The Long Noncoding RNA HOTAIR Contributes to Cisplatin Resistance of Human Lung Adenocarcinoma Cells via downregualtion of p21WAF1/CIP1 Expression

Abstract

HOTAIR, a long intervening non-coding RNA (lincRNA), associates with the Polycomb Repressive Complex 2 (PRC2) and is reported to reprogram chromatin organization and promote tumor progression. However, little is known about the roles of this gene in the development of chemoresistance phenotype of lung adenocarcinoma (LAD). Thus, we investigated the involvement of HOTAIR in the resistance of LAD cells to cisplatin. In this study, we show that HOTAIR expression was significantly upregulated in cisplatin-resistant A549/DDP cells compared with in parental A549 cells. Knockdown of HOTAIR by RNA interference could resensitize the responses of A549/DDP cells to cisplatin both in vitro and in vivo. In contrast, overexpression of HOTAIR could decrease the sensitivity of A549 and SPC-A1 cells to cisplatin. We also found that the siRNA/HOTAIR1-mediated chemosensivity enhancement was associated with inhibition of cell proliferation, induction of G0/G1 cell-cycle arrest and apoptosis enhancement through regulation of p21WAF1/CIP1 (p21) expression. Also, pcDNA/p21or siRNA/p21 could mimic the effects of siRNA/HOTAIR1 or pcDNA/HOTAIR on the sensitivity of LAD cells to cisplatin. Importantly, siRNA/p21 or pcDNA/p21 could partially rescue the effects of siRNA/HOTAIR1 or pcDNA/HOTAIR on both p21 expression and cisplatin sensitivity in LAD cells. Further, HOTAIR was observed to be significantly downregulated in cisplatin-responding LAD tissues, and its expression was inversely correlated with p21 mRNA expression. Taken together, our findings suggest that upregulation of HOTAIR contributes to the cisplatin resistance of LAD cells, at least in part, through the regulation of p21 expression.

Long noncoding RNA-HOTAIR affects chemoresistance by regulating HOXA1 methylation in small cell lung cancer cells

“…7,[19][20][21][22] However, the role of lncRNA-HOTAIR in the chemoresistance of SCLC remains unknown. In this study, we initially identified lncRNA-HOTAIR as a regulator in chemoresistance of SCLC by qRT-PCR in H69/H69AR and H446/H446AR cells.…”

Microarray expression profile of long non-coding RNAs in paclitaxel-resistant human lung adenocarcinoma cells

“…We also found aberrant expression of 1,733 mRNAs in A549/PTX cells compared with the parental A549 cells. Various of the differentially expressed lncRNAs and mRNAs including, MALAT1, TUG1, HOTAIR, ABCB1 (MDR1) and Wnt6 have been previously reported in other chemoresistant cancers (23)(24)(25)(26)(27). Whether the molecular mechanisms of chemoresistance are the same as in the A549/PTX cells warrants further investigation.…”

Long Non-coding RNAs and Drug Resistance

“…For instance, HOTAIR regulates cisplatin resistance through modulation of apoptosis and cell cycle distribution by affecting p21 expression in human LAD cells. This raises the possibility that anti-HOTAIR may have potential therapeutic value for those cisplatin-resistant LAD patients (Liu Z, et al, 2013). Because of the lower expression and baseline level of CUDR in human normal tissues compared with other current cancer biomarkers (for example, CEA), the gene might be a potential biomarker for assessment of cancer therapeutic response.…”