Received: 21 March 2017
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Revised: 15 September 2017
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Accepted: 18 September 2017
DOI: 10.1002/mc.22739
BRIEF COMMUNICATION
Serum HOTAIR and GAS5 levels as predictors of survival in patients with glioblastoma Jie Shen1 | Tiffany R. Hodges2 | Renduo Song1 | Ye Gong3 | George A. Calin4 | Amy B. Heimberger2 | Hua Zhao1 1 Department
of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas
2 Department
of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas
3 Department
Circulating long non-coding RNAs (lncRNAs) are a new class of cancer biomarkers. However, their significance in predicting outcomes in glioblastoma patients is unclear. We measured the levels of six known oncogenic lncRNAs—CRNDE, GAS5, H19, HOTAIR, MALAT1, and TUG1 in serum samples from 106 patients with primary
of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
glioblastoma and analyzed their association with outcomes. High levels of HOTAIR
4 Department
ratio [HR] = 2.04; 95% confidence interval [CI] = 1.08-9.76), and disease-free survival
were associated with decreased probability of 2-year overall survival (adjusted hazard
of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas
(adjusted HR = 1.82; 95% CI = 1.04-6.17). High levels of GAS5 were associated with increased probability of 2-year overall survival (adjusted HR = 0.44; 95% CI = 0.18-
Correspondence Dr. Hua Zhao, Department of Epidemiology, The University of Texas MD Anderson Cancer Center, 1155 Pressler Street, Houston, TX 77030. Email:
[email protected]
0.99), and disease-free survival (adjusted HR = 0.46; 95% CI = 0.16-0.98). HOTAIR and GAS5 levels could serve as reciprocal prognostic predictors of survival and disease progression in patients with glioblastoma. KEYWORDS
clinical outcomes, glioblastoma, lncRNAs
1 | INTRODUCTION
date, there is no published study investigating the relationship between circulating lncRNAs and the prognosis of gliomas, particularly
Long non-coding RNA (lncRNAs) are RNAs that lack functional protein
glioblastoma, the most common and aggressive type of brain tumor.
coding capabilities, but nonetheless play important roles in gene
Accordingly, in the current study, we analyzed six oncogenic or tumor
regulation. In carcinogenesis, deregulated lncRNA can affect both
suppressor lncRNAs, CRNDE, GAS5, H19, HOTAIR, MALA1, and
oncogenic and tumor-suppressing pathways.1–4 LncRNA signatures
TUG1 in serum samples from 106 primary glioblastoma patients for
can serve as potential biomarkers for diagnosis, prognosis, and
prognostic impact. The roles of these six circulating lncRNAs in cancer
5–7
response to therapy.
Intriguingly, lncRNAs are present in bodily
fluids, including serum, plasma, and urine. Although, it is still unknown
diagnosis and prognosis have been previously reported in multiple cancers.8–16
how lncRNAs are released into the extracellular environment, a variety of studies demonstrate the role of circulating lncRNAs as biomarkers for cancer detection and prognosis in multiple cancers.8–16 LncRNAs have been implicated in gliomagenesis.17–22 For example, H19, a lncRNA that binds to c-Myc, drives tumor
2 | MATERIALS AND METHO DS 2.1 | Patient population
transformation and is upregulated in gliomas.23 LncRNA-based
Detailed information on patient population was described in our
molecular classification has revealed three separate subtypes of
previous study.25 Study subjects were recruited from the MD
glioma with distinct overall survival.
24
Although, we have previously
Anderson Cancer Center (Houston, TX) Brain Tumor Center starting
characterized distinct prognostic serum miRNAs in glioblastoma,25 to
in April 2013 after obtaining informed consent under an Institutional
Molecular Carcinogenesis. 2018;57:137–141.
wileyonlinelibrary.com/journal/mc
© 2017 Wiley Periodicals, Inc.
