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Exosomal miRNA-166-5p derived from G-MDSCs promotes proliferation by targeting ITM3E in colorectal cancer
Tao Ma1, Jinling Jiang2, Min Shi2
1Department of Radiation Oncology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Background:
The immune milieu of colorectal cancer is a complex phenomenon. It is imperative to investigate the crucial immune factors that promote the progression of colorectal cancer. Immune suppressor cells are granulocytic myeloid-derived suppressor cells (G-MDSCs). However, they also increased cancer growth in other ways that need to be investigated further.
Methods:
Using flow cytometry, we isolated G-MDSCs from colorectal cancer tissues. Ultracentrifugation was used to separate exosomes from the supernatant of G-MDSCs, and western blotting, transmission electron microscopy (TEM), and flow cytometry were used to confirm their presence. RNA sequencing was used to identify unique miRNAs and transcripts, which were subsequently confirmed by RT-qPCR (real-time quantitative real-time PCR). The CCK-8 test was used to determine the rate of proliferation. Lentiviral vectors were employed to manipulate the expression of miRNAs and genes in order to investigate their role in the development of colorectal cancer.
Results:
Colorectal cancer tissues have been found to contain granulocyte-myeloid-derived suppressor cells (G-MDSCs) that secrete exosomes. These exosomes have been shown to accelerate cancer progression by promoting cell proliferation. Further research has identified microRNA-166-5p as a target from G-MDSC-derived exosomes. This downregulation leads to the inhibition of integral membrane protein 2B (ITM3E) transcription, which in turn activates the PI3K/Akt signaling pathway. This pathway promotes cell proliferation and can be inhibited using deguelin. The accelerated development of colorectal cancer has been further confirmed in mice models.
Conclusion:
The primary results of this work show that exosomes produced from G-MDSCs and the miR-166-5p/ITM3E axis have therapeutic and diagnostic promise in colorectal cancer.
Insights
Granulocytic myeloid-derived suppressor cells (G-MDSCs) in colorectal cancer secrete exosomes that promote tumor growth. Targeting the miR-166-5p/ITM3E pathway offers new therapeutic strategies for colorectal cancer.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Colorectal cancer (CRC) progression is influenced by its complex immune microenvironment.
- Granulocytic myeloid-derived suppressor cells (G-MDSCs) are key immune suppressors implicated in CRC growth.
- The precise mechanisms by which G-MDSCs enhance CRC progression require further elucidation.
Purpose of the Study:
- To investigate the role of G-MDSC-derived exosomes in colorectal cancer progression.
- To identify specific molecular targets within G-MDSC exosomes that influence cancer growth.
- To explore potential therapeutic strategies targeting the identified molecular axis.
Main Methods:
- Isolation of G-MDSCs from colorectal cancer tissues using flow cytometry.
- Characterization of exosomes derived from G-MDSCs via ultracentrifugation, western blotting, TEM, and flow cytometry.
- RNA sequencing and RT-qPCR to identify and validate microRNAs (miRNAs) and transcripts, including miR-166-5p and ITM3E; functional studies using CCK-8 assays and lentiviral vectors; in vivo validation in mouse models.
Main Results:
- G-MDSC-derived exosomes were identified in colorectal cancer tissues and shown to accelerate cancer progression by promoting cell proliferation.
- MicroRNA-166-5p was identified as a key miRNA downregulated in these exosomes, leading to increased ITM3E transcription.
- Activation of the PI3K/Akt signaling pathway by this mechanism promotes cell proliferation, a process inhibitable by deguelin; accelerated CRC development was confirmed in mouse models.
Conclusions:
- G-MDSC-derived exosomes play a significant role in promoting colorectal cancer progression.
- The miR-166-5p/ITM3E axis represents a critical pathway mediating the pro-tumorigenic effects of G-MDSC exosomes.
- This axis holds promise as a potential therapeutic and diagnostic target for colorectal cancer.
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