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Article

Exosomal Carboxypeptidase E (CPE) and CPE-shRNA-Loaded Exosomes Regulate Metastatic Phenotype of Tumor Cells

1
Section on Cellular Neurobiology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA
2
Biostatistics & Bioinformatics Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA
3
Maine Medical Center BioBank, Portland, ME 04074, USA
4
Department of Neurosurgery, University of Minnesota Medical School, Minneapolis, MN 55455, USA
*
Author to whom correspondence should be addressed.
Academic Editors: Bozena Smolkova, Julie Earl and Agapi Kataki
Int. J. Mol. Sci. 2022, 23(6), 3113; https://doi.org/10.3390/ijms23063113
Received: 10 February 2022 / Revised: 5 March 2022 / Accepted: 8 March 2022 / Published: 14 March 2022
Background: Exosomes promote tumor growth and metastasis through intercellular communication, although the mechanism remains elusive. Carboxypeptidase E (CPE) supports the progression of different cancers, including hepatocellular carcinoma (HCC). Here, we investigated whether CPE is the bioactive cargo within exosomes, and whether it contributes to tumorigenesis, using HCC cell lines as a cancer model. Methods: Exosomes were isolated from supernatant media of cancer cells, or human sera. mRNA and protein expression were analyzed using PCR and Western blot. Low-metastatic HCC97L cells were incubated with exosomes derived from high-metastatic HCC97H cells. In other experiments, HCC97H cells were incubated with CPE-shRNA-loaded exosomes. Cell proliferation and invasion were assessed using MTT, colony formation, and matrigel invasion assays. Results: Exosomes released from cancer cells contain CPE mRNA and protein. CPE mRNA levels are enriched in exosomes secreted from high- versus low-metastastic cells, across various cancer types. In a pilot study, significantly higher CPE copy numbers were found in serum exosomes from cancer patients compared to healthy subjects. HCC97L cells, treated with exosomes derived from HCC97H cells, displayed enhanced proliferation and invasion; however, exosomes from HCC97H cells pre-treated with CPE-shRNA failed to promote proliferation. When HEK293T exosomes loaded with CPE-shRNA were incubated with HCC97H cells, the expression of CPE, Cyclin D1, a cell-cycle regulatory protein and c-myc, a proto-oncogene, were suppressed, resulting in the diminished proliferation of HCC97H cells. Conclusions: We identified CPE as an exosomal bioactive molecule driving the growth and invasion of low-metastatic HCC cells. CPE-shRNA loaded exosomes can inhibit malignant tumor cell proliferation via Cyclin D1 and c-MYC suppression. Thus, CPE is a key player in the exosome transmission of tumorigenesis, and the exosome-based delivery of CPE-shRNA offers a potential treatment for tumor progression. Notably, measuring CPE transcript levels in serum exosomes from cancer patients could have potential liquid biopsy applications. View Full-Text
Keywords: cancer proliferation; hepatocellular carcinoma; metastasis; engineered exosomes; diagnostic biomarker; cancer therapy cancer proliferation; hepatocellular carcinoma; metastasis; engineered exosomes; diagnostic biomarker; cancer therapy
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MDPI and ACS Style

Hareendran, S.; Albraidy, B.; Yang, X.; Liu, A.; Breggia, A.; Chen, C.C.; Loh, Y.P. Exosomal Carboxypeptidase E (CPE) and CPE-shRNA-Loaded Exosomes Regulate Metastatic Phenotype of Tumor Cells. Int. J. Mol. Sci. 2022, 23, 3113. https://doi.org/10.3390/ijms23063113

AMA Style

Hareendran S, Albraidy B, Yang X, Liu A, Breggia A, Chen CC, Loh YP. Exosomal Carboxypeptidase E (CPE) and CPE-shRNA-Loaded Exosomes Regulate Metastatic Phenotype of Tumor Cells. International Journal of Molecular Sciences. 2022; 23(6):3113. https://doi.org/10.3390/ijms23063113

Chicago/Turabian Style

Hareendran, Sangeetha, Bassam Albraidy, Xuyu Yang, Aiyi Liu, Anne Breggia, Clark C. Chen, and Y. Peng Loh. 2022. "Exosomal Carboxypeptidase E (CPE) and CPE-shRNA-Loaded Exosomes Regulate Metastatic Phenotype of Tumor Cells" International Journal of Molecular Sciences 23, no. 6: 3113. https://doi.org/10.3390/ijms23063113

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