ELK3 expressed in lymphatic endothelial cells promotes breast cancer progression and metastasis through exosomal miRNAs

Kim, Kwangsoo; Park, Ji-In; Oh, Nuri; Cho, Hyeon-Ju; Park, Jihoon; Park, Kyung-Soon

doi:10.1038/s41598-019-44828-6

Cited by 43 publications

(30 citation statements)

References 32 publications

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“…Briefly, EXO and IDEM were loaded on a 96-well plate provided by the company and the CD63 positive particle number was quantified against a pre-set exosomes standard curve. The number of CD63+ particles obtained was then compared to the total amount of particles (quantified by NTA) to gather the amount of CD63+ particles out of the total (Kim et al, 2019). The percentage of EXO and IDEM presenting the exosomal surface markers CD81 was determined by flow cytometry.…”

Section: Evaluation Of Exosome-associated Markersmentioning

confidence: 99%

Immune (Cell) Derived Exosome Mimetics (IDEM) as a Treatment for Ovarian Cancer

Pisano

Pierini

et al. 2020

Front. Cell Dev. Biol.

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Exosomes are physiologically secreted nanoparticles recently established as natural delivery systems involved in cell-to-cell communication and content exchange. Due to their inherent targeting potential, exosomes are currently being harnessed for the development of anti-cancer therapeutics. Clinical trials evaluating their effectiveness are demonstrating safety and promising outcomes. However, challenging largescale production, isolation, modification and purification of exosomes are current limitations for the use of naturally occurring exosomes in the clinic. Exosome mimetics hold the promise to improve the delivery of bioactive molecules with therapeutic efficacy, while achieving scalability and increasing bioavailability. In this study, we propose the development of Immune Derived Exosome Mimetics (IDEM) as a scalable approach to target and defeat ovarian cancer cells. IDEM were fabricated from monocytic cells by combining sequential filtration steps through filter membranes with different porosity and size exclusion chromatography columns. The physiochemical and molecular characteristics of IDEM were compared to those of natural exosomes (EXO). Nanoparticle Tracking Analysis confirmed a 2.48-fold increase in the IDEM production yields compared to EXO, with similar exosomal markers profiles (CD81, CD63) as demonstrated by flow cytometry and ELISA. To exploit the prospective of IDEM to deliver chemotherapeutics, doxorubicin (DOXO) was used as a model drug. IDEM showed higher encapsulation efficiency and drug release over time compared to EXO. The uptake of both formulations by SKOV-3 ovarian cancer cells was assessed by confocal microscopy and flow cytometry, showing an incremental drug uptake over time. The analysis of the cytotoxic and apoptotic effect of DOXOloaded nanoparticles both in 2D and 3D culture systems proved IDEM as a more efficient system as compared to free DOXO, unraveling the advantage of IDEM in reducing side-effects while increasing cytotoxicity of targeted cells, by delivering smaller amount of the chemotherapeutic agent. The high yields of IDEM obtained compared to natural exosomes together with the time-effectiveness and reproducibility of their production method make this approach potentially exploitable for clinical applications.

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Section: Evaluation Of Exosome-associated Markersmentioning

confidence: 99%

Immune (Cell) Derived Exosome Mimetics (IDEM) as a Treatment for Ovarian Cancer

Pisano

Pierini

et al. 2020

Front. Cell Dev. Biol.

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“…This extensive study revealed that miR-1910-3p, contained in TNBC and ER- and PR-positive breast cancer cells, inhibited MTMR3, subsequently activating the NF-κB signaling pathway. Interestingly, tumor-associated lymphatic vessels contributed to increased invasion and migration by secreting exosomes containing miR-503-3p, -4269, and 30e-3p in TNBC cells [ 124 ]. All three exosomal miRNAs were identified as targets of ELK3, an ETS domain-containing protein with both transcriptional activation and repression capabilities downstream of the ERK1/2 and Ras signaling pathways.…”

