HOTAIR and its surrogate DNA methylation signature indicate carboplatin resistance in ovarian cancer

Abstract

BackgroundUnderstanding carboplatin resistance in ovarian cancer is critical for the improvement of patients’ lives. Multipotent mesenchymal stem cells or an aggravated epithelial to mesenchymal transition phenotype of a cancer are integrally involved in pathways conferring chemo-resistance. Long non-coding RNA HOTAIR (HOX transcript antisense intergenic RNA) is involved in mesenchymal stem cell fate and cancer biology.MethodsWe analyzed HOTAIR expression and associated surrogate DNA methylation (DNAme) in 134 primary ovarian cancer cases (63 received carboplatin, 55 received cisplatin and 16 no chemotherapy). We validated our findings by HOTAIR expression and DNAme analysis in a multicentre setting of five additional sets, encompassing 946 ovarian cancers. Chemo-sensitivity has been assessed in cell culture experiments.ResultsHOTAIR expression was significantly associated with poor survival in carboplatin-treated patients with adjusted hazard ratios for death of 3.64 (95 % confidence interval [CI] 1.78–7.42; P < 0.001) in the discovery and 1.63 (95 % CI 1.04–2.56; P = 0.032) in the validation set. This effect was not seen in patients who did not receive carboplatin (0.97 [95 % CI 0.52–1.80; P = 0.932]). HOTAIR expression or its surrogate DNAme signature predicted poor outcome in all additional sets of carboplatin-treated ovarian cancer patients while HOTAIR expressors responded preferentially to cisplatin (multivariate interaction P = 0.008).ConclusionsNon-coding RNA HOTAIR or its more stable DNAme surrogate may indicate the presence of a subset of cells which confer resistance to carboplatin and can serve as (1) a marker to personalise treatment and (2) a novel target to overcome carboplatin resistance.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-015-0233-4) contains supplementary material, which is available to authorized users.

Long Non-Coding RNAs: the New Horizon of Gene Regulation in Ovarian Cancer

“…Overexpression and methylation of the HOTAIR gene mediate the therapeutic resistance of OC cells; thus, HOTAIR is associated with poor OS [77]. Interestingly, as DNA is unlikely to change, HOTAIR DNA-based prognostic biomarkers could be used as reliable classifiers to distinguish patients for personalized treatment.…”

The Role of Long Non-Coding RNAs in Ovarian Cancer

“…Its knockdown inhibited cell proliferation, decreased the invasion ability of the cells and restored the cisplatin sensitivity of the cisplatin-resistant cells of corresponding cells [46] . Furthermore, it has been shown that it is involved in mesenchymal stem cell fate [47] . Its expression has been demonstrated to be higher in ovarian cancer stem cell (CSCs) than in non-CSCs [47] .…”

“…Furthermore, it has been shown that it is involved in mesenchymal stem cell fate [47] . Its expression has been demonstrated to be higher in ovarian cancer stem cell (CSCs) than in non-CSCs [47] . Considering the role of CSCs in tumorigenesis and drug resistance [48] , it can be a target for anti-cancer therapies.…”

“…Its knockdown has induced cell cycle arrest and apoptosis in ovarian cancer cell lines [22] . One study has revealed that its expression and surrogate DNA methylation signature have been significantly associated with poor survival in carboplatin-treated ovarian cancer patients and predict carboplatin resistance in ovarian cancer patients [47] . Consequently, it has been suggested as a marker for individualized treatment and a new target to defeat carboplatin resistance [47] .…”

Elevated HOTAIR expression associated with cisplatin resistance in non-small cell lung cancer patients

“…Compared with normal tumor cells, tumor stem cells are not easily killed by chemotherapy drugs (18). Tumor stem cells are a small population of special cells among other tumor cells with the potential to self-renew and differentiate, and are an important reason for tumor invasion, metastasis, and drug resistance (19)(20)(21). Tumor stem cells have a strong tendency to form spheres in vitro, and a minimal number of tumor stem cells can form tumors subcutaneously in nude mice; in addition, tumor stem cells are often drug-resistant (22).…”