miR-503-5p inhibits colon cancer tumorigenesis, angiogenesis, and lymphangiogenesis by directly downregulating VEGF-A

Wei, Luqing; Sun, Chaonan; Zhang, Yaotian; Han, Ning; Sun, Shichen

doi:10.1038/s41434-020-0167-3

Cited by 38 publications

(23 citation statements)

References 40 publications

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“…These data suggested that the effect of miR-503-5p in AML was partly mediated by INPP4B. In addition, previous studies have reported that miR-503-5p played essential roles in human diseases through regulating a series of targeted mRNAs such as WEE1 in hepatocellular carcinoma, 16 VEGF-A in colon cancer, 40 CDCA4 in osteosarcoma, 41 and so on. These well-known targeted genes whether mediated the function of miR-503-5p in AML should be explored in the future.…”

Section: Discussionmentioning

confidence: 78%

lncRNA RAET1K Promotes the Progression of Acute Myeloid Leukemia by Targeting miR-503-5p/INPP4B Axis

Li¹,

Wan²,

Li³

et al. 2021

OTT

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Background: Although long non-coding RNA (lncRNA) RAET1K has been observed to be abnormally expressed in patients with various cancers, its role and molecular mechanism in acute myeloid leukemia (AML) remain unclear. Methods: The expression of RAET1K and miR-503-5p in bone marrow tissues and cell lines was detected by qRT-PCR. Cell proliferation was evaluated by cell counting kit-8 and 5-ethynyl-20-deoxyuridine (EdU) staining assay. Cell invasion and migration were detected by transwell assay. Cell apoptosis was evaluated by flow cytometry. The relationship between RAET1K and miR-503-5p, as well as miR-503-5p and INPP4B, was determined by luciferase reporter assay and RNA immunoprecipitation (RIP) assay. In addition, the tumorigenesis of leukemia cells was evaluated by using a xenograft mouse model in vivo. Results: RAET1K was significantly upregulated and miR-503-5p was markedly downregulated in bone marrow tissues and cell lines (HL-60 and THP-1). Silencing of RAET1K (si-RAET1K) and overexpression of miR-503-5p inhibited cell proliferation, migration, and invasion but promoted apoptosis of HL-60 and THP-1 cells. RAET1K functioned as a sponge of miR-503-5p, and miR-503-5p inhibitor obviously attenuated the effect of si-RAET1K on AML progression in vitro. INPP4B was identified as a target of miR-503-5p, and INPP4B overexpression obviously reversed the effect of miR-503-5p mimics on cell proliferation, migration, invasion, and apoptosis of HL-60 and THP-1 cells in vitro. Knockdown of RAET1K effectively inhibited the tumorigenesis of leukemia cells in vivo. Conclusion:Our results demonstrated that RAET1K/miR-503-5p/INPP4B axis contributed to AML progression, suggesting that RAET1K might be a potential target for the treatment of AML.

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Section: Discussionmentioning

confidence: 78%

lncRNA RAET1K Promotes the Progression of Acute Myeloid Leukemia by Targeting miR-503-5p/INPP4B Axis

Li¹,

Wan²,

Li³

et al. 2021

OTT

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“…Down regulation of VEGFA (vascular endothelial growth factor A) inhibits angiogenesis and lymphangiogenesis [ 58 ]. VEGFA promotes lymphangiogenesis and high endothelial venule expansion in lymph nodes [ 59 ].…”

Section: Discussionmentioning

confidence: 99%

Decreased Lymphangiogenic Activities and Genes Expression of Cord Blood Lymphatic Endothelial Progenitor Cells (VEGFR3+/Pod+/CD11b+ Cells) in Patient with Preeclampsia

