Suppression of endothelial miR-22 mediates non-small cell lung cancer cell-induced angiogenesis
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Evaluation Summary:
This study reports a novel function of non-coding RNA miR-22 in the regulation of tumor-associated angiogenesis. The presented data suggest a possible link between microRNA and endothelial cell function. If the underlying mechanisms were further explored, this work would be interesting for people working on microRNA function in endothelial cells. Furthermore, considering the increasing interest of combination of anti-angiogenesis agents with anti-PD1 immunotherapy, this work may attract readers interested in immunology.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)
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Evaluation Summary:
This study reports a novel function of non-coding RNA miR-22 in the regulation of tumor-associated angiogenesis. The presented data suggest a possible link between microRNA and endothelial cell function. If the underlying mechanisms were further explored, this work would be interesting for people working on microRNA function in endothelial cells. Furthermore, considering the increasing interest of combination of anti-angiogenesis agents with anti-PD1 immunotherapy, this work may attract readers interested in immunology.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)
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Reviewer #1 (Public Review):
The study conducted by Gu et. al. has clarified the inhibitory role of miR-22 in in-vitro and in-vivo angiogenesis including tumor angiogenesis. The authors showed that miR-22 is less expressed in tumor endothelial cells (ECs) of human non-small cell lung cancer (NSCLC) tissues compared with ECs of adjacent normal tissues. The authors propose that this reduction of endothelial miR-22 could be induced by NSCLC cell-secreted TNFa and ILb. In addition, they showed that endothelial miR-22 reduces SIRT1 and FGFR1 in the ECs, leading to inactivation of AKT/mammalian target of rapamycin (mTOR) signaling. This study is novel, interesting and well-designed.
However, the concepts established in this study would need to be extended to other common cancers. The authors would also need to define how NFkB activation …
Reviewer #1 (Public Review):
The study conducted by Gu et. al. has clarified the inhibitory role of miR-22 in in-vitro and in-vivo angiogenesis including tumor angiogenesis. The authors showed that miR-22 is less expressed in tumor endothelial cells (ECs) of human non-small cell lung cancer (NSCLC) tissues compared with ECs of adjacent normal tissues. The authors propose that this reduction of endothelial miR-22 could be induced by NSCLC cell-secreted TNFa and ILb. In addition, they showed that endothelial miR-22 reduces SIRT1 and FGFR1 in the ECs, leading to inactivation of AKT/mammalian target of rapamycin (mTOR) signaling. This study is novel, interesting and well-designed.
However, the concepts established in this study would need to be extended to other common cancers. The authors would also need to define how NFkB activation induces reduction of miR-22 in endothelial cells. It is unclear how miR-22 inhibits S-phase of cell cycle, migration and sprouting in endothelial cells. What are the underlying mechanism? The explanation involving the reduction of FGFR1 and SIRT1 does not seem to be sufficient.
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Reviewer #2 (Public Review):
Gu et al reported a potential function of non-coding RNA miR-22 in the regulation of agiogenesis via tumor-associated endothelial cells. The authors showed that tumor-related soluble factors possibly inhibit the expression of miR-22 via activation of NF-kB pathway leading to upregulation of SIRT1 and FGFR1 expression in endothelial cells, thus promote the angiogenesis. The work is well designed in general and the data presented support their take-home message on how miR-22 impacts on the viability of endothelial cells. However, the mechanistic study still needs further exploring. In particular, the link between cancer cell and tumor-associated endothelial cells would need to be strengthened. The work has potential interest for the domain of microRNAs and their functional role in endothelial cells. The …
Reviewer #2 (Public Review):
Gu et al reported a potential function of non-coding RNA miR-22 in the regulation of agiogenesis via tumor-associated endothelial cells. The authors showed that tumor-related soluble factors possibly inhibit the expression of miR-22 via activation of NF-kB pathway leading to upregulation of SIRT1 and FGFR1 expression in endothelial cells, thus promote the angiogenesis. The work is well designed in general and the data presented support their take-home message on how miR-22 impacts on the viability of endothelial cells. However, the mechanistic study still needs further exploring. In particular, the link between cancer cell and tumor-associated endothelial cells would need to be strengthened. The work has potential interest for the domain of microRNAs and their functional role in endothelial cells. The identified microRNA-regulated pathways in endothelial cells may possibly be therapeutic targets, however, the current study needs to be further improved to support the major conclusion as stated in title of the paper.
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Reviewer #3 (Public Review):
The authors demonstrated the novel mechanism of angiogenesis in human non-small cell lung cancer (NSCLC). They showed that downregulation of miR-22 in endothelial cells in NSCLC (TEC) compared to normal endothelial cells after isolation by laser microdissection method. They demonstrated that NSCLC secreted tumor necrosis factor (TNF)-α and interleukin (IL)-1β cause downregulation of miR-22 in endothelial cells. Endothelial miR-22 inhibits sirtuin (SIRT) 1and fibroblast growth factor receptor (FGFR) 1, leading to inactivation of AKT/mammalian target of rapamycin (mTOR) signaling, suggesting that miR-22 is a potent angiogenic inhibitor. Since current angiogenic inhibitors which target VEGF signaling sometimes cause adverse effects via damage in normal endothelial cells (NECs), the strategy to recruit the …
Reviewer #3 (Public Review):
The authors demonstrated the novel mechanism of angiogenesis in human non-small cell lung cancer (NSCLC). They showed that downregulation of miR-22 in endothelial cells in NSCLC (TEC) compared to normal endothelial cells after isolation by laser microdissection method. They demonstrated that NSCLC secreted tumor necrosis factor (TNF)-α and interleukin (IL)-1β cause downregulation of miR-22 in endothelial cells. Endothelial miR-22 inhibits sirtuin (SIRT) 1and fibroblast growth factor receptor (FGFR) 1, leading to inactivation of AKT/mammalian target of rapamycin (mTOR) signaling, suggesting that miR-22 is a potent angiogenic inhibitor. Since current angiogenic inhibitors which target VEGF signaling sometimes cause adverse effects via damage in normal endothelial cells (NECs), the strategy to recruit the molecules which are specifically downregulated sounds promising.
However, the reviewer considers the authors should show additional data to help readers interpret the authors' conclusion; the potential of this miR-22 strategy as angiogenic inhibitors. Also, this reviewer is concerned about several experimental methods which the authors required in this study. In vivo anti-angiogenic effects of miR-22 expressing endothelial cells, 10 times more endothelial cells were mixed with tumor cells for implantation, although endothelial cells are much less numerous than tumor cells in real tumors. For the isolation of endothelial cells by laser microdissection, it is not clear whether endothelial cells were dissected. Did they perform CD31 staining before dissection? It would strengthen the significance of miR-22 if the authors tried to direct miR-22 to in vivo tumors besides co-implantation of endothelial cells.
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