of lung metastases. Mechanistically, we demonstrated a novel FOXC1‐LOX mechanism that was involved in the invasion and metastasis of NSCLC. Dual‐luciferase assay and ChIP identified that FOXC1 bound directly in the LOX promoter region and activated its transcription. Collectively, the present study offered new insight into FOXC1 in the mediation of NSCLC metastasis through interaction with the LOX promoter and further revealed that targeted inhibition of LOX protein activity could prevent lung metastasis in murine xenograft models. These data implicated FOXC1 as a potential therapeutic strategy for the treatment of NSCLC metastasis.

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Section: Discussionsupporting

confidence: 93%

Forkhead box C1 promotes metastasis and invasion of non–small cell lung cancer by binding directly to the lysyl oxidase promoter

et al. 2019

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“…For example, B-lymphoma moloney murine leukemia virus insertion region-1 (BMI1) is required for self-renewal of both CSCs and normal stem/progenitor cells (Goto et al, 2018). CD133 + CSCs are found in cancers like glioblastoma, ependymoma, lung, and colorectal cancer (CRC; Baumann et al, 2008;Cao et al, 2018;Gilbertson & Rich, 2007), CD44 + CSCs are found in cancers like breast cancer (Gilbertson & Rich, 2007). In the brain, CD133 is used as both a marker for identifying normal neural precursors in human and for the enrichment of CSCs (Vescovi et al, 2006).…”

Section: Identification Of Cscsmentioning

confidence: 99%

Cancer stem cells (CSCs) in cancer progression and therapy

Najafi

Farhood

Mortezaee

2018

Journal Cellular Physiology

446

268

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Cancer stem cells (CSCs) are self‐renewable cell types that are identified in most types of liquid and solid cancers and contributed to tumor onset, expansion, resistance, recurrence, and metastasis after therapy. CSCs are identified from the expression of cell surface markers, which is tumor‐type dependent. The transition between CSCs with cancer cells and other non‐CSCs occurs in cancers, which is possibly under the control of signals from CSCs and tumor microenvironment (TME), including CSC niche. Cancer‐associated fibroblasts are among the most influential cells for promoting both differentiation of CSCs and dedifferentiation of non‐CSCs toward attaining a CSC‐like phenotype. WNT/β‐catenin, transforming growth factor‐β, Hedgehog, and Notch are important signals for maintaining self‐renewal in CSCs. An effective therapeutic strategy relies on targeting both CSCs and non‐CSCs to remove a possible chance of tumor relapse. There are multiple ways to target CSCs, including immunotherapy, hormone therapy, (mi)siRNA delivery, and gene knockout. Such approaches can be designed for suppressing CSC stemness, tumorigenic cues from TME, CSC extrinsic and/or intrinsic signaling, hypoxia or for promoting differentiation in the cells. Because of sharing a range of characteristics to normal stem/progenitor cells, CSCs must be targeted based on their unique markers and their preferential expression of antigens.

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“…The pancRNA_FOXCUT is transcribed upstream of the Forkhead box C1 (FOXC1) gene and its expression is positively correlated with FOXC1 mRNA [48]. The transcription factor FOXC1 is a key regulator of several biological processes and its abnormal expression was found associated to poor survival in various malignant tumors and in the epithelial to mesenchymal transition (EMT) process [24,49,50]. Recent studies showed that the FOXCUT-FOXC1 regulatory network is associated with tumorigenesis and cancer progression in esophageal squamous cell carcinoma (ESCC) [50], oral squamous cell carcinoma (OSCC) [51] and nasopharyngeal carcinoma (NPC) [52].…”

Section: Rna-directed Transcriptional Gene Regulation By Pancrnas In mentioning

confidence: 99%

Dissecting the transcriptional regulatory networks of promoter-associated noncoding RNAs in development and cancer

Chellini

Frezza

Paronetto

2020

J Exp Clin Cancer Res

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In-depth analysis of global RNA sequencing has enabled a comprehensive overview of cellular transcriptomes and revealed the pervasive transcription of divergent RNAs from promoter regions across eukaryotic genomes. These studies disclosed that genomes encode a vast repertoire of RNAs beyond the well-known protein-coding messenger RNAs. Furthermore, they have provided novel insights into the regulation of eukaryotic epigenomes, and transcriptomes, including the identification of novel classes of noncoding transcripts, such as the promoterassociated noncoding RNAs (pancRNAs). PancRNAs are defined as transcripts transcribed within few hundred bases from the transcription start sites (TSSs) of protein-coding or non-coding genes. Unlike the long transacting ncRNAs that regulate expression of target genes located in different chromosomal domains and displaying their function both in the nucleus and in the cytoplasm, the pancRNAs operate as cis-acting elements in the transcriptional regulation of neighboring genes. PancRNAs are very recently emerging as key players in the epigenetic regulation of gene expression programs in development and diseases. Herein, we review the complex epigenetic network driven by pancRNAs in eukaryotic cells, their impact on physiological and pathological states, which render them promising targets for novel therapeutic strategies.

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FOXC1 induces cancer stem cell-like properties through upregulation of beta-catenin in NSCLC

Cited by 71 publications

References 56 publications

Forkhead box C1 promotes metastasis and invasion of non–small cell lung cancer by binding directly to the lysyl oxidase promoter

Forkhead box C1 promotes metastasis and invasion of non–small cell lung cancer by binding directly to the lysyl oxidase promoter

Cancer stem cells (CSCs) in cancer progression and therapy

Dissecting the transcriptional regulatory networks of promoter-associated noncoding RNAs in development and cancer

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