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Abstract

OBJECTIVE:

This study aimed to investigate the expression level and clinical significance of serum NT5E protein (ecto-5’-nucleotidase) in patients with colorectal cancer.

METHODS:

The expression level of serum NT5E protein in 232 patients with colorectal cancer and 158 normal controls was detected using enzyme-linked immunosorbent assay. Moreover, the relationship between the expression level of serum NT5E and the clinicopathological features of colorectal cancer was analyzed.

RESULTS:

The expression level of serum NT5E in patients with colorectal cancer was significantly higher compared with that in normal controls ( $P<$ 0.05). The expression level of serum NT5E in patients with colorectal cancer closely correlated with the family history of tumors ( $P=$ 0.001), expression level of CA19-9 ( $P=$ 0.031), lymph node metastasis ( $P=$ 0.001), distant metastasis ( $P=$ 0.010), nerve invasion ( $P=$ 0.049), degree of differentiation ( $P=$ 0.013), and TNM staging ( $P=$ 0.001), but not with gender, age, smoking and drinking histories, expression level of carcinoembryonic antigen (CEA), tumor locations, vascular tumor thrombus, cancer nodules, and pathological type ( $P>$ 0.05). Moreover, the overall survival rate of patients with colorectal cancer was significantly lower in the NT5E high-expression group, with statistical significance ( $\chi^{2}=$ 11.184, $P=$ 0.001).

CONCLUSIONS:

The expression level of serum NT5E increased in patients with colorectal cancer, and closely correlated with the malignant evolution and clinical prognosis of colorectal cancer. NT5E might serve as a serological indicator for molecular diagnosis and prognosis of colorectal cancer clinically.

Keywords

NT5E colorectal cancer prognosis

1. Introduction

Colorectal cancer is currently the third most malignant tumor in the world, posing a serious threat to human health. The incidence rate of colorectal cancer in China ranks the fourth among all malignant tumors, and the mortality rate ranks the fifth [1]. A gradually increasing trend of colorectal cancer has been observed with rapid economic development and lifestyle changes. As the early symptoms of colon cancer are not obvious, a majority of patients are in the advanced stage at diagnosis. The treatment effect is often unsatisfactory. Recurrence and metastasis are important causes of death due to colorectal cancer [2]. Therefore, early detection and diagnosis have important significance in improving the survival rate clinically. At present, serum tumor markers are highly effective and noninvasive, and hence are vital in the adjuvant diagnosis, disease assessment, and diagnosis and treatment of cancers. Finding molecular markers that assist in the diagnosis of colorectal cancer and predict recurrence and metastasis is a hot topic in the current oncology research, which has important clinical value in early diagnosis and individualized treatment for patients.

NT5E is a type of glycoprotein expressed in a variety of cells in mammals, including hepatocytes, intestinal epithelial cells and fibroblasts, endothelial cells, lymphocytes, glial cells, and so on [3, 4]. The main function of NT5E is to catalyze nucleotide dephosphorylation to hydrolyze nucleotides, which is one of the key enzymes of nucleotide catabolism. Current studies in China and abroad have found that NT5E is highly expressed in many human solid tumors and is closely related to the occurrence, progression, and metastasis, as well as prognosis of tumors [5, 6, 7, 8, 9]. Therefore, NT5E is expected to provide a new target for the molecular therapy of tumors [10]. In this study, the expression level of NT5E protein was detected in various patients with colorectal cancer to investigate the value of the measurement of serum NT5E protein concentration in clinical diagnosis, disease monitoring, and prognosis determination of patients with colorectal cancer.

2. Materials and methods

2.1 Study participants

A total of 232 patients (aged 28–85 years, with an average age of 60.15 $\pm$ 11.23 years) with colorectal cancer in our hospital were enrolled as the study group, including 155 males and 77 females. The inclusion criteria were as follows: (1) The patients were pathologically confirmed to have colorectal cancer. (2) They had no previous history of other malignancies. (3) They did not receive adjuvant therapy before the surgery, such as chemoradiotherapy. Meanwhile, 158 serum specimens were collected from healthy people who underwent physical examination in the physical examination center of the hospital. The average age of the healthy controls was 58.38 $\pm$ 10.22 years. The possibility of malignancies in the control group was excluded by systematic examination in the hospital. Among the 232 patients with colorectal cancer, 82 had colon cancer and 150 had rectal cancer. No significant differences in age, gender, and so on were found between the two groups ( $P>$ 0.05). The TNM staging was performed for patients with colorectal cancer based on the staging criteria for colorectal cancer of the American Joint Committee on Cancer in 2010 [11]. Informed consent was obtained from all the patients, and this study was approved by the ethics committee of the hospital.

