MiRNA pattern in hypoxic microenvironment of kidney cancer – role of PTEN
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ABSTRACT:
PROVIDER: PRJNA809699 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18115263.fastq.gz | Fastqsanger.gz | |||
| SRR18115264.fastq.gz | Fastqsanger.gz | |||
| SRR18115265.fastq.gz | Fastqsanger.gz | |||
| SRR18115266.fastq.gz | Fastqsanger.gz | |||
| SRR18115267.fastq.gz | Fastqsanger.gz |
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Project description:MicroRNAs are post-transcriptional regulators of gene expression, and disturbances of their expression are the basis of many pathological states, including cancers. The miRNA pattern in the context of tumor microenvironment explains mechanisms related to cancer progression and provides a potential target of modern therapies. Here we show the miRNA pattern in renal cancer focusing on hypoxia as a characteristic feature of the tumor microenvironment and dysregulation of PTEN, being a major tumor suppressor. Methods comprised the CRSPR/Cas9 mediated PTEN knockout in the Renca kidney cancer cell line and global miRNA expression analysis in both in vivo and in vitro (in normoxic and hypoxic conditions). The results were validated on human cancer models with distinct PTEN status. The increase in miR-210-3p in hypoxia was universal; however, the hypoxia-induced decrease in PTEN was associated with an increase in miR-221-3p, the loss of PTEN affected the response to hypoxia differently by decreasing miR-10b-5p and increasing miR-206-3p. In turn, the complete loss of PTEN induces miR-155-5p, miR-100-5p. Upregulation of miR-342-3p in knockout PTEN occurred in the context of the whole tumor microenvironment. Thus, effective identification of miRNA patterns in cancers must consider the specificity of the tumor microenvironment together with the mutations of key suppressors.
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Project description:As a simple lipid mediator, Lysophosphatidic acid (LPA) exerts its function by binding to 6 GPCRs (LPAR1-6) on the cell membrane. Among the 6 LPA receptors, LPAR3 is highly expressed in mouse kidney, where it has only been found to play a harmful role in kidney ischemia-reperfusion injury and diabetic nephropathy. Our previous research and other researchers found the correlation between the ATX-LPA-LPAR axis and hypoxia-related biological processes. The kidney is one of the most susceptible organs to hypoxia. It is therefore interesting to identify the function of LPAR3 in hypoxic mice kidneys. In this study, the wild-type (WT) and Lpar3-/- mice were put into a normobaric hypoxic installation and RNA sequencing analysis showed that Lpar3-/- mice showed a significant decrease in hypoxia-induced EPO expression in the kidney compared with WT mice. The impaired EPO gene expression resulted in reduced plasma EPO levels and lower hematocrit and hemoglobin levels. The KEGG enrichment analysis revealed the reduced accumulation of HIF-2α caused by LPAR3 deficiency may be the reason for insufficient hypoxic renal EPO production. In in-vitro hypoxic cell models (Hep3B cells and HK2 cells), targeting LPAR3 can also regulate HIF-2α and EPO expression. KEGG analysis revealed that the PI3K/Akt signaling pathway was involved in the regulation of LPAR3 on HIF-2α-EPO, which was validated at the tissue level and cell level. Taken together, this study demonstrates that the murine renal LPAR3 promotes HIF-2α accumulation to maintain renal EPO production by activating the downstream PI3K/Akt pathway, ensuring the generation of red blood cells in mice and plays an important role in the body's adaptation to hypoxia.
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