title: The long noncoding RNA HOTAIR contributes to cisplatin resistance of human lung adenocarcinoma cells via downregualtion of p21(WAF1/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 p21(WAF1/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.
authors.affiliation: Department of Oncology, the Second Affiliated Hospital of Nanjing Medical University, Nanjing, P.R. China.
authors.forename: Zhili
authors.initials: Z
authors.lastname: Liu
authors.forename: Ming
authors.initials: M
authors.lastname: Sun
authors.forename: Kaihua
authors.initials: K
authors.lastname: Lu
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.forename: Meiling
authors.initials: M
authors.lastname: Zhang
authors.forename: Weiqin
authors.initials: W
authors.lastname: Wu
authors.forename: Wei
authors.initials: W
authors.lastname: De
authors.forename: Zhaoxia
authors.initials: Z
authors.lastname: Wang
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics*; D000077192:Adenocarcinoma of Lung; D000818:Animals; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology / Q000627:therapeutic use*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics* / Q000378:metabolism; D018076:DNA, Complementary / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D062085:RNA, Long Noncoding / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D018076:DNA, Complementary; C561566:HOTAIR long untranslated RNA, human; D062085:RNA, Long Noncoding; D034741:RNA, Small Interfering; D002945:Cisplatin