Section: Roles Of Exosomal Micrornas In Breast Cancer Metastasismentioning

confidence: 99%

Exosomal MicroRNAs and Organotropism in Breast Cancer Metastasis

Wong

Jalboush

2020

Cancers

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Breast cancer is the most frequent malignancy for women in which one in eight women will be diagnosed with the disease in their lifetime. Despite advances made in treating primary breast cancer, there is still no effective treatment for metastatic breast cancer. Consequently, metastatic breast cancer is responsible for 90% of breast cancer-related deaths while only accounting for approximately one third of all breast cancer cases. To help develop effective treatments for metastatic breast cancer, it is important to gain a deeper understanding of the mechanisms by which breast cancer metastasizes, particularly, those underlying organotropism towards brain, bone, and lungs. In this review, we will primarily focus on the roles that circulating exosomal microRNAs (miRNAs) play in organotropism of breast cancer metastasis. Exosomes are extracellular vesicles that play critical roles in intercellular communication. MicroRNAs can be encapsulated in exosomes; cargo-loaded exosomes can be secreted by tumor cells into the tumor microenvironment to facilitate tumor–stroma interactions or released to circulation to prime distant organs for subsequent metastasis. Here, we will summarize our current knowledge on the biogenesis of exosomes and miRNAs, mechanisms of cargo sorting into exosomes, the exosomal miRNAs implicated in breast cancer metastasis, and therapeutic exosomal miRNAs.

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“…Moreover, the current work proved that ELK3 was a direct target of miR-3612, and LINC01116 could promote the expression of ELK3 by absorbing miR-3612 in BCa cells. According to previous reporters, ELK3 was closely associated with the development of breast cancer 34,35 , liver cancer 36 , colorectal cancer 37 , and prostate cancer 38 . In our study, we confirmed that ELK3 knockdown could markedly suppress cell growth and metastasis in BCa.…”

Section: Discussionmentioning

confidence: 90%

LINC01106 post-transcriptionally regulates ELK3 and HOXD8 to promote bladder cancer progression

Zeng

Guo

et al. 2020

Cell Death Dis

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Bladder cancer (BCa) is a kind of common urogenital malignancy worldwide. Emerging evidence indicated that long noncoding RNAs (lncRNAs) play critical roles in the progression of BCa. In this study, we discovered a novel lncRNA LINC01116 whose expression increased with stages in BCa patients and closely related to the survival rate of BCa patients. However, the molecular mechanism dictating the role of LINC01116 in BCa has not been well elucidated so far. In our study, we detected that the expression of LINC01116 was boosted in BCa cells. Moreover, the results of a series of functional assays showed that LINC01116 knockdown suppressed the proliferation, migration, and invasion of BCa cells. Thereafter, GEPIA indicated the closest correlation of LINC01116 with two protein-coding genes, ELK3 and HOXD8. Interestingly, LINC01116 was mainly a cytoplasmic lncRNA in BCa cells, and it could modulate ELK3 and HOXD8 at post-transcriptional level. Mechanically, LINC01116 increased the expression of ELK3 by adsorbing miR-3612, and also stabilized HOXD8 mRNA by binding with DKC1. Rescue experiments further demonstrated that the restraining influence of LINC01116 knockdown on the progression of BCa, was partly rescued by ELK3 promotion, but absolutely reversed by the co-enhancement of ELK3 and HOXD8. More intriguingly, HOXD8 acted as a transcription factor to activate LINC01116 in BCa. In conclusion, HOXD8-enhanced LINC01116 contributes to the progression of BCa via targeting ELK3 and HOXD8, which might provide new targets for treating patients with BCa.

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ELK3 expressed in lymphatic endothelial cells promotes breast cancer progression and metastasis through exosomal miRNAs

Cited by 43 publications

References 32 publications

Immune (Cell) Derived Exosome Mimetics (IDEM) as a Treatment for Ovarian Cancer

Immune (Cell) Derived Exosome Mimetics (IDEM) as a Treatment for Ovarian Cancer

Exosomal MicroRNAs and Organotropism in Breast Cancer Metastasis

LINC01106 post-transcriptionally regulates ELK3 and HOXD8 to promote bladder cancer progression

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