circLARP4 induces cellular senescence through regulating miR‐761/RUNX3/p53/p21 signaling in hepatocellular carcinoma

Abstract

Circular RNAs (circRNAs), a novel class of non‐coding RNAs, have emerged as indispensable modulators in human malignancies. Aberrant cellular senescence is a phenotype observed in various cancers. The association of circRNAs with cellular senescence in tumors is yet to determined. Here, we investigated the role of circLARP4 in cellular senescence and cell proliferation in hepatocellular carcinoma (HCC). Downregulated circLARP4 level was observed in HCC tissues and cell lines. Low expression level of circLARP4 independently predicted poor survival outcome. Gain‐of‐function and loss‐of‐function assays demonstrated that circLARP4 suppressed HCC cell proliferation, mediated cell cycle arrest and induced senescence in vitro. Levels of p53 and p21, 2 key regulatory molecules in cellular senescence, were increased in circLARP4‐overexpressed HCC cells and decreased in circLARP4‐silenced HCC cells. In vivo experiments further confirmed the tumor‐suppressing activity of circLARP4. Further mechanistic studies showed that circLARP4 dampened HCC progression by sponging miR‐761, thereby promoting the expression level of RUNX3 and activating the downstream p53/p21 signaling. Our study revealed the role of circLARP4/miR‐761/RUNX3/p53/p21 signaling in HCC progression, providing a potential survival predictor and therapeutic candidate for HCC.

The long noncoding RNA Arrl1 inhibits neurite outgrowth by functioning as a competing endogenous RNA during neuronal regeneration in rats

“…MiR-761 was firstly reported in the regulation of mitochondrial network via affecting the mitochondrial fission factor (39). Previous researches have illustrated that miR-761 is involved in tumorigenesis (40) and synaptic plasticity in hippocampal neurons (41). However, the role of miR-761 in axon regeneration is still unknown.…”

<p>CircLARP4 Suppresses Cell Proliferation, Invasion and Glycolysis and Promotes Apoptosis in Non-Small Cell Lung Cancer by Targeting miR-135b</p>

“…17 CircLARP4, a circRNA deriving from LARP4 gene locus, has been revealed to be downregulated and serve as a potential biomarker in ovarian cancer prognosis, 18 gastric cancer, 10 and hepatocellular carcinoma. 19 Moreover, the tumor-suppressive roles of circLARP4 in gastric cancer 10 and hepatocellular carcinoma 19 have been also well documented. However, the expression and functional roles of circLARP4 in NSCLC have not yet been elucidated.…”

Circular RNA LARP4 correlates with decreased Enneking stage, better histological response, and prolonged survival profiles, and it elevates chemosensitivity to cisplatin and doxorubicin via sponging microRNA‐424 in osteosarcoma

“…A previous study shows that circ‐LAPR4 suppresses cancer cell proliferation and invasion via sponging miR‐424‐5p and mediating the expression of the larger tumor suppressor kinase 1 (LATS1) in gastric cancer . Another study elucidates that circ‐LARP4 activates cancer cell senescence through modulating miR‐761/RUNX3/p53/p21 signaling pathway in hepatocellular carcinoma . And the LARP4 gene, the location of circ‐LARP4, has also been found to be a tumor suppressor, for example, a recent experiment elucidates that LARP4 gene represses cell motility and migration in ovarian cells .…”

“…12 Another study elucidates that circ-LARP4 activates cancer cell senescence through modulating miR-761/RUNX3/p53/p21 signaling pathway in hepatocellular carcinoma. 23 And the LARP4 gene, the location of circ-LARP4, has also been found to be a tumor suppressor, for example, a recent experiment elucidates that LARP4 gene represses cell motility and migration in ovarian cells. 11 Another experiment illuminates that LARP4 inhibits prostate cancer cell migration and invasion.…”