Exosomal miR-30a and miR-222 derived from colon cancer mesenchymal stem cells promote the tumorigenicity of colon cancer through targeting MIA3

Qiong Du; Xuan Ye; Sheng-Rong Lu; Huan Li; Hong-Yue Liu; Qing Zhai; Bo Yu

doi:10.21037/jgo-20-513

Exosomal miR-30a and miR-222 derived from colon cancer mesenchymal stem cells promote the tumorigenicity of colon cancer through targeting MIA3

J Gastrointest Oncol. 2021 Feb;12(1):52-68. doi: 10.21037/jgo-20-513.

Authors

Qiong Du^{1

2}, Xuan Ye^{1

2}, Sheng-Rong Lu³, Huan Li^{1

2}, Hong-Yue Liu^{1

2}, Qing Zhai^{2

3

4}, Bo Yu⁴

Affiliations

¹ Department of Pharmacy, Fudan University Shanghai Cancer Center, Shanghai, China.
² Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
³ Department of Pharmacy, The Central Hospital of Min-Hang District, Shanghai, China.
⁴ Department of Pharmacy, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Abstract

Background: Multipotent mesenchymal stem cells (MSCs) derived from virus tumors have been reported to contribute to malignant cell growth, invasion, and metastasis. However, the mechanism of communication between MSCs and colon cancer cells is poorly understood. Recent studies have suggested that exosomes are an important player in crosstalk between cells and could significantly suppress the invasion ability of human cancer cells (hCCs) when transfected with a microRNA inhibitor. However, to date, no study has illuminated the miRNA changes in exosomes derived from hCC-MSCs.

Methods: Colon cancer stem cells were cultured in medium and passaged to develop fibroblast-like morphology. Exosomes were collected using ExoQuick precipitation and exosome morphology was visualized by transmission electron microscopy. Small RNA sequencing was analyzed using an Illumina HiSeq4000 analyzer, and the expression of MIA3 was assessed by real-time PCR and Western blot. The functional roles of miR-30a and miR-222 in colon cancer cells were evaluated through cell and animal experiments.

Results: Our results showed that the characteristics of MSC-like cells (hCC-MSCs) derived from human colon cancer stem cells were comparable to those of bone marrow-derived MSCs, including surface antigens and the ability to multi-differentiate to osteocytes and adipocytes. Furthermore, we screened the microRNA (miRNA) profiles of exosomes derived from hCC-MSCs and the corresponding parent hCC-MSCs. We found a significant enrichment in the miR-30a and miR-222 level in hCC-MSC-derived exosomes. Furthermore, in vitro and in vivo experiments demonstrated that miR-30a and miR-222 bound to their shared downstream target, MIA3, to promote the ability of colon cells to proliferate, migrate, and metastasize, thus evidencing their functional roles as oncogenic miRNAs.

Conclusions: These data suggest that hCC-MSC-secreted exosomes promote colon cancer cell proliferation and metastasis through delivering miR-30a and miR-222. Subsequently, exosomal miR-30a and miR-222 simultaneously target MIA3, suppress its expression, and promote colon cell proliferation, migration, and metastasis.

Keywords: Colon cancer; MIA3; exosomes; miR-222; miR-30a; multipotent mesenchymal stem cells (MSCs); tumorigenesis.