Horizontal transfer of miR‐23a from hypoxic tumor cell colonies can induce angiogenesis

Sruthi, T. V.; Edatt, Lincy; Raji, Grace R.; Kunhiraman, Haritha; Shankar, S. Sharath; Shankar, Vandana; Ramachandran, Vishnu; Poyyakkara, Aswini; Kumar, Vijai

doi:10.1002/jcp.26202

Cited by 72 publications

(52 citation statements)

References 48 publications

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“…Further, report from our group suggests that miR-106a regulates the expression of MMP9 during cell migration by directly targeting SIRT1 mRNA (151). Our group has also reported that the horizontal transfer of miR-23a from tumor cell colonies can induces angiogenesis by targeting SIRT1 in the recipient endothelial cells (152). Further, miR-212 has been reported to exhibit anti-angiogenic properties, by targeting SIRT1 and Gab1 in endothelial cells (153).…”

Section: Post Transcriptional Regulation Of Sirtuins: Importance Of Mmentioning

confidence: 84%

Role of Sirtuins in Tumor Angiogenesis

et al. 2020

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Generally, changes in the metabolic status of cells under conditions like hypoxia and accumulation of lactate can be sensed by various sensing mechanisms, leading to modulation of a number of signal transduction pathways and transcription factors. Several of the proangiogenic cytokines like VEGF, FGF, PDGF, TGF-β, Ang-2, ILs, etc. are secreted by cancer cells, under hypoxic microenvironment. These cytokines bind to their receptors on the endothelial cells and activates a number of signaling pathways including Akt/PIP3, Src, p38/MAPK, Smad2/3, etc., which ultimately results in the proliferation and migration of endothelial cells. Transcription factors that are activated in response to the metabolic status of tumors include HIFs, NF-κb, p53, El-2, and FOXO. Many of these transcription factors has been reported to be regulated by a class of histone deacetylase called sirtuins. Sirtuins are NAD + dependent histone deacetylases that play pivotal role in the regulation of tumor cell metabolism, proliferation, migration and angiogenesis. The major function of sirtuins include, deacetylation of histones as well as some non-histone proteins like NF-κB, FOXOs, PPAR , PGC1-α, enzymes like acetyl coenzymeA and structural proteins like α tubulin. In the cell, sirtuins are generally considered as the redox sensors and their activities are dependent on the metabolic status of the cell. Understanding the intricate regulatory mechanisms adopted by sirtuins, is crucial in devising effective therapeutic strategies against angiogenesis, metastasis and tumor progression. Keeping this in mind, the present review focuses on the role of sirtuins in the process of tumor angiogenesis and the regulatory mechanisms employed by them.

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Section: Post Transcriptional Regulation Of Sirtuins: Importance Of Mmentioning

confidence: 84%

Role of Sirtuins in Tumor Angiogenesis

et al. 2020

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“…Studies have shown that miR-23a can be carried by tumor cell-secreted exosomes such as nasopharyngeal carcinoma or lung cancer cells and then exert their regulatory functions on angiogenesis (22)(23)(24), which suggested that miR-23a carried by GC cell-derived exosomes might be involved in angiogenesis. To validate this hypothesis, exosomes were extracted from GES-1, NCI-N87, HGC-27, AGS, and MKN45 using the ExoQuick method and then identified.…”

Section: Mir-23a Is Enriched In Gc Cells-derived Exosomesmentioning

confidence: 99%

Gastric Cancer Cell-Derived Exosomal microRNA-23a Promotes Angiogenesis by Targeting PTEN

Liu

et al. 2020

Front. Oncol.

