Notably, patients with advanced clinical TNM stage (n=16) or distal metastasis (n=5) demonstrated higher miR-21 expression than those without them (n=26, or n=37) (p<0.05, or p<0.001).
In conclusion, miR-21 is a key player in oncogenic EMT, its overexpression is controlled by the cooperation of genetic and epigenetic alterations, and its levels, along with ITGβ4 and PDCD4 expression, could be exploited as a prognostic tool for CRC metastasis.
For the first time, a high expression of miR-21 was associated with lymph node positivity (p = 0.025) and the development of distant metastases (p = 0.009) in CRC patients.
With the tumor, node, and metastasis stage developed (Stage I vs. III and IV, P < 0.05), the serum miR-21 expression level increased, but there was no statistical difference between Stage I patients and hepatolithiasis patients or healthy control (P > 0.05 for both).
Mechanistically, miR-21-5p and miR-155-5p were transferred to colorectal cancer cells by MDE and bound to the BRG1 coding sequence, downregulating expression of BRG1, which has been identified as a key factor promoting the colorectal cancer metastasis, yet is downregulated in metastatic colorectal cancer cells.
Higher levels of serum miR-21 were also correlated with tumors of higher grades, more nodal involvement, distal metastasis and advanced clinical stages (p < 0.01).
Moreover, the expression levels of miR-182, miR-183, miR-141, and miR-21 were demonstrated to be associated with a gradual increase in fold change expression with depth of tumor invasion (all P < .05), lymph node invasion (all P < .001), and maximal increase with distant metastasis (all P < .001).
In addition, miR-21 downregulation induced by MMP-8 increases the levels of tumor suppressors such as programmed cell death 4, which may also contribute to the decrease in tumor formation and metastasis of breast cancer cells overexpressing this metalloproteinase.
Finally, we investigated the regulatory mechanism of XIST acting as a competitive endogenous RNA (ceRNA) of miR-21-5p in OS progression and metastasis. lncRNA XIST was significantly downregulated in osteosarcoma tissues and osteosarcoma cells, and associated with recurrence and short overall survival in OS patients.
The combined data for the prognostic meta-analysis (seven studies) suggested that miR-21 overexpression in HCC correlated with poor overall survival [HR = 1.19 (95%CI = 0.44-1.94)], and higher miR-21 expression was associated with tumor, node, metastases (TNM) stage [OR = 0.34 (95%CI = 0.13-0.91)].
Using a mouse xenograft tumor model, we found that the overexpression of MEG3 suppressed tumor growth and metastasis while overexpression of miR‑21 had the opposite effects.
We firstly showed that increased levels of microRNA-21 expression were shown from dysplastic nevi to primary cutaneous melanomas to melanoma metastases.
Inverse correlation was observed between miR-21 expression and the metastasis suppressor PDCD4, while miR-21 repression increased the release of PDCD4 protein, suggesting negative regulation of PDCD4 by miR-21 in MB cells.
Previous reports showed an over-expression of miRNA-21 (miR-21) in various cancer cells, and its up-regulation is closely related to cancer initiation, proliferation and metastasis.
PTENP1 and PTEN are direct targets of miRNA miR21 and their expression is suppressed by miR21 in ccRCC cell lines. miR21 expression promotes ccRCC cell proliferation, migration, invasion in vitro, and tumor growth and metastasis in vivo.
MiRNA-21 is recognized as the main active candidate and high expression in many solid tumors consequential cell proliferation, differentiation, apoptosis, and closely related to metastasis of disease.