The diagnostic effect of serum miR-139-5p as an indicator in osteosarcoma

Abstract

BACKGROUND:

The microRNA, miR-139-5p, plays an important role in the initiation and progression of various tumor types including osteosarcoma (OS).

OBJECTIVE:

This study aimed to detect the serum miR-139-5p expression in OS and analyze its association with clinical variables.

METHODS:

Blood samples were taken from 98 OS patients and 50 healthy individuals, and serum miR-139-5p levels were measured by quantitative reverse transcription-polymerase chain reaction.

RESULTS:

We found the expression of serum miR-139-5p in OS patients was significantly lower than that in healthy individuals, and miR-139-5p levels were dramatically decreased in patients with distant metastasis or in higher clinical stage. Receiver-operating characteristic (ROC) analysis revealed that serum miR-139-5p could well discriminate OS patients from healthy controls with a high sensitivity and specificity. Moreover, low serum miR-139-5p expression was strongly associated with distant metastasis, tumor stage and shorter overall survival. Both univariate and multivariate analyses showed that serum miR-139-5p level could serve as an independent prognostic marker for OS.

CONCLUSIONS:

Taken together, data from this study demonstrates that serum miR-139-5p could be used as a tumor biomarker for OS diagnosis and prognosis.

Keywords

Osteosarcoma miR-139-5p biomarker diagnosis prognosis

1. Introduction

Osteosarcoma (OS) is a primary malignant bone tumor with high incidence in young children and adolescents around the world [1, 2]. Though multimodality treatments including chemotherapy and surgical resection have greatly increased the survival rate of OS patients in the past few decades, the prognosis remains very poor mainly due to its high risk of metastasis or recurrence [3, 4]. Early detection of OS contribute to improve the clinical outcome of this malignancy, it is therefore very important to identify novel biomarkers for the diagnosis and prognosis of OS.

MicroRNAs (miRNAs) are a class of single-stranded non-coding RNAs that bind to the 3’-untranslated region (UTR) of target mRNAs, leading to mRNA degradation or translational repression [5, 6]. MiRNAs were found to play critical roles in multiple biological processes of cancer progression either through their oncogenic or tumor suppressive functions [7, 8]. It has been reported that several abnormally expressed miRNAs in the peripheral blood such as miR-21 [9], miR-95-3p [10], miR-490-3p [11], were associated with OS and identified as blood-based biomarkers. MiR-139-5p is one of the most common cancer-associated miRNAs. For instance, miR-139-5p was reduced in ovarian cancer [17], hepatocellular carcinoma [18, 19], glioblastoma multiforme [20], endometrial cancer [21], paediatric low-grade glioma [22], nasopharyngeal carcinoma [23], bladder cancer [24, 25], lung cancer [26], tongue squamous cell carcinoma [27], esophageal squamous cell carcinoma [28] and acted as a tumor suppressor miR. On the contrary, miR-139-5p expression was upregulated in prostate cancer [29] and acted as an oncomiR. However, the role of serum miR-139-5p in OS diagnosis and prognosis remained unclear.

In this study, we investigated the expression of miR-139-5p in the blood samples from OS patients and healthy volunteers, thereby evaluating the correlation between serum miR-139-5p expression and clinical variables of OS. Our findings suggested that miR-139-5p served a promising biomarker for prognosis and prognosis of OS.

2. Materials and methods

2.1 Ethics statement

This study was approved by the Ethics Committee of Beijing Chao-yang Hospital Affiliated with Capital Medical University. All specimens were handled and made anonymous according to the ethical and legal standards and written informed consent was provided by all participants.

2.2 Population and sample collection

A total of 98 patients diagnosed with OS and 50 healthy volunteers were enrolled in our study. None of the patients had received any chemotherapy or radiotherapy before surgery. Tumor stage was determined according to the criteria of the International Union against Cancer (UICC) Staging System, 63 tumors were stage I/II, 35 tumors were stage III. The clinical characteristics of OS cases were presented in Table 1. The control serum sample were from healthy controls who received regular physical examination in our hospital. For comparison with the patients with cancer, healthy individuals with no prior history of OS or any other types of cancer. In addition, the OS patients and healthy control were matched by age and gender. All the participants were Han Chinese.

Table 1
Correlation between serum miR-139-5p status and clinicopathological characteristics

Factors	No. of	MiR-139-5p expression		$P$ -value
	patients	High	Low
		( $n=$ 45)	( $n=$ 53)
Gender
Male	62	28	34	NS
Female	36	17	19
Age
$<$ 19	47	22	25	NS
$\geqslant$ 19	51	23	28
Tumor site
Femur/tibia	73	31	42	NS
Others	25	14	11
Tumor size
$<$ 6 cm	50	26	24	NS
$\geqslant$ 6 cm	48	19	29
Distant metastasis
Present	30	8	22	0.0111
Absent	68	37	31
Tumor stage
I–II	63	36	27	0.0028
III	35	9	26
Differentiation status
Low	34	14	20	NS
High	64	31	33

NS, not significant.