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Hypoxia-exposed lung cancer-released exosomal microRNA-23a (miR-23a) has been shown to enhance angiogenesis as well as vascular permeability, contributing to the close correlation between exosomal miR-23a and tumorigenesis. The current study aimed to investigate whether gastric cancer (GC) cell-derived exosomal miR-23a could induce angiogenesis and to elucidate the potential mechanisms associated with the process. Differentially expressed miRNAs in GC were initially screened from the Gene Expression Omnibus database. Target genes were selected following miRNA-mRNA prediction and subsequently verified by dual luciferase reporter assay. RT-qPCR was conducted to detect miR-23a and PTEN expression in GC tissues, cells and exosomes. Human umbilical venous endothelial cells (HUVECs) were co-cultured with GC cell-derived exosomes to assess the angiogenesis mediated by exosomes in vitro. Additionally, PTEN was overexpressed in HUVECs to analyze the mechanism by which miR-23a regulates angiogenesis. miR-23a was highly expressed in GC tissues and cells and GC cell-derived exosomes. Angiogenesis was promoted by the co-culture of HUVECs and GC cells-derived exosomes, as evidenced by the increased expression of VEGF but decreased expression of TSP-1. PTEN was targeted by miR-23a and was lowly expressed in GC tissues. In a co-culture system, miR-23a carried by GC cells-derived exosomes promoted angiogenesis via the repression of PTEN. Collectively, GC cell-derived exosomal miR-23a could promote angiogenesis and provide blood supply for growth of GC cells. This study contributes to advancement of miRNA-targeted therapeutics.

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“…30 Recent studies from our group have substantiated the importance miR-23a among other cluster members, as it is significantly up regulated in exosomes secreted by hypoxic tumor cells colonies and horizontal transfer of which induced angiogenesis in the recipient endothelial cells. 40 Interestingly, the in silico analysis using online tools at miRBase suggested that miR-23a has got target site on the 3′ UTR of LDH A and LDH B mRNAs ( Figure 3A(1-3)). So, we went on to check the role of miR-23a if any, in regulating LDH expression during ER stress.…”

Section: Discussionmentioning

confidence: 99%

ER stress mediated regulation of miR23a confer Hela cells better adaptability to utilize glycolytic pathway

Poyyakkara

Raji

Kunhiraman

et al. 2018

J of Cellular Biochemistry

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Cancer cells exhibit increased dependency on aerobic glycolysis, a phenomenon referred as the "Warburg effect" and therefore, blocking glycolysis by using non-metabolizable analogues of glucose, like 2-Deoxy glucose (2-DG), has been proposed to be of huge therapeutic importance. One of the major drawbacks of using 2-DG as a chemotherapeutic agent is that it can induce ER stress. ER stress is a hall mark in many solid tumors and the unfolded protein response (UPR) associated with it initiates many survival mechanisms in cancer cells. In the present study, we report a novel survival mechanism associated with ER stress, by which the cancer cells become more adapted to aerobic glycolysis. When ER stress was induced in Hela cells by treating them with 2-DG or Thapsigargin (TG) the expression and activity of LDH was significantly up regulated, conferring the cells a greater glycolytic potential. A simultaneous decrease was observed in the expression of miR-23a, which was predicted in silico to have target site on the 3'UTR of LDH A and B mRNAs. miRNA over expression studies and mRNA degradation assays suggest that miR-23a could target LDH A and LDH B mRNAs. Further on the basis of our results and previous scientific reports, we propose that "c-Myc," which is over expressed during ER stress, repress the expression of miR-23a, which in turn regulates the expression of its target genes viz., LDH A and LDH B, thereby making the cells more competent to survive in tumor microenvironment, which requires efficient use of aerobic glycolysis.

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Horizontal transfer of miR‐23a from hypoxic tumor cell colonies can induce angiogenesis

Cited by 72 publications

References 48 publications

Role of Sirtuins in Tumor Angiogenesis

Role of Sirtuins in Tumor Angiogenesis

Gastric Cancer Cell-Derived Exosomal microRNA-23a Promotes Angiogenesis by Targeting PTEN

ER stress mediated regulation of miR23a confer Hela cells better adaptability to utilize glycolytic pathway

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