Cancer-secreted exosomal miR-21-5p induces angiogenesis and vascular permeability by targeting KRIT1

Abstract

Cancer-secreted exosomes are critical mediators of cancer-host crosstalk. In the present study, we showed the delivery of miR-21-5p from colorectal cancer (CRC) cells to endothelial cells via exosomes increased the amount of miR-21-5p in recipient cells. MiR-21-5p suppressed Krev interaction trapped protein 1 (KRIT1) in recipient HUVECs and subsequently activated β-catenin signaling pathway and increased their downstream targets VEGFa and Ccnd1, which consequently promoted angiogenesis and vascular permeability in CRC. A strong inverse correlation between miR-21-5p and KRIT1 expression levels was observed in CRC-adjacent vessels. Furthermore, miR-21-5p expression in circulating exosomes was markedly higher in CRC patients than in healthy donors. Thus, our data suggest that exosomal miR-21-5p is involved in angiogenesis and vascular permeability in CRC and may be used as a potential new therapeutic target.

Tumor-Derived Extracellular Vesicles Regulate Cancer Progression in the Tumor Microenvironment

“…Tumor-derived EVs are thought to regulate protumoral functions of endothelial cells in numerous types of cancers including hepatocellular carcinoma (HCC) ( Lin et al, 2018 ), colorectal cancer ( Huang and Feng, 2017 ; Zeng et al, 2018 ; He et al, 2021 ), cervical cancer ( Wu et al, 2019 ), nasopharyngeal carcinoma ( Bao et al, 2018 ; Tian et al, 2021 ; Zhang K. et al, 2021 ), glioma ( Ma et al, 2017 ; Wang Z.-F. et al, 2019 ), and lung cancer ( Hsu et al, 2017 ). As EVs can be internalized by an endocytic-like process, they may deliver regulatory biomolecules into vascular endothelial cells.…”

“…After taking up by human umbilical vein endothelial cells (HUVECs), miR-210 stimulates angiogenesis via down-regulating the expression of SMAD4 and STAT6 ( Lin et al, 2018 ). Vesicular miR-21-5p from colorectal cancer decreases Krev interaction trapped protein 1 expression to activate β-catenin signaling pathway and promote the expression of angiogenesis-related factors like VEGFA, thereby stimulating vascular permeability and angiogenesis ( He et al, 2021 ). In addition, cervical cancer-derived vesicular miR-221-3P promotes angiogenesis by inhibiting the expression of thrombospondin-2 in HUVECs, which consequently enhances tumor growth in vivo ( Wu et al, 2019 ).…”

“… Ning et al (2021) believe that the elevated miR-208b expression level is associated with oxaliplatin resistance in colorectal cancer patients. In addition, the expression level of vesicular miR-21-5p decreases in colorectal cancer patients after surgical resection ( He et al, 2021 ). Recent studies have found that tumor-derived EVs may be a potential biomarker for cancer prognosis ( Table 3 ).…”

Aberrantly reduced expression of miR-342-5p contributes to CCND1-associated chronic myeloid leukemia progression and imatinib resistance

“…Given that both K562 and MEG01 are TP53-deficient CML cell lines, inhibition of CCND1 expression by miR-342-5p did lead to ATR-chk1 inhibition with ATM-chk2 activation and subsequent cell apoptosis (Fig. 5D-F ) [ 69 , 70 ]. We suggest that miR-342-5p expression directly or indirectly inhibits CCND1 and BCR-ABL expression, thereby possibly increasing ATM activation by dispersing BCR-ABL-associated ATM repression and reducing CCND1-ATR-Chk1-induced protection, as a result of ATM/ATR switching.…”

The Role of Exosomal Non-Coding RNAs in Colorectal Cancer Drug Resistance

“…Several miRNA-enriched exosomes promote angiogenesis via HIF-1 downregulation and overexpression of proangiogenic factors [47]. Recently, He et al suggested that ex-miR-21-5p is involved in angiogenesis and vascular permeability in CRC, by targeting trapped protein 1 (KRIT1) [48]. Notably, Simon et al have reported a potential EV-mediated mechanism for bevacizumab resistance in glioblastoma.…”