Forkhead Box Q1 Is Critical to Angiogenesis and Macrophage Recruitment of Colorectal Cancer

Angiogenesis and the tumor microenvironment (TME) play important roles in tumorigenesis. Forkhead box Q1 (FOXQ1) is a well-established oncogene in multiple tumors, including colorectal cancer (CRC); however, whether FOXQ1 contributes to angiogenesis and TME modification in CRC remains largely uncharacterized. Here, we demonstrate an essential role of FOXQ1-induced angiogenesis and macrophage recruitment in CRC that is related to its ability to promote the migration of endothelial cells and macrophages through activation of the EGF/PDGF pathway and the Twist1/CCL2 axis. We also provide evidence showing that the clinical significance between FOXQ1, Twist1, CCL2, and macrophage infiltration is associated with reduced 8-year survival in CRC patients. Our findings suggest FOXQ1 plays critical roles in the malignancy and progression of CRC, Therefore, FOXQ1 may serve as a therapeutic target for inhibiting angiogenesis and reducing macrophage recruitment in CRC.

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Faculty Opinions recommendation of An essential role of the Forkhead-box transcription factor Foxo1 in control of T cell homeostasis and tolerance.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1158391.618543 ◽

2009 ◽

Author(s):

David Fruman

Keyword(s):

Transcription Factor ◽

T Cell ◽

Essential Role ◽

T Cell Homeostasis ◽

Cell Homeostasis ◽

Forkhead Box

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PI3K/ Akt/ mTOR Pathway as a Therapeutic Target for Colorectal Cancer: A Review of Preclinical and Clinical Evidence

Current Drug Targets ◽

10.2174/1389450120666190618123846 ◽

2019 ◽

Vol 20 (12) ◽

pp. 1217-1226 ◽

Cited By ~ 14

Author(s):

Arunaksharan Narayanankutty

Keyword(s):

Colorectal Cancer ◽

Drug Resistance ◽

Therapeutic Target ◽

Clinical Evidence ◽

Mtor Pathway ◽

Colorectal Cancers ◽

Patent Literature ◽

Mtor Signalling ◽

Natural And Synthetic

Background: Phosphoinositide 3-kinase (PI3Ks) is a member of intracellular lipid kinases and involved in the regulation of cellular proliferation, differentiation and survival. Overexpression of the PI3K/Akt/mTOR signalling has been reported in various forms of cancers, especially in colorectal cancers (CRC). Due to their significant roles in the initiation and progression events of colorectal cancer, they are recognized as a striking therapeutic target. Objective: The present review is aimed to provide a detailed outline on the role of PI3K/Akt/mTOR pathway in the initiation and progression events of colorectal cancers as well as its function in drug resistance. Further, the role of PI3K/Akt/mTOR inhibitors alone and in combination with other chemotherapeutic drugs, in alleviating colorectal cancer is also discussed. The review contains preclinical and clinical evidence as well as patent literature of the pathway inhibitors which are natural and synthetic in origin. Methods: The data were obtained from PubMed/Medline databases, Scopus and Google patent literature. Results: PI3K/Akt/mTOR signalling is an important event in colorectal carcinogenesis. In addition, it plays significant roles in acquiring drug resistance as well as metastatic initiation events of CRCs. Several small molecules of natural and synthetic origin have been found to be potent inhibitors of CRCs by effectively downregulating the pathway. Data from various clinical studies also support these pathway inhibitors and several among them are patented. Conclusion: Inhibitors of the PI3K/mTOR pathway have been successful for the treatment of primary and metastatic colorectal cancers, rendering the pathway as a promising clinical cancer therapeutic target.

