Abstract
Chemoresistance remains a great obstacle in effective lung adenocarcinoma (LUAD) treatment. Previously, we verified the role of microRNA-200b (miR-200b) in the formation of docetaxel (DTX)-resistant LUAD cells. This study aims to investigate the mechanism underlying the low level of miR-200b in DTX-resistant LUAD cells. The real-time reverse transcription (RT2) lncRNA PCR array system was applied to explore lncRNAs that potentially regulated miR-200b in DTX-resistant LUAD cells. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) contributed to the low miR-200b level in DTX-resistant LUAD cells. Functional assays were conducted to determine the role of MALAT1 in regulating the growth and metastasis of parental and DTX-resistant LUAD cells. Investigation revealed the mechanism of the competing endogenous RNA (ceRNA) pathway. MALAT1 regulated miR-200b by acting as a ceRNA. MALAT1 modulated the sensitivity of LUAD cells to DTX. E2F transcription factor 3 (E2F3) and zinc-finger E-box binding homeobox 1 (ZEB1) were two targets of miR-200b and mediated the function of MALAT1 in DTX-resistant LUAD cells. Transcription factor AP-2 gamma (TFAP2C) and ZEB1 activated the MALAT1 transcription. In conclusion, TFAP2C-activated MALAT1 modulated the chemoresistance of LUAD cells by sponging miR-200b to upregulate E2F3 and ZEB1. Our findings may provide novel therapeutic targets and perspectives for LUAD treatment.
Highlights
Lung cancer is a kind of malignant tumor that has the high morbidity and mortality rates.[1,2] Among all kinds of lung cancers, non-smallcell lung cancer (NSCLC) accounts for approximately 85% of cases
We assessed the levels of pri-miR200b and pre-miR-200b in DTX-resistant lung adenocarcinoma (LUAD) cells transfected with Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1)-specific small interfering RNAs (siRNAs) and found that MALAT1 knockdown didn’t affect the levels of both pri-miR-200b and pre-miR-200b (Figure S1D), indicating that MALAT1 might regulate miR-200b in DTXresistant LUAD cells at the post-transcription level
Reports have pointed out that some long noncoding RNAs (lncRNAs) serve as a scaffold of protein complex to promote or inhibit gene expression at the transcription level,[31,32] but lncRNAs can act as a mediator in competing endogenous RNA (ceRNA) pathway to regulate tumorigenesis.[33,34,35,36]
Summary
Lung cancer is a kind of malignant tumor that has the high morbidity and mortality rates.[1,2] Among all kinds of lung cancers, non-smallcell lung cancer (NSCLC) accounts for approximately 85% of cases. Lung adenocarcinoma (LUAD) is most common subtype of NSCLC.[3] new technology regarding cancer treatment has developed and improved, the five-year survival rate of LUAD patients is still less than 10%.4. In the early stage of chemotherapy, the NSCLC patients have relatively high sensitivity, while extensive metastasis and rapid progression result in chemoresistance.[5,6] Docetaxel (DTX) is a chemotherapeutic medicine that is quite useful for treating multiple cancers.[7] Despite the extensive use of DTX, the recurrence of LUAD is still common due to the chemoresistance.[8]
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