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Decipering the molecular mechanism of ACE2 regulating A549 cells

ABSTRACT: In the current study, using a lentivirus-based expression system in lung cancer cells (A549), we show that ACE2 overexpression reduces the viability and migratory potential of cancer cells, highlighting the robust anti-tumorigenic effects of ACE2 function. Moreover, a quantitative proteome-level comparison between ACE2 overexpressed (OE) and empty vector-controlled (NC) cells reveals a large number (227) of differentially expressed proteins (DEPs) that may have contributed to this phenomenon. Functional enrichment of these DEPs has uncovered that most of them perform binding activities and enzymatic reactions associated with metabolic pathways and various post-transcriptional gene expression regulatory mechanisms. Besides, cellular component analysis reveals that the DEPs function across a range of compartments within a cell with a relatively heterogeneous distribution.

ORGANISM(S): Homo Sapiens

SUBMITTER: Linxin Xie

PROVIDER: PXD024899 | iProX | Mon Mar 22 00:00:00 GMT 2021

REPOSITORIES: iProX

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Decipering the Molecular Mechanism of ACE2 Regulating A549 Cells.

Xiao Kun K Song Licheng L Bai Ying Y Liu Pengfei P Liu Yuhong Y Xie Fei F Xie Lixin L

Frontiers in genetics 20210719

Angiotensin-converting enzyme 2 (ACE2) is an aminopeptidase that functions as a part of the renin-angiotensin system (RAS). The RAS pathway plays a crucial role in regulating the local blood flow within a tissue. As a consequence, the role of ACE2 in regulating vasculature properties has been widely appreciated. Additionally, ACE2 has also been reported to show anti-tumorigenic activity. However, the mechanistic basis of this function has remained largely unexplored. In the current study, using ...[more]

PMID: 34354732

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Project description:For decades, it has been well accepted that corneal epithelial stem cells and their immediate progeny, the early transit amplifying (eTA) cells, reside in the limbal epithelial basal layer. Activation of quiescent stem/eTA cells is required for proper re-epithelialization during wound healing. The molecular profile of activated stem/eTA cells remains unclear because of difficulties in obtaining discrete cell populations for analyses. Single cell RNA sequencing (scRNA-seq) technology can profile the transcriptome at a single cell level, providing information on how stem/eTA cell activation is regulated. Using this technology, we report that ACE2, a key component in the renin-angiotensin system (RAS), functions as a negative regulator of stem/eTA activation. Methods: Mouse corneal epithelium was exposed to 1M NaOH for 30s or mechanically removed with a diamond burr. Corneas were processed for scRNA-seq and data was analyzed using R with a Seurat package. Limbal epithelial cell proliferation was assessed using BrdU incorporation. RT-qPCR, western blotting and immunostaining were conducted to determine the change of gene expression. Results: ACE2 was predominantly expressed in the stem cell-enriched limbal basal epithelium. scRNA-seq combined with GO analysis suggested that ACE2 was involved in limbal stem/eTA cell proliferation. Interestingly, immunostaining and RT-qPCR indicated that ACE2 expression was reduced following corneal injuries. Reduction in ACE2 promoted proliferation in human limbal epithelial cell culture as well as in mouse limbal epithelium after corneal epithelial debridement. Significantly, the negative effect of ACE2 on proliferation was not reversed following treatment with the angiotensin II receptor blocker losartan, indicating that the function of ACE2 in limbal epithelium is independent of RAS. scRNA-seq also revealed that reduction of ACE2 caused activation of the TGFA/EGFR pathway, which reduced expression of Lcn2. Lcn2 is a negative regulator of proliferation in a variety of cells. Inhibition of EGFR or overexpression of Lcn2 reversed the increased proliferation in limbal epithelial cells lacking ACE2. Conclusion: Our findings strongly support the idea that in response to corneal injury, ACE2 is downregulated, which results in the activation of stem/eTA cell proliferation via a novel TGFA/EGFR/Lcn2 signaling pathway in an angiotensin-independent way.

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Decipering the molecular mechanism of ACE2 regulating A549 cells

Publications

Decipering the Molecular Mechanism of ACE2 Regulating A549 Cells.

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