circ‑LRP6 contributes to osteosarcoma progression by regulating the miR‑141‑3p/HDAC4/HMGB1 axis

Abstract

Circular RNA-lipoprotein receptor 6 (circ-LRP6) serves a role in promoting the tumorigenesis of retinoblastoma, esophageal squamous cell cancer and oral squamous cell carcinoma; however, whether circ-LRP6 demonstrates the same effect in osteosarcoma (OS) is yet to be fully elucidated.The present study aimed to analyze the expression, role and potential molecular mechanism of circ-LRP6 in OS. The expression levels of circ-LRP6, microRNA (miR)-141-3p, histone deacetylase 4 (HDAC4) and high mobility group protein 1 (HMGB1) were evaluated by reverse transcriptionquantitative PCR in OS tissues and cell lines. Cell Counting Kit-8, Transwell and Matrigel assays were conducted to evaluate cell proliferation, migration and invasion, respectively. Western blotting was also performed to determine HDAC4 and HMGB1 protein expression levels. Bioinformatics and dual-luciferase reporter assays were used to predict and analyze the interactions between circ-LRP6 and miR-141-3p, miR-141-3p and HDAC4, as well as between miR-141-3p and HMGB1. Additionally, RNA immunoprecipitation was performed to verify the association between circ-LRP6 and miR-141-3p. The results confirmed that circ-LRP6 was highly expressed in OS tissues and cell lines. In addition, circ-LRP6 negatively regulated the expression of miR-141-3p and, in turn, miR-141-3p negatively regulated HDAC4 and HMGB1 expression. Functional assays revealed that circ-LRP6 knockdown inhibited the proliferation, migration and invasion of OS cells, whereas the inhibition of miR-141-3p or the overexpression of either HDAC4 or HMGB1 partly reversed the inhibitory effect of circ-LRP6 knockdown. In summary, the present study determined that circ-LRP6 knockdown inhibited the proliferation, migration and invasion of OS cells by regulating the miR-141-3p/HDAC4/HMGB1 axis.

HDAC4 in cancer: A multitasking platform to drive not only epigenetic modifications

“…circ-LRP6 is highly expressed in osteosarcoma (OS) tissues and cell lines and its expression correlates with cell proliferation and a lower overall survival in OS metastatic patients. On the contrary high levels of its target miR-141-3p, correlate with higher overall survival ( Yu et al, 2022 ).…”

Circ_001422 aggravates osteosarcoma progression through targeting miR-497-5p/E2F3 axis

“…MiR-497-5p serves as circ_001422's target circRNAs often play a role of miRNA sponges for regulating the expression of miRNAs, thereby participating in cellular functions [13,14] . The StarBase database estimated miR-497-5p containing circ_001422 binding sites (Figure 2A).…”

“…As an important participant in the ceRNA network, circRNAs can adsorb miRNAs through sponges, thereby affecting the latter downstream target gene levels, resulting in changes in cell phenotypes [12][13][14] . Here, we have demonstrated miR-497-5p as circ_001422's target, while E2F3 as miR-497-5p's target.…”

“…To take an example, circ_0008259 can suppress OS occurrence and development via the miR-21-5p/PDCD4 axis [12] . Circ-LRP6 expression increases in OS cells as well as tissues, whereas its down-regulation can inhibit the OS cell growth, migration and invasion by miR-141-3p/HDAC4/HMGB1 axis [13] . Circ_001422, the newly reported circRNA, has been reported to promote OS tumorigenesis [14] .…”

Circ_001422 aggravates osteosarcoma progression through targeting miR‐497‐5p/E2F3 axis

“…[ 12 ] Circ‐LRP6 expression increases in OS cells as well as tissues, whereas its downregulation can inhibit the OS cell growth, migration and invasion by miR‐141‐3p/HDAC4/HMGB1 axis. [ 13 ] Circ_001422, the newly reported circRNA, has been reported to promote OS tumorigenesis. [ 14 ] However, the mechanism of the involvement of circ_001422 in OS is not completely clear at present.…”