Abstract
BackgroundThis study incorporates fundamental research referring to considerable amounts of gene-sequencing data and bioinformatics tools to analyze the pathological mechanisms of diffuse large B-cell lymphoma (DLBCL).MethodsA lncRNA-miRNA-mRNA ceRNA network of DLBCL was constructed through database analysis combining GTEx and TCGA. qPCR was used to detect the expression of LINC00963 and miR-320a in DLBCL cell lines. After LINC00963 or miR-320a overexpression in vitro, western blot was performed to assess the protein levels of UPR sensors (GRP78, p-IRE1, IRE1, active ATF6, ATF4 and XBP1), along with apoptosis markers (Bcl-2, Bax, caspase 3) and autophagy indicators (Beclin1, LC3II, LC3I and p62). Additionally, the expression of LC3 was analyzed through immunofluorescence (IF) assay. ResultsFollowing LINC00963 overexpression in vitro, SUDHL4 cell line showed a marked increase in the level of UPR-related GRP78, p-IRE1 and spliced XBP-1/XBP-1(s), apoptosis-related Bax and cleaved caspase 3, as well as autophagy-related Beclin1 and LC3II, whereas miR-320a mimic greatly diminished the effects of LINC00963 overexpression. Moreover, LINC00963 targeted miR-320a while miR-320a bound to the 3’UTR of XBP1. It was also found that LINC00963 overexpression resulted in significantly delayed tumor growth in a xenograft model of DLBCL. ConclusionMechanistically, LINC00963/miR-320a regulated XBP1-apoptosis pathwayand autophagy, implying the therapeutic potential ofthis pathway for selective targeting. The data presented here illustratedthe mechanism of LINC00963/miR-320a/XBP1 in DLBCL forthe first time.
Highlights
Diffuse large B-cell lymphoma (DLBCL) accounts for 30–40% percent of non-Hodgkin’s lymphoma (NHL) and is the most common form of NHL
Through lncRNA screening, 5 lncRNAs (NRAV, LINC00937, LINC00963, DTX2P1UPK3BP1-PMS2P1 and SNHG3) were identified that share miRNA binding sites, and the expression levels of which in normal tissue and diffuse large B-cell lymphoma (DLBCL) are shown in Fig. 1 C
Overexpression of LINC00963 inhibits the proliferation of DLBCL cells To study possible involvement of LINC00963/has-miR320a/XBP1, we firstly evaluate the role of LINC00963 following the induction of LINC00963 overexpression
Summary
Diffuse large B-cell lymphoma (DLBCL) accounts for 30–40% percent of non-Hodgkin’s lymphoma (NHL) and is the most common form of NHL. Many studies have demonstrated that LINC00963 as a sponge of miRNA is involved in tumor growth [5,6,7]. Activation of the IRE1-XBP1 ER stress signaling pathway is thought to have a pro-oncogenic effect. IRE1XBP1 expression was found to decrease in diffuse large B-cell lymphoma originating from germinal center B cells (GCB-DLBCL), exerting a negative effect on tumor growth. XBP1s may be directly involved in pro-apoptotic processes and may contribute to the suppression of tumor growth in the lymphoma subtype [15]. This study incorporates fundamental research referring to considerable amounts of gene-sequencing data and bioinformatics tools to analyze the pathological mechanisms of diffuse large B-cell lymphoma (DLBCL)
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