Long Noncoding RNA MRUL Promotes ABCB1 Expression in Multidrug-Resistant Gastric Cancer Cell Sublines

Abstract

bMultidrug resistance (MDR) is the most common cause of chemotherapy failure in gastric cancer (GC) treatment; however, the underlying molecular mechanisms remain elusive. Long noncoding RNAs (lncRNAs) can be involved in carcinogenesis, but the effects of lncRNAs on MDR are poorly understood. We show here that the lncRNA MRUL (MDR-related and upregulated lncRNA), located 400 kb downstream of ABCB1 (ATP-binding cassette, subfamily B, member 1), was significantly upregulated in two multidrug-resistant GC cell sublines, SGC7901/ADR and SGC7901/VCR. Furthermore, the relative expression levels of MRUL in GC tissues were negatively correlated with in vitro growth inhibition rates of GC specimens treated with chemotherapeutic drugs and indicated a poor prognosis for GC patients. MRUL knockdown in SGC7901/ADR and SGC7901/VCR cells led to increased rates of apoptosis, increased accumulation, and reduced doxorubicin (Adriamycin [ADR]) release in the presence of ADR or vincristine. Moreover, MRUL depletion reduced ABCB1 mRNA levels in a dose-and time-dependent manner. Heterologous luciferase reporter assays demonstrated that MRUL might positively affect ABCB1 expression in an orientation-and position-independent manner. Our findings indicate that MRUL promotes ABCB1 expression and is a potential target to reverse the MDR phenotype of GC MDR cell sublines.T he development of multidrug resistance (MDR) followed by failure to respond to chemotherapy is a crucial problem in gastric cancer (GC) (1, 2). However, to date, the molecular mechanisms underlying MDR have not been fully elucidated.Chemotherapeutic drugs, such as doxorubicin (Adriamycin [ADR]) and vincristine (VCR), can induce Bax-and Bak-mediated apoptosis of tumor cells through DNA damage. Ribosomal protein (RP) S13 (RPS13) or RPL23 can promote MDR in gastric cancer cells by suppressing drug-induced apoptosis (3), while the activation of c-Jun N-terminal kinase 1 (JNK1) and caspase 3 (CPP32) is associated with enhancement of apoptosis in Baxtransfected gastric cancer cells (4). Among the MDR-related proteins, P-glycoprotein (P-gp), a 170-kDa transmembrane glycoprotein encoded by ABCB1, has been extensively studied (5-7). P-gp is an ATP-dependent efflux pump in the ATP-binding cassette (ABC) family and is expressed constitutively in the liver, kidney, intestine, brain, and many other tissues (5, 8). P-gp exhibits broad substrate specificity and is necessary for the elimination of intracellular toxic metabolic products or materials to maintain body homeostasis. Hence, P-gp can reduce intracellular chemotherapeutic drug concentrations by transporting cytotoxic agents out of the cell. P-gp upregulation often results in a compromised chemotherapy response and a worse prognosis for malignant tumor patients. However, the mechanism by which P-gp is upregulated remains unclear.Long noncoding RNAs (lncRNAs) refer to RNAs that lack coding potential, are Ͼ200 bp in length, and are responsible for at least 80% of all genome transcripts. lncRNAs play important roles in regulating t...

Linc00441 interacts with DNMT1 to regulate RB1 gene methylation and expression in gastric cancer

“…Increasing studies have revealed that lncRNAs have important influence in tumorigenesis, metastasis, and prognosis and drug resistance of gastric cancer [1]. While the functional role and molecular mechanism of many GCassociated lncRNAs remain undetermined, recent studies revealed that several lncRNAs are associated with GC progression, such as H19, FENDRR, and MRUL [14][15][16].…”

lncRNA uc009yby.1 promotes renal cell proliferation and is associated with poor survival in patients with clear cell renal cell carcinomas

“…Furthermore, the function of uc009yby.1 in renal cells was investigated using two siRNAs to inhibit uc009yby.1 expression, revealing that this lncRNA could enhance renal cell proliferation; this suggests that uc009yby.1 may be a novel therapeutic target for ccRCC. Numerous studies have indicated that certain lncRNAs have aberrant expression profiles in various kinds of tumors, such as gastric (15)(16)(17), colon (18,19), esophageal (20)(21)(22) and liver (23) cancers. Yu et al (12) recently reported on a class of lncRNAs that are aberrantly expressed in ccRCC cells, in which multiple lncRNAs were upregulated.…”

Role of long non-coding RNA in tumor drug resistance

“…One more study conducted by Ying Wang et al indicated that the lncRNA-MRUL, MDR-related lncRNA, was significantly upregulated in two multidrugresistant GC cell sublines, SGC7901/ADR and SGC7901/ VCR. Furthermore, the relation between the expression levels of MRUL and growth inhibition rates of GC cell treated with chemotherapy drugs or a poor prognosis for GC patients were significantly negative correlation [43].…”