Approximately 5 ml of fasting venous blood samples were obtained from OS patients and healthy controls, and all the blood samples were collected in EDTA-containing tubes. Then the supernatant was divided into aliquots after centrifugation and stored in cryotubes at $-$ 80 ${}^{\circ}$ C further processing.

Figure 1.

(A) Serum expression levels of miR-139-5p in healthy controls and OS patients. (B) Patients with distant metastasis had lower miR-139-5p levels than those without. (C) Patients in higher clinical stage had lower miR-139-5p levels than those in lower clinical stage.

2.3 RNA isolation and quantitative reverse transcription-polymerase chain reaction (qRT-PCR)

Total RNA was isolated from 600 $\mu$ l serum samples using Qiagen miRNeasy Mini kit (Qiagen, Hilden, Germany) according to the manufacturer’s protocol. RNA concentration was measured using a NanoDrop ND-1000 spectrophotometer (NanoDrop Technologies, Wilmington, DE, USA) and a 15% denatured polyacrylamide gel.

Reverse transcription was conducted using a TaqMan MicroRNA Reverse Transcription Kit (Applied Biosystems, Foster City, CA, USA). Subsequently, quantitative PCR was carried out with TaqMan Universal PCR Master Mix (Applied Biosystems, Foster City, CA, USA) on an ABI 7500 Real-Time PCR system (Applied Biosystems, Foster City, CA, USA). The expression level of miR-139-5p was normalized to a spike-in control, cel-miR-39 and was calculated by using the 2 ${}^{-\Delta\Delta\text{Ct}}$ method. Each experiment was run in triplicate.

2.4 Statistical analysis

All statistical analyses were performed using MedCalc 17.11.5 (MedCalc, Ostend, Belgium). The median level of serum miR-139-5p in the healthy controls was considered as the normal level. The Mann-Whitney U test was used to perform statistical analysis of serum miR-139-5p levels between groups. A chi-square test was used to evaluate the relationship between miR-139-5p and various clinicopathologic variables. The receiver operating characteristic (ROC) curve was constructed for identifying OS cases from the normal controls. Overall survival curves were established by the KaplanMeier method and the log-rank test. Cox proportional hazards regression analysis was used to estimate independent prognostic indicators for OS. Overall survival was defined as the time from the date of diagnosis to the date of death or last follow-up. A difference was defined statistically significant when $P<$ 0.05.

Figure 2.

Diagnostic value of serum miR-139-5p levels for OS patients.

Figure 3.

(A) Low serum miR-139-5p expression was significantly associated with worse overall survival. (B) Patients with distant metastasis had worse overall survival than those without. (C) Patients in higher clinical stage had worse overall survival than those in low clinical stage.

3. Results

3.1 Serum detection of miR-139-5p expression

We performed qRT-PCR analysis for serum miR-139-5p levels in all participants. Our data showed that miR-139-5p expression was greatly downregulated in OS subjects than that of controls ( $P<$ 0.05, Fig. 1A). Furthermore, a significant decrease in serum miR-139-5p expression was found in patients with distant metastasis ( $n=$ 30) compared with those without ( $n=$ 68, $P<$ 0.05, Fig. 1B). Also, serum miR-139-5p levels in stage III patients ( $n=$ 35) was much lower than those in stage I/II subjects ( $n=$ 63, $P<$ 0.05, Fig. 1C).

3.2 Serum miR-139-5p as diagnosis signature for OS

Furthermore, ROC curve was plotted to determine a cut-off value that could differentiate OS cases from healthy individuals. The result revealed at the optimal cut-off value, serum miR-139-5p had a specificity of 80.0% and a sensitivity of 76.5% for discriminating OS subjects from healthy volunteers with an area under the curve (AUC) of 0.846 (Fig. 2).

3.3 Correlation between clinical features and serum miR-139-5p levels of OS patients

The correlation between serum miR-139-5p expression and clinical parameters was analyzed. The parameters included gender, age, tumor site, tumor size, distant metastasis, tumor stage and differentiation status. All OS cases were divided into miR-139-5p low ( $n=$ 53) and high ( $n=$ 45) groups based on the median value. We found that decreased miR-139-5p expression was strongly associated with distant metastasis and tumor stage ( $P<$ 0.05, Table 1), whereas there were no significant associations between miR-139-5p and gender, age, tumor site, tumor size, differentiation status (all $P>$ 0.05, Table 1).