2.2 Detection method

A total of 5 mL of peripheral venous blood was extracted from patients under fasting state half an hour before the surgery. It was centrifuged at 3000 rpm for 10 min to separate the serum. The separated serum was stored at $-$ 80 ${}^{\circ}$ C to be used as serum specimen. The serum specimen was slowly equilibrated to recover to room temperature before use. The enzyme-linked immunosorbent assay (ELISA) kit was purchased from USCN KIT INC (SEB250Hu; Wuhan, China). The expression level of serum NT5E was detected using ELISA, and the procedures were performed strictly in accordance with the kit instructions.

2.3 Evaluation criteria

The receiver-operating characteristic (ROC) was applied to analyze the significance of the expression level of serum NT5E in the diagnosis of colorectal cancer. The Youden index was used to analyze the optimal cut-point value, which was the critical value (cut-off value). The expression of NT5E was considered to be high if the Youden index exceeded the cut-off value.

2.4 Follow-up

The follow-up included outpatient and telephone follow-ups. The endpoint event was defined as death. The overall survival (OS) was calculated from the date of diagnosis. The last follow-up was on September 1, 2017. The date of the last effective follow-up was the censored data for patients lost to follow-up.

2.5 Statistical analysis

Continuous data were expressed as mean $\pm$ standard deviation, and the $t$ test was used. Categorical data were analyzed using the $\chi^{2}$ test, and $P<$ 0.05 was considered to be statistically significant. Univariate survival analysis was performed using the Kaplan-Meier method, and the survival curve was plotted. Statistical analysis was performed using the SPSS (version 18.0, IBM Corporation, Armonk, NY, USA) and GraphPad Prism (version 5; GraphPad Software, La Jolla, CA, USA) software.

Figure 1.

Receiver operating characteristic (ROC) analysis was performed to determine the sensitivity and specificity of serum NT5E protein level. AUC $=$ 0.831 (0.791–0.870); Sensitivity $=$ 0.759; Specificity $=$ 0.753; Cut-off value $=$ 1.73 ng/mL.

3. Results

3.1 Expression level of serum NT5E in patients with colon cancer

As shown in Fig. 1, the area under the ROC curve was 0.831 for the diagnosis of colorectal cancer using the expression level of serum NT5E. The 95% confidence interval was (0.791–0.870), which was statistically significant compared with 0.5 ( $P<$ 0.001). According to the formula that corrects diagnostic index $=$ sensitivity $+$ specificity $-$ 1, the correct diagnostic index corresponding to the cut-off point of 1.73 was the largest in the ROC curve. Therefore, 1.73 ng/mL was used as the best diagnostic cut-off point (cut-off value), meaning that when NT5E concentration was greater than 1.73 ng/mL, NT5E was highly expressed. Otherwise, NT5E was lowly expressed. Among the serum specimens from 110 patients with early-stage colorectal cancer, 65 patients showed high expression of NT5E, with the rate of expression of 59.1%. In the serum specimens from 122 patients with advanced colorectal cancer, 107 patients showed high expression of NT5E, with the rate of expression rising to 87.7%. On the contrary, in the serum samples of 158 normal controls, only 39 showed high expression of NT5E, with the rate of expression of only 24.7%. As shown in Fig. 2, the expression level of NT5E in patients with colorectal cancer was significantly higher compared with that in normal controls, with statistical significance ( $\chi^{2}=$ 111.646, $P<$ 0.001).

Figure 2.

Association between serum NT5E expression and the CRC patients clinicopathological variables. Comparison of serum NT5E expression between healthy controls and different stage CRC patients ( $p<$ 0.01).

