MYBL2-induced PITPNA-AS1 upregulates SIK2 to exert oncogenic function in triple-negative breast cancer through miR-520d-5p and DDX54

Bolong Liu,Feng Xiao,Lianghui Wu,Jianjin Guo,Pingbo Yao,Yong Yang

doi:10.1186/s12967-021-02956-6

Abstract

BackgroundIn recent years, long non-coding RNAs (lncRNAs) have attracted much attention because of its regulatory role in occurrence and progression of tumors, including triple-negative breast cancer (TNBC). LncRNA PITPNA antisense RNA 1 (PITPNA-AS1) has been explored in some cancers, whereas its function and molecular mechanism in TNBC remain unclear.MethodsPITPNA-AS1 expression in TNBC tissues and cells was determined by RT-qPCR. TNBC cell viability, proliferation, migration, invasion were assessed with CCK-8, colony formation, wound healing, transwell assays. Cell apoptosis was evaluated by flow cytometry. Expression of EMT-related markers was detected by western blot analyses. The molecular mechanism of PITPNA-AS1 was explored by RNA pull down, luciferase reporter, RIP and ChIP assays.ResultsPITPNA-AS1 showed high expression levels in TNBC tissues and cells. PITPNA-AS1 knockdown suppressed TNBC cell viability, proliferation, migration, invasion in vitro and inhibited xenograft tumor growth in mice. Mechanistically, PITPNA-AS1 upregulated SIK2 expression by sponging miR-520d-5p and recruiting DDX54 protein. Results of rescue assays suggested that the inhibitive effects of silenced PITPNA-AS1 on TNBC cellular processes were partially rescued by overexpressing SIK2 or combination of miR-520d-5p inhibition and DDX54 overexpression. More importantly, we found that the upregulation of PITPNA-AS1 in TNBC cells was attributed to transcription factor MYBL2.ConclusionPITPNA-AS1 activated by MYBL2 plays an oncogenic role in TNBC through upregulating SIK2.

Highlights

There is a rapid rising trend in the incidence of breast cancer (BC) with more than 1 million new-diagnosedLiu et al J Transl Med (2021) 19:333 significantly higher rates of metastasis and recurrence [4, 5]
Our findings revealed that MYB proto-oncogene Like 2 (MYBL2)-activated PITPNA-AS1 sponged miR-520d-5p and recruited DDX54 protein to increase Salt inducible kinase 2 (SIK2) expression, thereby promoting cellular activities in triple-negative breast cancer (TNBC)
PITPNA‐AS1 was upregulated in TNBC and localized in the cytoplasm First, the expression pattern of PITPNA-AS1 in TNBC was detected by RT-qPCR

Summary

Introduction

There is a rapid rising trend in the incidence of breast cancer (BC) with more than 1 million new-diagnosedLiu et al J Transl Med (2021) 19:333 significantly higher rates of metastasis and recurrence [4, 5]. Long non-coding RNAs (lncRNAs) are generally regarded as genomic transcripts exceeding 200 nucleotides in length [8]. Lacking open reading structure of indispensable length, lncRNAs are limited in protein-coding [9]. It has been highlighted by diverse researches that lncRNAs are associated with molecular mechanisms underlying cancer development and can be used as promising biomarkers and therapeutic targets for cancers [10]. Long non-coding RNAs (lncRNAs) have attracted much attention because of its regulatory role in occurrence and progression of tumors, including triple-negative breast cancer (TNBC). LncRNA PITPNA antisense RNA 1 (PITPNA-AS1) has been explored in some cancers, whereas its function and molecular mechanism in TNBC remain unclear

Methods

Results

Discussion

Conclusion