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Hyperglycaemia up-regulates placental growth factor (PlGF) expression and secretion in endothelial cells via suppression of PI3 kinase-Akt signalling and activation of FOXO1

Scientific Reports ◽

10.1038/s41598-021-95511-8 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Samir Sissaoui ◽

Stuart Egginton ◽

Ling Ting ◽

Asif Ahmed ◽

Peter W. Hewett

Keyword(s):

Endothelial Cells ◽

Growth Factor ◽

Endothelial Dysfunction ◽

Akt Activation ◽

Forkhead Box ◽

Pi3k Activity ◽

Binding Sequence

AbstractPlacenta growth factor (PlGF) is a pro-inflammatory angiogenic mediator that promotes many pathologies including diabetic complications and atherosclerosis. Widespread endothelial dysfunction precedes the onset of these conditions. As very little is known of the mechanism(s) controlling PlGF expression in pathology we investigated the role of hyperglycaemia in the regulation of PlGF production in endothelial cells. Hyperglycaemia stimulated PlGF secretion in cultured primary endothelial cells, which was suppressed by IGF-1-mediated PI3K/Akt activation. Inhibition of PI3K activity resulted in significant PlGF mRNA up-regulation and protein secretion. Similarly, loss or inhibition of Akt activity significantly increased basal PlGF expression and prevented any further PlGF secretion in hyperglycaemia. Conversely, constitutive Akt activation blocked PlGF secretion irrespective of upstream PI3K activity demonstrating that Akt is a central regulator of PlGF expression. Knock-down of the Forkhead box O-1 (FOXO1) transcription factor, which is negatively regulated by Akt, suppressed both basal and hyperglycaemia-induced PlGF secretion, whilst FOXO1 gain-of-function up-regulated PlGF in vitro and in vivo. FOXO1 association to a FOXO binding sequence identified in the PlGF promoter also increased in hyperglycaemia. This study identifies the PI3K/Akt/FOXO1 signalling axis as a key regulator of PlGF expression and unifying pathway by which PlGF may contribute to common disorders characterised by endothelial dysfunction, providing a target for therapy.

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Role of serine/threonine kinase 33 methylation in colorectal cancer and its clinical significance

Oncology Letters ◽

10.3892/ol.2017.7614 ◽

2017 ◽

Cited By ~ 2

Author(s):

Ming‑Di Yin ◽

Si‑Ping Ma ◽

Fang Liu ◽

Yu‑Ze Chen

Keyword(s):

Colorectal Cancer ◽

Clinical Significance ◽

Serine Threonine Kinase ◽

Threonine Kinase

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The essential role of TAp73 in bortezomib-induced apoptosis in p53-deficient colorectal cancer cells

Scientific Reports ◽

10.1038/s41598-017-05813-z ◽

2017 ◽

Vol 7 (1) ◽

Cited By ~ 19

Author(s):

Yasamin Dabiri ◽

Sara Kalman ◽

Clara-Marie Gürth ◽

Jee Young Kim ◽

Viola Mayer ◽

...

Keyword(s):

Colorectal Cancer ◽

Cancer Cells ◽

Essential Role ◽

Colorectal Cancer Cells ◽

Induced Apoptosis

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The lncRNA XIST promotes colorectal cancer cell growth through regulating the miR-497-5p/FOXK1 axis

Cancer Cell International ◽

10.1186/s12935-020-01647-4 ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Nan Wang ◽

Jia-Xing He ◽

Guo-Zhan Jia ◽

Ke Wang ◽

Shuai Zhou ◽

...

Keyword(s):