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Review Board approved protocol. A total of 106 glioblastoma patients
age, IDH1 mutation status, sex, race, smoking status, timing of blood
were included in the study. Before blood drawn, all patients received
draw, and body mass index (BMI). Patients with survival durations
initial standard of care treatment of resection, radiation, and
longer than 24 months were censored at 24 months in the Cox
chemotherapy.
regression analysis. All patients were dichotomized by the median lncRNA levels in the event-free groups. In all statistical analyses, a P value < 0.05 was considered significant. Then, an estimate of the
2.2 | RNA isolation
false discovery rate (q value) was calculated to take into account the
Isolation of lncRNAs from serum samples was performed using a
multiple comparisons for any lncRNA significantly associated with
mirVana PARIS Kit (Thermo Fisher Scientific, Waltham, MA) according
2-year overall survival or disease-free survival in two sets. A low q
to the manufacturer's protocol. For each sample, 400 µL of serum
value (q < 0.15) is an indication of high confidence.
sample was used. RNA from the filter column was eluted in 25 µL of ribonuclease-free water. Quality and quantity of the RNA was
3 | RESULTS
evaluated using NanoDrop spectrophotometry (Thermo Scientific) and an Agilent 2100 Bioanalyzer (Agilent Technologies).
Demographic and clinical characteristics of the patient cohort have been described in our previous publication.25 Overall, the mean age
2.3 | Quantification of lncRNA by quantitative real-time polymerase chain reaction (qRT-PCR)
was 58 years, 66% of the study subjects were male, and 94.3% were Caucasians (94.3%). The median follow-up interval was 19 months. During the follow-up period, 68 study subjects (64.8%) experienced
Quantification of lncRNA expression was performed using the TaqMan
disease recurrence or progression.
lncRNA assays (Thermo Scientific) according to the manufacturer's
The biological function of these six lncRNAs in gliogenesis is
protocol. Each sample was analyzed in triplicate using qRT-PCR.
shown in Table 1. Four of the six analyzed lncRNAs, GAS5, H19,
GAPDH was used as the endogenous control in the current study. The
HOTAIR, and MALAT1, were detected in at least 90% of the serum
expression levels of lncRNAs was calculated using the Δ cycle
samples, while CRNDE and TUG1 were detected in less than 20% of
threshold (Ct) method, where ΔCt = Cttarget − Ctreference and smaller
the serum samples and were not included for further analyses. The
ΔCt values indicate higher expression levels. The relative expression
median levels of four expressed LncRNAs were 0.838 for HOTAIR
levels of lncRNAs were calculated using the 2−ΔΔCt method normalized
(range: 0.479, 1.047), 0.873 for GAS5 (range: 0.639, 1.246), 0.578 for
to the endogenous control, where ΔCt = Cttarget − Ctreference and
H19 (range: 0.348, 0.792), and 1.045 for MALAT1 (range 0.721,
−ΔΔCt = − (sample ΔCt − control ΔCt). To assess the reproducibility
1.674). The associations between these four serum lncRNA levels and
of the assays, we re-analyzed the expression of GAS5, H19, HOTAIR,
2-year overall and disease-free survival were then evaluated (Table 2).
and MALAT1 in six duplicate samples in two separate occasions. A
For overall survival, when HOTAIR and GAS5 levels were dichoto-
strong correlation was observed for all four lncRNAs between two
mized into two groups (high or low) using the median levels of HOTAIR
occasions (P ≥ 0.98).
(0.838) and GAS5 (0.873) in the event-free group, high levels of HOTAIR were associated with a 2.04-fold increase in the likelihood of death (adjusted HR = 2.04; 95% CI = 1.08-9.76), whereas high levels of
2.4 | Statistical analysis
GAS5 were associated with a 56% decrease in the likelihood of death
Statistical analyses were performed using the Stata statistical package
(adjusted HR = 0.44; 95% CI = 0.18-0.99) after adjusting covariates.
