Hox transcript antisense RNA knockdown inhibits osteosarcoma progression by regulating the phosphoinositide 3-kinase/AKT pathway through the microRNA miR-6888-3p/spleen tyrosine kinase axis

Abstract

Long non-coding RNA HOX transcript antisense RNA (lncRNA HOTAIR) is thought to be a key regulator of the occurrence and development of osteosarcoma (OS). The expression of HOTAIR, microRNA miR-6888-3p, spleen tyrosine kinase (SYK), and phosphoinositide 3-kinase/AKT (PI3K/AKT) pathway-related proteins in OS was detected by quantitative reverse transcription-PCR (qRT-PCR) and western blotting. Changes in the proliferation and migration of OS cells were detected by Cell Counting Kit-8 (CCK-8) and transwell assays after the knockdown of HOTAIR, miR-6888-3p, or SYK. Luciferase assays, RNA immunoprecipitation (RIP), and RNA pull-down assays were used to detect the relationship between miR-6888-3p and HOTAIR or SYK. We found that HOTAIR and SYK were highly expressed in OS, whereas miR-6888-3p expression was low. In addition, downregulation of HOTAIR or SYK significantly inhibited the growth and migration of OS cells and the PI3K/AKT pathway, both in vitro and in vivo . Additionally, downregulation of miR-6888-3p promoted the proliferation and migration of OS cells and activated the PI3K/AKT pathway. Mechanistically, these results suggest that the HOTAIR sponge, miR-6888-3p, regulates SYK expression. To summarize, HOTAIR regulates SYK by acting on miR-6888-3p, thereby promoting the proliferation and migration of OS cells.

Knowledge atlas and emerging trends on ncRNAs of osteosarcoma: A bibliometric analysis

“…In terms of MALAT1, a study suggested that high MALAT1 expression is also associated with advanced clinicopathological features as well as poor prognosis in osteosarcoma ( 54 ), which might emerge as potential therapeutic targets in the treatment of patients with osteosarcoma. Most long non-coding RNAs could play regulatory roles in various biological processes of osteosarcoma cells through some miRNA-related axes, such as lncRNA HOTAIR ( 55 ) and lncRNA HCP5 ( 56 ). Evolutionary trends of the keywords in ncRNAs of osteosarcoma indicated that non-coding RNAs were characterized by the lack of ability to encode proteins; however, they gradually attracted great attention and became the latest research hotspots in recent years.…”

Functional role of MicroRNA/PI3K/AKT axis in osteosarcoma

“…It was found that by overexpressing miR-101 and miR-139 ( Figure 6D ) can downregulate rock1 while causing PI3K/AKT and JAK/STAT signaling pathway inactivation, ultimately leading to the malignant behavior of osteosarcoma cells can be partially suppressed, including biological behaviors such as abnormal proliferation, migration and invasion ( 191 , 197 ). MiR-340-5p ( 165 ), miR-506-3p ( 159 ), miR-615 ( 59 ), miR-18a ( 192 ), miR-122-5p ( 193 ), miR-451a ( 26 ), miR-449a ( 172 ), miR-142 ( 199 ), miR-499a-5p ( 175 ), miR-6888-3p ( 202 ), miR-384 ( 203 ), and miR-223 ( 205 ), miR-29c-3p ( 178 ), miR-152 ( 207 ), miR-149-5p ( 180 ), miR-652 ( 212 ), miR-1224-5p ( 213 ), miR-146b-5p ( 204 ), miR-141-3p ( 209 ), miR-141 [198], miR-29b ( 187 ), and miR-223 ( 188 ) are all lowly expressed in osteosarcoma cells as tumor suppressors, and they can act directly on NRF2, RAB3D, HK2, MED27, TP53, YTHDC1, EZH2, CDK6, PPM1D, SYK, SLBP, Hsp90B1, TPX2, c-MET, Fn14, HOXA9, PLK1, PDK1, SIX1, AUF1, Spin 1, Ect2 and thus inhibit the PI3K/AKT pathway, which ultimately leads to the impact of osteosarcoma cells in proliferation, migration, invasion, apoptosis, autophagy, cell cycle, cell growth, etc., and inhibits the development of osteosarcoma and progression of osteosarcoma. In addition, miR-206 can also act on both PAX3 and MET target genes to achieve the inhibition of PI3K/AKT pathway through two pathways, so the inhibitory effect of miR-206 on osteosarcoma may be more obvious ( Figure 6E ) ( 189 ).…”