Abstract
Development of chemoresistance is a persistent problem during cancer treatment. Long non-coding RNAs (LncRNAs) are currently emerging as an integral functional component of the human genome and as critical regulators of cancer development and progression. In the present study, we investigated the role and molecular mechanism of H19 lncRNA in chemoresistance development by using doxorubicin (Dox) resistance in breast cancer cells as a model system. H19 lncRNA expression was significantly increased in anthracycline-treated and Dox-resistant MCF-7 breast cancer cells. This H19 overexpression was contributed to cancer cell resistance to anthracyclines and paclitaxel as knockdown of H19 lncRNA by a specific H19 shRNA in Dox-resistant cells significantly improved the cell sensitivity to anthracyclines and paclitaxel. Furthermore, gene expression profiling analysis revealed that a total of 192 genes were associated with H19-mediated Dox resistance. These genes were enriched in multiple KEGG pathways that are related to chemoresistance. Using genetic and pharmacological approaches, we demonstrated that MDR1 and MRP4 were major effectors of H19-regulated Dox resistance in breast cancer cells as MDR1 and MRP4 expression was markedly elevated in Dox-resistant cells while dramatically reduced when H19 was knocked down. Moreover, we found that CUL4A, an ubiquitin ligase component, was a critical factor bridging H19 lncRNA to MDR1 expression, and a high tumor CUL4A expression was associated with low survival in breast cancer patients treated with chemotherapy. These data suggest that H19 lncRNA plays a leading role in breast cancer chemoresistance, mediated mainly through a H19-CUL4A-ABCB1/MDR1 pathway.
Highlights
Breast cancer is the most common malignancy in women in the United States and is second only to lung cancer as a cause of cancer death [1]
We found that CUL4A, an ubiquitin ligase component, was a critical factor bridging H19 long non-coding RNAs (lncRNAs) to MDR1 expression, and a high tumor CUL4A expression was associated with low survival in breast cancer patients treated with chemotherapy
To determine if H19 lncRNA expression is influenced by anthracycline drugs, we first examined the effects of anthracycline drugs doxorubicin (Dox), epirubicin and pirarubicin on H19 lncRNA expression in MCF-7 cells
Summary
Breast cancer is the most common malignancy in women in the United States and is second only to lung cancer as a cause of cancer death [1]. Chemotherapy is one of the basic treatments for cancers [4]. With the advent of various anticancer drugs, cytotoxic and molecularly targeted compounds have become the www.impactjournals.com/oncotarget first-line standard treatment regimens for most cancer patients when surgery is not an appropriate option [5, 6]. The combination of anthracycline antibiotics such as doxorubicin and cyclophosphamide is one of the most basic and important parts in the recommended first-line chemotherapy of breast cancer [1]. About 30% of clinical patients under systemic chemotherapy for breast cancer develop multidrug resistance (MDR) and relapse with a worse prognosis due to drug resistance [7]. There is a high incidence of chemoresistance with a poor prognosis in breast cancer
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