(version 13.0, STATA Inc., College Station, TX). The determinations of
After adjusting for multiple comparisons, the association for HOTAIR
disease-free survival and overall survival were previously described.25
remained significant (q < 0.15). The Kaplan-Meier 2-year overall
For each lncRNA, we estimated the associations between 2-year
survival curves showed that patients with high HOTAIR and low
survival rates and serum lncRNA expression levels as hazard ratios
GAS5 levels had worse survival rates relative to patients with low
(HRs) and 95% confidence intervals (CIs) using the Cox proportional
HOTAIR and high GAS5 levels (P = 0.007 and 0.062, respectively)
hazards model adjusted for Karnofsky performance scale (KPS) score,
(Figures 1A and 1B).
TABLE 1 lncRNA
Known biological functions of six studied lncRNAs in gliogenesis Length (bp)
Chromosome
Biological function in gliogenesis
References
CRNDE
10 327
Chr16
The most upregulated lncRNA in glioma. Promote tumor growth and migration.
42,43
H19
6308
Chr11
Considered oncogenic lncRNA. Also serve as a precursor for miR-675.
44,45
HOTAIR
12 649
Chr12
Promote tumor invasion and progression
30,31
MALAT1
8755
Chr11
Considered dual functions, oncogenic and tumor suppressor
46,47
GAS5
4983
Chr1
Considered tumor suppressor gene
39
TUG1
9748
Chr22
Considered tumor suppressor gene by promoting cell apoptosis
18
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TABLE 2
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Serum lncRNAs associated with 2-year survival in patients with primary glioblastoma Expression level
Event, N (%)
Event-free, N (%)
Adj. HR (95% CI)*
Low (≤0.838)
7 (21.2%)
37 (50.7%)
Reference
High (>0.838)
26 (78.8%)
36 (49.3%)
2.04 (1.08-9.76)
Low (≤0.873)
23 (69.7%)
36 (49.3%)
Reference
High (>0.873)
10 (30.3%)
37 (50.7%)
0.44 (0.18-0.99)
P value
Overall survival HOTAIR
GAS5
H19
MALAT1
Low (≤0.578)
17 (51.5%)
37 (50.7%)
Reference
High (>0.578)
16 (48.5%)
36 (49.3%)
1.13 (0.59-8.24)
Low (≤1.045)
19 (57.6%)
36 (49.3%)
Reference
High (>1.045)
14 (42.4%)
37 (50.7%)
0.94 (0.23-3.21)
0.019
0.047
0.638
0.427
Disease-free survival HOTAIR
GAS5
H19
MALAT1
Low (≤0.801)
22 (32.4%)
19 (51.4%)
Reference
High (>0.801)
46 (67.6%)
18 (48.6%)
1.82 (1.04-6.17)
Low (≤0.919)
47 (69.1%)
18 (48.6%)
Reference
High (>0.919)
21 (30.9%)
19 (51.4%)
0.46 (0.16-0.98)
Low (≤0.562)
31 (45.6%)
19 (51.4%)
Reference
High (>0.562)
37 (54.4%)
18 (48.6%)
1.17 (0.52-7.02)
Low (≤1.169)
38 (55.9%)
18 (48.6%)
Reference
High (>1.169)
30 (44.1%)
19 (51.4%)
0.98 (0.24-3.16)
0.042
0.048
0.472
0.681
Adj., adjusted; CI, confidence interval; HR, hazard ratio; lncRNA, long non-coding ribonucleic acid. *Adjusted by age, sex, race, smoking status, Karnofsky performance scale score, timing of blood draw, IDH1 mutation status, and body mass index.