3.4 Correlation between serum miR-139-5p level and patients’ prognosis

A Kaplan-Meier survival analysis demonstrated that low serum miR-139-5p expression was closely correlated with worse patient survival ( $P=$ 0.0020, Fig. 3A). In addition, OS patients with distant metastasis ( $P=$ 0.0010, Fig. 3B) or in the advanced tumor stage ( $P<$ 0.0001, Fig. 3C) suffered shorter overall survival compared to those controls respectively.

Table 2
Univariate and multivariate Cox regression analyses for overall survival in patients with osteosarcoma

Variables	Univariate analysis		Multivariate analysis
	HR (95% CI)	$P$	HR (95% CI)	$P$
Gender	1.21 (0.96–1.48)	NS	1.43 (1.08–1.94)	NS
Age	1.09 (0.83–1.31)	NS	1.18 (0.92–1.46)	NS
Tumor site	1.34 (1.07–1.76)	NS	1.61 (1.20–2.07)	NS
Tumor size	1.47 (1.12–1.88)	NS	1.76 (1.32–2.25)	NS
Distant	2.67 (1.62–3.82)	0.017*	3.13 (1.78–4.71)	0.010*
metastasis
Tumor stage	3.04 (1.74–4.57)	0.011*	3.52 (1.91–5.44)	0.005*
Differentiation	1.65 (1.23–2.24)	NS	1.94 (1.36–2.65)	NS
status
MiR-139-5p	2.85 (1.66–4.17)	0.013*	3.24 (1.81–4.76)	0.007*

HR, Hazard Ratio; CI, Confidence Interval; NS, not significant.

Next, the univariate Cox hazard regression analysis showed that serum miR-139-5p (HR $=$ 2.85; 95% CI, 1.66–4.17; $P=$ 0.013), distant metastasis (HR $=$ 2.67; 95% CI, 1.62–3.82; $P=$ 0.017), tumor stage (HR $=$ 3.04; 95% CI, 1.74–4.57; $P=$ 0.011) were significant prognostic indicators of OS. The multivariate Cox proportional hazard regression analysis revealed that serum miR-139-5p (HR $=$ 3.24; 95% CI, 1.81–4.76; $P=$ 0.007), distant metastasis (HR $=$ 3.13; 95% CI, 1.78–4.71; $P=$ 0.010), tumor stage (HR $=$ 3.52; 95% CI, 1.91–5.44; $P=$ 0.005) were independent prognostic predictors for OS patients (Table 2).

4. Discussion

MiRNAs are stably detectable in the serum and the expression patterns of serum miRNAs are closely associated with various cancers, and can be used as non-invasive indicators for diagnosing and monitoring human cancer. In the present study, we found that miR-139-5p expression was significantly decreased in OS patients, and reduced serum miR-139-5p levels were associated with distant metastasis and advanced tumor stage. Patients with low serum miR-139-5p expression had shorter overall survival. Moreover, univariate and multivariate analyses revealed that serum miR-139-5p was an independent marker for predicting poorer overall survival in OS subjects. The data showed detection of serum miR-139-5p expression could be further evaluated as a reliable biomarker for OS diagnosis and prognosis. We speculated that methylation of miR-139-5p in its promoter region is the major reason accounting for the reduction of miR-139-5p in OS. Increased methylation of miR-139-5p has been reported in non small lung cell carcinoma and head and neck cancer [12, 13]. Therefore, the OS cells might secret less miR-139-5p into the circulating system. Exosomes, which contain proteins, DNA, mRNA, miRNA, and lipids, are important mediators for cellular communication and can be detected in the biofluids [14]. It is also possible that less miR-139-5p is packaged into the exosomes, leading to the downregulation of miR-139-5p in the serum samples from OS patients.

Indeed, to date, some studies had reported the suppressive role of miR-139-5p in OS. Shi et al showed miR-139-5p was significantly downregulated in both OS tissues and cell lines. MiR-139-5p directly targeted DNMT1, and high miR-139-5p expression greatly inhibited OS cell growth, migration and invasion in vitro and suppressed tumor growth in vivo [15]. Likewise, Delsin et al. revealed miR-139-5p levels in OS samples were dramatically lower than those in non-tumor controls, indicating miR-139-5p acted as a tumor suppressor [16].