Kwon

Song

et al. 2021

IJMS

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The abnormal development or disruption of the lymphatic vasculature has been implicated in metabolic and hypertensive diseases. Recent evidence suggests that the offspring exposed to preeclampsia (PE) in utero are at higher risk of long-term health problems, such as cardiovascular and metabolic diseases in adulthood, owing to in utero fetal programming. We aimed to investigate lymphangiogenic activities in the lymphatic endothelial progenitor cells (LEPCs) of the offspring of PE. Human umbilical cord blood LEPCs from pregnant women with severe PE (n = 10) and gestationally matched normal pregnancies (n = 10) were purified with anti-vascular endothelial growth factor receptor 3 (VEGFR3)/podoplanin/CD11b microbeads using a magnetic cell sorter device. LEPCs from PE displayed significantly delayed differentiation and reduced formation of lymphatic endothelial cell (LEC) colonies compared with the LEPCs from normal pregnancies. LECs differentiated from PE-derived LEPCs exhibited decreased tube formation, migration, proliferation, adhesion, wound healing, and 3D-sprouting activities as well as increased lymphatic permeability through the disorganization of VE-cadherin junctions, compared with the normal pregnancy-derived LECs. In vivo, LEPCs from PE showed significantly reduced lymphatic vessel formation compared to the LEPCs of the normal pregnancy. Gene expression analysis revealed that compared to the normal pregnancy-derived LECs, the PE-derived LECs showed a significant decrease in the expression of pro-lymphangiogenic genes (GREM1, EPHB3, VEGFA, AMOT, THSD7A, ANGPTL4, SEMA5A, FGF2, and GBX2). Collectively, our findings demonstrate, for the first time, that LEPCs from PE have reduced lymphangiogenic activities in vitro and in vivo and show the decreased expression of pro-lymphangiogenic genes. This study opens a new avenue for investigation of the molecular mechanism of LEPC differentiation and lymphangiogenesis in the offspring of PE and subsequently may impact the treatment of long-term health problems such as cardiovascular and metabolic disorders of offspring with abnormal development of lymphatic vasculature.

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“…VEGF-A was also reported to be a negative regulator of miR-503-5p. The downregulation of miR-503-5p resulted in the induction of tumorigenesis, angiogenesis, and lymphangiogenesis in colon cancer by stimulating the AKT signaling pathway [108].…”

Section: Mirnas In Tumor-associated Lymphangiogenesismentioning

confidence: 99%

“…In contrast, VEGF-D was found to regulate the enzyme that breaks down prostaglandin in endothelial cells, namely 15-hydroxyprostaglandin dehydrogenase (15-PGDH), resulting in the prolonged exposure of LECs in collecting lymphatics to prostaglandins and enlargement of the lymphatic vessels, hence allowing the dissemination of tumor cells [100,101]. The increased level of VEGF-C was found to have accelerated the growth of tumors in renal cell carcinoma [102],chondrosarcoma [103,104], breast [105][106][107], colon [108], lung [109], and skin cancer [110,111]. Of note, the prostaglandin-lymphangiogenesis induction is not specific to cancer, but also occurs in the inflammation setting.…”

Section: Genes Involved In Tumor-associated Lymphangiogenesismentioning

confidence: 99%

The Roles of Non-Coding RNAs in Tumor-Associated Lymphangiogenesis

Yusof

Rosli

Abdullah

et al. 2020

Cancers

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Lymphatic vessels are regarded as the ”forgotten” circulation. Despite this, growing evidence has shown significant roles for the lymphatic circulation in normal and pathological conditions in humans, including cancers. The dissemination of tumor cells to other organs is often mediated by lymphatic vessels that serve as a conduit and is often referred to as tumor-associated lymphangiogenesis. Some of the most well-studied lymphangiogenic factors that govern tumor lymphangiogenesis are the vascular endothelial growth factor (VEGF-C/D and VEGFR-2/3), neuroplilin-2 (NRP2), fibroblast growth factor (FGF), and hepatocyte growth factor (HGF), to name a few. However, recent findings have illustrated that non-coding RNAs are significantly involved in regulating gene expression in most biological processes, including lymphangiogenesis. In this review, we focus on the regulation of growth factors and non-coding RNAs (ncRNAs) in the lymphatic development in normal and cancer physiology. Then, we discuss the lymphangiogenic factors that necessitate tumor-associated lymphangiogenesis, with regards to ncRNAs in various types of cancer. Understanding the different roles of ncRNAs in regulating lymphatic vasculature in normal and cancer conditions may pave the way towards the development of ncRNA-based anti-lymphangiogenic therapy.

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miR-503-5p inhibits colon cancer tumorigenesis, angiogenesis, and lymphangiogenesis by directly downregulating VEGF-A

Cited by 38 publications

References 40 publications

lncRNA RAET1K Promotes the Progression of Acute Myeloid Leukemia by Targeting miR-503-5p/INPP4B Axis

lncRNA RAET1K Promotes the Progression of Acute Myeloid Leukemia by Targeting miR-503-5p/INPP4B Axis

Decreased Lymphangiogenic Activities and Genes Expression of Cord Blood Lymphatic Endothelial Progenitor Cells (VEGFR3+/Pod+/CD11b+ Cells) in Patient with Preeclampsia

The Roles of Non-Coding RNAs in Tumor-Associated Lymphangiogenesis

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