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Long noncoding RNA MRUL promotes ABCB1 expression in multidrug-resistant gastric cancer cell sublines
Ying Wang1, Dexin Zhang2, Kaichun Wu2
1State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi, China Oncology Department of the First Affiliated Hospital of Henan University of Science and Technology, Luoyang, Henan, China.
Abstract:
Multidrug 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.
Insights
The long noncoding RNA MRUL is upregulated in gastric cancer (GC) with multidrug resistance (MDR). MRUL promotes ABCB1 expression, contributing to chemotherapy failure and poor prognosis in GC patients.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Multidrug resistance (MDR) is a major cause of chemotherapy failure in gastric cancer (GC).
- The molecular mechanisms underlying GC MDR, particularly the role of long noncoding RNAs (lncRNAs), are not fully understood.
Purpose of the Study:
- To investigate the role of the lncRNA MRUL (MDR-related and upregulated lncRNA) in GC MDR.
- To determine if MRUL affects the expression of ABCB1 (ATP-binding cassette, subfamily B, member 1) and its impact on GC treatment outcomes.
Main Methods:
- Quantification of MRUL expression in GC cell lines and tissues.
- Assessment of MRUL's correlation with in vitro drug sensitivity and patient prognosis.
- MRUL knockdown experiments in resistant GC cells to evaluate apoptosis, drug accumulation, and ABCB1 mRNA levels.
- Luciferase reporter assays to confirm MRUL's effect on ABCB1 expression.
Main Results:
- MRUL was significantly upregulated in multidrug-resistant GC cell sublines.
- Higher MRUL levels in GC tissues correlated with lower in vitro growth inhibition rates and poorer patient prognosis.
- MRUL knockdown increased apoptosis, enhanced doxorubicin accumulation, and reduced drug release in resistant cells.
- MRUL depletion dose- and time-dependently reduced ABCB1 mRNA levels.
- MRUL was shown to positively regulate ABCB1 expression.
Conclusions:
- The lncRNA MRUL promotes ABCB1 expression, contributing to the multidrug resistance phenotype in gastric cancer.
- MRUL is a potential therapeutic target for overcoming MDR in GC patients.
- Targeting MRUL could reverse MDR and improve chemotherapy efficacy in gastric cancer treatment.
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