A similar approach was applied to analyze 2-year disease-free
patterns are positively correlated with glioma grade and tumor
survival using the median levels of HOTAIR (0.801) and GAS5 (0.919) in
progression.30 Functional studies have also shown that the loss of
the event-free group (Table 2). High levels of HOTAIR were associated
HOTAIR leads to cell-cycle arrest and slows down tumor growth and
with a 1.82-fold increase in the likelihood of recurrence or progression
tumor cell invasiveness specifically in glioblastoma.31 No previous studies
(adjusted HR = 1.82; 95% CI = 1.04-6.17). In contrast, high levels of
have investigated the role of circulating HOTAIR in glioblastoma
GAS5 were associated with a 54% decrease in the likelihood of
prognosis. However, studies in other cancers have shed light on circulating
recurrence or progression (adjusted HR = 0.46, 95% CI = 0.16-0.98)
HOTAIR's potential as a biomarker for cancer diagnosis and progno-
after adjusting covariates. After adjusting for multiple comparisons, the
sis.12,32 Li et al12 reported that serum levels of HOTAIR are significantly
association
The
higher in cervical cancer patients than in healthy controls and that high
Kaplan-Meier 2-year disease-free survival curves showed that patients
serum levels of HOTAIR are significantly correlated with poor prognosis.
for
HOTAIR
remained
significant
(q < 0.15).
with high HOTAIR and low GAS5 levels had worse survival rates relative
In contrast, GAS5 has been shown to act as a tumor suppressor in
to glioblastoma patients with low HOTAIR and high GAS5 levels
renal and bladder cancer,33,34 likely by inhibiting proliferation.35 GAS5
(P = 0.046 and 0.030, respectively) (Figures 1C and 1D). No statistically
plays an important role in regulating cancer cell survival36 and in
significant associations were observed for H19 and MALAT1.
prostate cancer, can induce apoptosis by inhibiting androgen-receptor signaling.37 GAS5 down-regulation is correlated with poor prognosis in breast cancer and head and neck squamous cell carcinoma.38 In glioma,
4 | DISCUSSION
GAS5 expression is lower in cancerous tissues and cell lines than in their normal counterparts.39 Although ours is the first study to explore
In the current study, we analyzed six oncogeneic lncRNAs in the serum
the role of circulating GAS5 in glioblastoma, studies in lung and breast
from 106 patients with primary glioblastoma and identified two that are
cancers have shown that circulating GAS5 may be a promising
associated with prognosis. Our findings regarding serum HOTAIR and
biomarker.40,41 In breast cancer, it has been reported that GAS5 levels
GAS5 are consistent with their biological functions in glioblastoma
are inversely correlated with the Ki67 proliferation index before
carcinogenesis. Specifically, HOTAIR, a HOX transcript antisense RNA,
surgery (P = 0.012) and are positively correlated with lymph node
can drive tumor cell proliferation, invasion, and metastasis, maintain
metastasis after surgery (P = 0.029).41
stemness of cancer stem cell.26,27 HOTAIR has been shown to act as a
In summary, we have shown that serum HOTAIR and GAS5
negative prognostic factor in several cancers including glioblastoma28 and
levels are associated with 2-year overall survival and disease-free
to be significantly associated with overall survival.29 HOTAIR's expression
survival in patients with glioblastoma. Unfortunately, no matched
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FIGURE 1 Kaplan-Meier 2-year overall and disease-free survival curves for patients with primary glioblastoma grouped by low (blue line) and high (red line) lncRNA expression levels. N = number of patients with an event at 2 years/the total number of patients in the dataset. A, HOTAIR expression levels and overall survival; B, HOTAIR expression levels and disease-free survival; C, GAS5 expression levels and overall survival; and D, GAS5 expression levels and disease-free survival
tumor tissues are available so we do not have the ability to assess the correlation between tumor and circulation. Nevertheless, our study provides the first evidence to support the role of circulating lncRNAs in predicting survival of patients with glioblastoma. Larger independent studies are needed to validate these results and further characterize the roles of HOTAIR and GAS5 in glioblastoma carcinogenesis.
CONFLICTS OF INTEREST Authors have declared there are no any competing financial interests in relation to the work described.
ORCID Hua Zhao
http://orcid.org/0000-0002-1629-8695
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How to cite this article: Shen J, Hodges TR, Song R, et al. Serum HOTAIR and GAS5 levels as predictors of survival in patients with glioblastoma. Molecular Carcinogenesis. 2018;57:137–141. https://doi.org/10.1002/mc.22739
