LncRNA BCYRN1-induced autophagy enhances asparaginase resistance in extranodal NK/T-cell lymphoma

Abstract

Background: Asparaginase (ASP) is the cornerstone drug in the treatment of extranodal NK/T-cell lymphoma (ENKTCL), and the mechanisms of resistance to ASP remain largely unknown. Long non-coding RNAs play important roles in chemotherapy resistance in various cancers. However, the expression of BCYRN1 and its role in ENKTCL still remain unidentified. Methods: Lentivirus-mediated BCYRN1 overexpression and knockdown were performed in SNK-6 cells. Cell autophagy was analyzed by adenovirus expressing GFP-LC3B fusion protein. RNA pull-down and RNA Binding Protein Immunoprecipitation Assay were performed to investigate the relationship between BCYRN1 and p53. Western blot analysis was performed to assess the effect of BCYRN1 on different autophagy pathways. Finally, in vivo xenograft tumor model was constructed to analyze the effect of BCYRN1 on tumor growth and ASP resistance. Results: BCYRN1 was overexpressed in ENKTCL than normal NK cells, and patients with higher expression had significantly inferior progression-free survival (PFS). The IC50 value of ASP was significantly increased in BCYRN1-overexpressed SNK-6 cells and BCYRN1 overexpression could resist the inhibitory effect of ASP on proliferation. ASP could induce concurrent apoptosis and autophagy in ENKTCL, and the latter process was enhanced by overexpression of BCYRN1, mainly through affecting both PI3K/AKT/mTOR and p53/mTOR pathways. BCYRN1 could induce the degradation of p53 via ubiquitination, thus resulting in enhancement of autophagy and ASP resistance, which could be reversed by drug-induced autophagy inhibition. The effect of BCYRN1 on tumor growth and autophagy were confirmed in vivo xenograft model. Conclusions: It was found that BCYRN1 was a valuable prognostic biomarker in ENKTCL. BCYRN1 could promote resistance to ASP by inducing autophagy, which could be reversed by inhibition of autophagy. Our findings highlight the feasibility of combining autophagy inhibition and ASP in the treatment of ENKTCL.

ATF3 -activated accelerating effect of LINC00941/lncIAPF on fibroblast-to-myofibroblast differentiation by blocking autophagy depending on ELAVL1/HuR in pulmonary fibrosis

“…LncRNA SNHG11 aggravates oncogenic autophagy to facilitate cell proliferation, stemness, migration, invasion and epithelial-to-mesenchymal transition in gastric cancer [ 53 ]. LncRNA BCYRN1 -induced autophagy enhances asparaginase resistance in extranodal NK/T-cell lymphoma [ 54 ]. In pulmonary fibrosis, Ni’s group found that silica-induced pulmonary fibrosis is facilitated by lncHOTAIR through the sponging of MIR326 and attenuated by the increased MIR326 expression through the promotion of the autophagy activity of fibroblasts by targeting PTBP1 (polypyrimidine tract binding protein 1).…”

LncRNA TUG1 promotes pulmonary fibrosis progression via up-regulating CDC27 and activating PI3K/Akt/mTOR pathway

“…mTOR is a major autophagy regulator, and its phosphorylation can restrain autophagy-related protein expression [ 33 ]. Inactivation of PI3K/Akt pathway and its downstream mTOR could increase LC3-II and Beclin-1 expressing, suggesting the induction of autophagy [ 34 ]. Consistent with these studies, we demonstrated that TUG1 depletion repressed TGF-β or BLM-induced PI3K/Akt/mTOR activation in vitro and in vivo.…”

Clinicopathological Significance and Prognostic Values of Long Noncoding RNA BCYRN1 in Cancer Patients: A Meta-Analysis and Bioinformatics Analysis

“…Peng et al discovered that BCYRN1 was highly expressed in cervical cancer and that miR-138 inhibition increased cervical cancer proliferation and invasion [ 31 ]. In addition, BCYRN1 is upregulated in extranodal lymphomas and may enhance ASP resistance by activating autophagy [ 36 ]. BC200 is expressed at low levels in ovarian cancer and may inhibit tumor cell proliferation [ 32 ].…”