Circular RNAs are a new class of non-coding RNAs that have been shown to play critical roles in the development and progression of
renal cell carcinoma (RCC). However, little is known about the functional mechanisms and therapeutic role of ciRS-7 in RCC. A series of in vitro and in vivo experiments were performed to investigate the functional mechanism and therapeutic role of ciRS-7, such as real-time quantitative PCR,
CCK-8, wound healing, transwell, colony formation, Edu,
tumor xenograft and lung
metastasis in NSG mice.
RNA pull-down, dual
luciferase reporter, fluorescence in situ hybridization (FISH) and rescue assays were used to determine the relationship between ciRS-7, miR-139-3p and TAGLN. In addition, we constructed PBAE/si-ciRS-7 nanocomplexes with PBAE material to evaluate the
therapeutic effect of the nanocomplexes on
tumor in vivo. ciRS-7 was highly expressed in RCC
tumor tissues and cell lines, and high ciRS-7 expression correlated with
tumor size, high Fuhrman grade and poor survival. Depletion of ciRS-7 significantly inhibited RCC cell proliferation, invasion,
tumor growth and
metastasis in vivo, while overexpression of ciRS-7 had the opposite effect. Mechanistically, ciRS-7 acts as a "
ceRNA" for miR-139-3p to prevent TAGLN degradation and promoting RCC progression and
metastasis via the PI3K/AKT signaling pathway. In addition, miR-139-3p mimics or inhibitor could reverse the altered malignant
tumor behavior caused by ciRS-7 overexpression or silencing. Furthermore, the PBAE/siciRS-7 nanocomplexes could significantly inhibit RCC
tumor progression and
metastasis in vivo. ciRS-7 acts as a
tumor promoter by regulating the miR-139-3p/TAGLN axis and activating the PI3K/AKT signaling pathway to promote RCC progression and
metastasis.
Drug development of PBAE/si-ciRS-7 nanocomplexes targeting ciRS-7 may represent a promising gene therapeutic strategy for RCC.