SNORA70E promotes the occurrence and development of ovarian cancer through pseudouridylation modification of RAP1B and alternative splicing of PARPBP

Abstract

The present study demonstrated for the first time that SNORA70E, which belongs to box H/ACA small nucleolar noncoding RNAs (snoRNAs) who could bind and induce pseudouridylation of RNAs, was significantly elevated in ovarian cancer tissues and was an unfavourable prognostic factor of ovarian cancer. The over‐expression of SNORA70E showed increased cell proliferation, invasion and migration in vitro and induced tumour growth in vivo. Further research found that SNORA70E regulates RAS‐Related Protein 1B ( RAP1B ) mRNA through pseudouracil modification by combing with the pyrimidine synthase Dyskerin Pseudouridine Synthase 1 (DKC1) and increase RAP1B protein level. What's more, the silencing of DKC1 / RAP1B in SNORA70E overexpression cells both inhibited cell proliferation, migration and invasion through reducing β‐catenin, PI3K, AKT1, mTOR, and MMP9 protein levels. Besides, RNA‐Seq results revealed that SNORA70E regulates the alternative splicing of PARP‐1 binding protein ( PARPBP ), leading to the 4th exon‐skipping in PARPBP‐88 , forming a new transcript PARPBP‐15 , which promoted cell invasion, migration and proliferation. Finally, ASO‐mediated silencing of SNORA70E could inhibit ovarian cancer cell proliferation, invasion, migration ability in vitro and inhibit tumorigenicity in vivo. In conclusion, SNORA70E promotes the occurrence and development of ovarian cancer through pseudouridylation modification of RAP1B and alternative splicing of PARPBP . Our results demonstrated that SNORA70E may be a new diagnostic and therapeutic target for ovarian cancer.

RNA methylation‐related inhibitors: Biological basis and therapeutic potential for cancer therapy

“…It was also shown that DKC1 was able to further promote NB cell survival by increasing SNORA50C expression 100 . In addition, SNORA70E binds DKC1 to regulate Ras‐associated protein 1B (RAP1B) mRNA and increase RAP1B protein level through pseudouridine modification, thereby promoting cancer cell progression in ovarian cancer 101 …”

“… 100 In addition, SNORA70E binds DKC1 to regulate Ras‐associated protein 1B (RAP1B) mRNA and increase RAP1B protein level through pseudouridine modification, thereby promoting cancer cell progression in ovarian cancer. 101 …”

MiRNAs and snoRNAs in Bone Metastasis: Functional Roles and Clinical Potential

“…However, most of the in vitro studies were performed using primary tumours with a bone tropism, suggesting a role of snoRNAs in metastatic progression in bone. Indeed, experimental modulation of snoRNAs has been shown to regulate migration/invasion in different cancer cell lines derived from prostate (SNORA42, SNORA55) [88,89], breast (SNORA7B, SNORA71A, SNORD50A/B) [90][91][92], lung (SNORA42, SNORA47, SNORA71A, SNORD38, SNORD78) [86,[93][94][95][96], and ovarian cancer (SNORA70E, SNORA72, SNORD89) [97][98][99]. In addition, some of these snoRNAs have also been shown to modulate stemness capabilities in these different cancer types having a bone metastatic tropism (SNORD78, SNORA42, SNORD89, SNORA72, SNORA71A).…”

“…Although these signalling pathways are regulated in response to snoRNA modulation, molecular mechanisms behind them remain poorly described and mostly rely on non-canonical activities of snoR-NAs. Another study reported SNORA70E as a promoter of cell migration/invasion by modulating the alternative splicing of PARPBP [97]. As stemness is a key feature in the metastatic progression, it is particularly interesting that a study identified a signature of 22 snoRNAs associated with an elevated activity of the aldehyde dehydrogenase (ALDH) enzyme, a marker of stemness, in tumour-initiating cells from non-small cell lung carcinomas [44,93], suggesting that these snoRNAs are good candidates to be investigated at a functional level.…”

Fibrillin-1 mutation contributes to Marfan syndrome by inhibiting Cav1.2-mediated cell proliferation in vascular smooth muscle cells

“…After growth factor stimulation, c-Fos transcriptional activity occurs within minutes and precedes that of other IEGs [ 19 ]. Additionally, Cav1.2 is associated with the proliferation of bladder SMCs, osteoblasts, and glial cells [ 18 , 20 , 21 ]. The proliferation of HASMCs is beneficial to the stability of vascular function.…”