Colorectal Cancer ◽

Cell Counting ◽

Luciferase Reporter ◽

Migration And Invasion ◽

Cancer Cell Growth ◽

Forkhead Box ◽

Proliferation And Apoptosis ◽

Lncrna Xist

Abstract Background Recent studies suggest that long noncoding RNAs (lncRNAs) play an important role in tumorigenesis. As a newly identified lncRNA, the role of XIST in colorectal cancer (CRC) has not been established. Here, we sought to characterize the role of XIST and its associated regulatory network in CRC cells. Methods Expression of XIST mRNA, miR-497-5p, and forkhead box k1 (FOXK1) in CRC cells and tissues were detected using quantitative real-time polymerase chain reaction (qRT-PCR). Proliferation and apoptosis of CRC cells were determined using the CCK-8 cell counting assay and flow cytometry. The rate of cell migration and invasion was determined using a transwell assay. The relationships between XIST, miR-497-5p, and FOXK1 were predicted and confirmed using a dual-luciferase reporter assay. Expression of FOXK1 protein was quantified by Western blot. Results XIST and FOXK1 expression were significantly upregulated in CRC tissues and cell lines, while miR-497-5p expression was downregulated. XIST knockdown significantly suppressed CRC cell proliferation, migration, and invasion. Silencing of XIST also reversed the downregulation of miR-497-5p and upregulation of FOXK1. Moreover, blocking XIST expression was shown to inhibit CRC tumor growth in vivo and the effects were antagonized by the loss of miR-497-5p. miR-497-5p was shown to act as a sponge of XIST and also targeted FOXK1 in CRC cells. Conclusions XIST was shown to promote the malignancy of CRC cells by competitively binding to miR-497-5p, resulting in an increase in FOXK1 expression. These results suggest that targeting of XIST may represent a possible treatment for CRC.

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Role of γ-glutamyl cyclotransferase as a therapeutic target for colorectal cancer based on the lentivirus-mediated system

Anti-Cancer Drugs ◽

10.1097/cad.0000000000000407 ◽

2016 ◽

Vol 27 (10) ◽

pp. 1011-1020 ◽

Cited By ~ 5

Author(s):

Jian Dong ◽

Yuanhang Zhou ◽

Zhiwei Liao ◽

Qi Huang ◽

Shidong Feng ◽

...

Keyword(s):

Colorectal Cancer ◽

Therapeutic Target

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Specific tumor-derived CCL2 mediated by pyruvate kinase M2 in colorectal cancer cells contributes to macrophage recruitment in tumor microenvironment

Tumor Biology ◽

10.1177/1010428317695962 ◽

2017 ◽

Vol 39 (3) ◽

pp. 101042831769596 ◽

Cited By ~ 10

Author(s):

Kejian Zou ◽

Yaodong Wang ◽

Yan Hu ◽

Liansheng Zheng ◽

Wanfu Xu ◽

...

Keyword(s):

Colorectal Cancer ◽

Tumor Microenvironment ◽

Pyruvate Kinase ◽

Quantitative Polymerase Chain Reaction ◽

Nuclear Factor Κb ◽

Enzyme Linked Immunosorbent Assay ◽

Cancer Tissue ◽

Nuclear Factor ◽

Pyruvate Kinase M2 ◽

Macrophage Recruitment

Development of colorectal cancer has been considered as a result of imbalance of pro- and anti-inflammatory intestinal microenvironment accompanied by macrophage recruitment. Despite macrophages are implicated in remodeling tumor microenvironment, the mechanism of macrophage recruitment is not fully elucidated yet. In this study, we reported clinical association of highly expressed pyruvate kinase M2 in colorectal cancer with macrophage attraction. The conditioned medium from Caco-2 and HT-29 cells with depleted pyruvate kinase M2 dramatically reduced macrophage recruitment, which is reversed by addition of, a critical chemotaxis factor to macrophage migration, rCCL2. Silencing of endogenous pyruvate kinase M2 markedly decreased CCL2 expression and secretion by real-time quantitative polymerase chain reaction and enzyme-linked immunosorbent assay. Endogenous pyruvate kinase M2 interacted with p65 and mediated nuclear factor-κB signaling pathway and mainly regulated phosphorylation of Ser276 on p65 nuclear factor-κB. In addition, inhibition of macrophage recruitment caused by pyruvate kinase M2 silencing was rescued by ectopic expression of p65. Interestingly, pyruvate kinase M2 highly expressed in colorectal cancer tissue, which is correction with macrophage distribution. Taken together, we revealed a novel mechanism of pyruvate kinase M2 in promoting colorectal cancer progression by recruitment of macrophages through p65 nuclear factor-κB–mediated expression of CCL2.

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