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Onco Targets Ther
2018 Jun 22;11:3649-3657. doi: 10.2147/OTT.S165290.
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lincROR influences the stemness and crizotinib resistance in EML-ALK+ non-small-cell lung cancer cells.
Yang Y
,
Huang J
,
Xie N
,
Huang H
,
Xu S
,
Cai J
,
Qi S
.
Abstract
INTRODUCTION: Echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) is identified as an important pathogenic factor in patients with non-small-cell lung cancer (NSCLC) and could induce a stem-like phenotype in NSCLC cells. Crizotinib is commonly used for EML4-ALK+ NSCLC treatment, but its acquired resistance results in tumor recurrence. Long intergenic noncoding RNA, regulator of reprogramming (lincROR) is related to the acquisition and maintenance of self-renewal and stemness features of cancer stem cells. It has been documented that lincROR is implicated in chemoresistance. However, the correlations of lincROR and EML4-ALK in stem cell-like properties and of lincROR and crizotinib resistance in NSCLC cells are yet to be elucidated.
PATIENTS AND METHODS: In the present study, we investigated the expression profile of lincROR in EML-ALK NSCLC tissues, and the potential role of lincROR in prognosis was then analyzed. Subsequently, its association with stem cell-like properties of EML-ALK+ NSCLC cells was determined. Furthermore, the correlation of lincROR with crizotinib and the effects of lincROR and crizotinib on cell viability of EML4-ALK+ NSCLC cells were all explored.
RESULTS: The results showed that lincROR expression was upregulated in EML4-ALK+ NSCLC tissues relative to EML4-ALK- NSCLC tissues. Low-expressed lincROR was related to a favorable prognosis of patients with EML-ALK NSCLC. lincROR overexpression could enhance the stemness features of EML-ALK+ NSCLC cells which were repressed by ALK knockdown.
CONCLUSION: We found that lincROR expression was significantly inhibited because of the increased concentration of crizotinib in EML4-ALK+ NSCLC cells. Furthermore, lincROR overexpression increased cell viability of EML4-ALK+ NSCLC cells, which was impaired by crizotinib. Conjointly, these results suggested the important role of lincROR in EML-ALK+ NSCLC. lincROR may serve as a potential therapeutic target to overcome chemotherapy resistance in EML-ALK+ NSCLC.
Figure 1. Relative expression levels of lincROR in 106 NSCLC tissue samples and PFS of EML–ALK NSCLC patients in lincROR high expression and lincROR low expression were analyzed, respectively.Notes: (A) lincROR expression was evaluated in 106 cases of EML–ALK tumor tissues. lincROR expression was significantly upregulated in 11 cases of EML–ALK+ NSCLC tumor tissues in comparison with EML–ALK− NSCLC tumor tissues. **P<0.01. (B) The association between lincROR expression and prognosis was explored by Kaplan–Meier and log-rank tests. The low-expressed lincROR was significantly associated with favorable prognosis in patients with EML–ALK+ NSCLC. P=0.027.Abbreviations: EML–ALK, echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase; lincROR, long intergenic noncoding RNA, regulator of reprogramming; NSCLC, non-small-cell lung cancer; PFS, progression-free survival.
Figure 2. lincROR expression was evaluated in H3122 cells. qPCR assay was performed to examine the expression levels of lincROR in H3122 cells transfected with ALK-si.Notes: ALK knockdown inhibited the expression level of lincROR in H3122 cells. *P<0.05.Abbreviations: lincROR, long intergenic noncoding RNA, regulator of reprogramming; qPCR, quantitative polymerase chain reaction.
Figure 3. Stem cell-like properties of EML–ALK+ NSCLC cells were assessed in H3122 cells by sphere formation assay, flow cytometry analysis, and qRT-PCR.Notes: (A) The influence of ALK and lincROR on the stem cell-like properties of H3122 cells was analyzed by sphere formation assay. The stem cell-like properties of H3122 cells was impaired by ALK knockdown, but could be partly rescued by lincROR overexpression. (B) The influence of ALK and lincROR on the percentage of CD133+CD44+ in H3122 cells was explored by flow cytometry analysis. ALK knockdown reduced the percentage of CD133+CD44+ from 6.857%±0.025% to 1.327%±0.03% in H3122 cells, but lincROR overexpression increased the percentage of CD133+CD44+ from 1.327%±0.03% to 4.583%±0.03% in H3122 cells. (C) Relative mRNA expression of CSC markers Sox2, Nanog, and OCT4 was evaluated by qRT-PCR in H3122 cells. Overexpression of lincROR upregulated the Sox2, Nanog, and OCT4 expression, when they were repressed by ALK knockdown. *P<0.05.Abbreviations: CSC, cancer stem cell; EML–ALK, echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase; lincROR, long intergenic noncoding RNA, regulator of reprogramming; NSCLC, non-small-cell lung cancer; qRT-PCR, quantitative reverse transcription-polymerase chain reaction.
Figure 4. The correlation between lincROR and crizotinib was assessed by qPCR assay.Notes: (A) The effect of different concentrations of crizotinib on lincROR expression was detected in A549 cells. No obvious effect of different concentrations of crizotinib on lincROR expression was observed in A549 cell. (B, C) The effects of different concentrations of crizotinib on lincROR expression were detected in H2228 and H3122 cells, respectively. A gradually reduction of lincROR expression was separately detected at an increased concentration of crizotinib in both H2228 and H3122 cells. *P<0.05.Abbreviations: lincROR, long intergenic noncoding RNA, regulator of reprogramming; qPCR, quantitative polymerase chain reaction.
Figure 5. The relationship between lincROR and crizotinib in cell viability of H3122 and H2228 cells was examined by CCK-8 assay, respectively.Notes: (A) The impact of crizotinib and lincROR in cell viability of H3122 cells was analyzed. Cell viability of H3122 cells was gradually inhibited by an increased concentration of crizotinib, but lincROR overexpression enhanced the cell viability of H3122 cells. (B) The impact of crizotinib and lincROR on cell viability of H2228 cells was analyzed. lincROR overexpression elevated cell viability of H2228 cells, which was repressed by crizotinib. *P<0.05.Abbreviations: CCK-8, cell counting kit-8; lincROR, long intergenic noncoding RNA, regulator of reprogramming.
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