Besides OS, accumulating evidence revealed miR-139-5p played as a tumor suppressor in different tumor types. In ovarian cancer, the expression of miR-139-5p was reduced in cancerous tissues and cell lines, and enforced miR-139-5p expression markedly repressed the oncogenic activities of cancer cells both in vitro and in vivo through regulating ROCK2 [17]. Hua and colleagues showed miR-139-5p overexpression inhibited aerobic glycolysis, proliferation and metastasis of hepatocellular carcinoma (HCC), ETS1 was identified as the downstream target [18]. Similar study was conducted on HCC cells showing miR-139-5p expression was inversely correlated with ZEB1 and ZEB2, miR-139-5p upregulation or ZEB1/ZEB2 inhibition attenuated carcinogenesis and metastasis of HCC [19]. In glioblastoma multiforme (GBM), ectopic miR-139-5p expression decreased ZEB1 and ZEB2 expression and caused the inhibition of GBM cell migration and invasion, low miR-139-5p expression predicted poor overall survival of GBM patients [20]. In endometrial cancer (EC), miR-139-5p expression was decreased in EC tissues in comparison with matched normal tissues, enhanced miR-139-5p expression restrained cell viability and migration via targeting HOXA10 [21]. Moreover, Catanzaro et al. reported high miR-139-5p resulted in decreased cell proliferation in pediatric low-grade gliomas cells by regulating PI3K/AKT signaling [22]. In nasopharyngeal carcinoma (NPC), Shao et al. found reintroduction of miR-139-5p inhibited NPC cell proliferation, invasion and epithelial-to-mesenchymal transition [23]. In bladder cancer (BC), the levels of miR-139-5p were relatively lower in BC tissues. MiR-139-5p upregulation was attributed to reduced invasion and migration of BC cells, the direct targets of miR-139-5p were Bmi1 [24] and MMP11 [25]. Also, a reduced level of miR-139-5p was found in lung cancer tissues compared with normal samples, increased expression of miR-139-5p significantly inhibited lung cancer cell proliferation, metastasis, and induced apoptosis by negatively regulating c-Met oncogene [26]. In tongue squamous cell carcinoma (TSCC), Duz et al. showed miR-139-5p levels in saliva samples were underexpressed in TSCC patients. MiR-139-5p expression was significantly elevated after treatment, and showed good performance to identify TSCC patients from healthy controls [27]. Similarly, the downregulation of miR-139-5p was closely associated with aggressive features of esophageal squamous cell carcinoma (ESCC) patients, high miR-139-5p expression dramatically repressed cell proliferation capability and induction of apoptosis in ESCC cells in vitro by degrading NR5A2 [28].

In contrast, miR-139-5p was frequently and highly expressed in blood samples of prostate cancer (PC) patients, thus enabling discrimination between PC patients and benign prostatic hyperplasia (BPH) subjects, suggesting that miR-139-5p functioned as an oncogene [29]. Interestingly, miR-139-5p was found to function as a tumor suppressor in early-stage colorectal cancer (CRC) by some reports. For example, downregulation of miR-139-5p was noted in cancer tissues compared to normal tissues. Re-expression of miR-139-5p decreased CRC cell migration and invasion, enhanced chemotherapeutic sensitivity in vitro, as well as suppressed metastasis in vivo by directly targeting BCL2 [30], AMFR and NOTCH1 [31]. Whereas, Miyoshi et al. reported miR-139-5p overexpression can promote CRC cell colonization and enhance peritoneal metastasis. The levels of miR-139-5p were significantly elevated in patients with recurrent CRC and liver metastatic CRC, and the patients with high miR-139-5p expression had significantly worse prognosis [32]. The controversial properties of miR-139-5p suggested this miR might behave differently depending on cancer progression.

5. Conclusions

Conclusively, our study highlights the potential role of serum miR-139-5p expression for the early diagnosis and prognosis of OS. We found serum miR-139-5p expression was markedly downregulated in OS patients, and low miR-139-5p expression was associated with poor prognosis. Therefore, serum miR-139-5p might be useful as a non-invasive biomarker for OS.

Footnotes

Conflict of interest

None.

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The diagnostic effect of serum miR-139-5p as an indicator in osteosarcoma

Abstract

BACKGROUND:

OBJECTIVE:

METHODS:

RESULTS:

CONCLUSIONS:

Keywords

1. Introduction

2. Materials and methods

2.1 Ethics statement

2.2 Population and sample collection

Table 1 Correlation between serum miR-139-5p status and clinicopathological characteristics

2.4 Statistical analysis

3.1 Serum detection of miR-139-5p expression

3.2 Serum miR-139-5p as diagnosis signature for OS

3.3 Correlation between clinical features and serum miR-139-5p levels of OS patients

3.4 Correlation between serum miR-139-5p level and patients’ prognosis

Table 2 Univariate and multivariate Cox regression analyses for overall survival in patients with osteosarcoma

5. Conclusions

Footnotes

Conflict of interest

References

Table 1
Correlation between serum miR-139-5p status and clinicopathological characteristics

Table 2
Univariate and multivariate Cox regression analyses for overall survival in patients with osteosarcoma