Table 1

Correlation between serum NT5E expression levels and clinicopathological parameters of colorectal cancer

Clinicopathological parameters	No. of cases	NT5E expression				$\chi^{2}$	$P$ -value
		Low	(%)	High	(%)
Gender						0.966	0.326
Female	77	23	29.9	54	70.1
Male	155	37	25.9	118	76.1
Age(years)						0.676	0.411
$\leqslant$ 60	115	27	23.5	88	76.5
$>$ 60	117	33	28.2	84	71.8
Smoking status						1.734	0.188
No	146	42	28.8	104	71.2
Yes	86	18	20.9	68	79.1
Drinking status						0.094	0.760
No	147	39	26.5	108	73.5
Yes	85	21	24.7	64	75.3
Family history						10.119	0.001
No	178	55	30.9	123	69.1
Yes	54	5	9.3	49	90.7
HBV infection						1.728	0.189
No	201	49	24.4	152	75.6
Yes	31	11	35.5	20	64.5
CEA						0.498	0.480
$<$ 5 ng/ml	138	38	27.5	100	72.5
$\geqslant$ 5 ng/ml	94	22	23.4	72	76.6
CA19-9						4.677	0.031
$<$ 37 U/ml	182	53	29.1	129	70.9
$\geqslant$ 37 U/ml	50	7	14.0	43	86.0
Primary tumor location						0.681	0.711
Left	34	7	20.6	27	79.4
Right	48	12	25.0	36	75.0
Rectum	150	41	27.3	109	72.7
Invasion depth						2.200	0.138
T1 $+$ T2	57	19	33.3	38	66.7
T3 $+$ T4	175	41	23.4	134	76.6
Lymph node metastasis						21.522	0.001
N0	122	47	38.5	75	61.5
N1	69	8	11.6	61	88.4
N2	41	5	12.2	36	87.8
Distant metastasis						11.377	0.010
M0	188	57	30.3	131	69.7
M1a	24	2	8.3	22	91.7
M1b	16	0	0.0	16	100.0
M1c	4	1	25.0	3	75.0
Vascular invasion						1.763	0.184
No	192	53	27.6	139	72.4
Yes	40	7	17.5	33	82.5
Nerve invasion						3.870	0.049
No	171	50	29.2	121	70.8
Yes	61	10	16.4	51	83.6
Tumor deposit						2.558	0.110
No	180	51	28.3	129	71.7
Yes	52	9	17.3	43	82.7
Pathological type						0.788	0.375
Adenocarcinoma	219	58	26.5	161	73.5
Mucous adenocarcinoma	13	2	15.4	11	84.6
Differentiation						8.754	0.013
Low	47	9	19.1	38	80.9
Middle	180	47	26.1	133	73.9
High	5	4	80.0	1	20.0
TNM stages						24.701	0.001
I $+$ II	110	45	40.9	65	59.1
III $+$ IV	122	15	12.3	107	87.7

Table 2

Univariate and multivariate Cox analysis of variables considered for overall survivval rates of colorectal cancer patients

Variables	Univariate			Multivariate
	HR	95% CI	$P$ value	HR	95% CI	$P$ value
Age	1.173	0.729–1.889	0.51
Gender	1.107	0.662–1.851	0.699
Lymph node metastasis	3.216	2.365–4.373	0.001	1.546	0.995–2.402	0.053
Vascular invasion	2.963	1.768–4.965	0.001	1.535	0.884–2.665	0.128
Nerve invasion	5.435	3.356–8.801	0.001	1.91	1.025–3.560	0.042
Tumor deposit	3.987	2.466–6.446	0.001	0.76	0.354–1.631	0.482
Distant metastasis	3.561	2.736–4.634	0.001	2.897	2.033–4.129	0.001
CEA status	3.141	1.917–5.146	0.001	2.301	1.295–4.091	0.005
CA19-9 status	3.685	2.278–5.960	0.001	0.877	0.440–1.749	0.709
NT5E status	3.467	1.585–7.582	0.001	1.681	0.738–3.830	0.217

3.2 Correlation between the expression level of serum NT5E and the clinicopathological features of patients with colorectal cancer

Correlation analysis was performed for the expression level of serum NT5E and its clinicopathological data. The results showed that the expression level of serum NT5E did not closely correlate with gender, age, smoking and drinking histories, expression level of carcinoembryonic antigen (CEA), drinking history, tumor location, depth of local infiltration, presence of vascular tumor thrombus, presence of cancer nodules, and pathological type ( $P>$ 0.05). However, this study found a significantly high expression of serum NT5E in patients with a family history of cancer ( $P=$ 0.001). Also, the high expression of CA19-9 correlated positively with the expression of NT5E. Moreover, the expression level of serum NT5E was found to significantly correlate with lymph node metastasis, distant metastasis, and advanced tumor staging ( $P<$ 0.001, $P=$ 0.010, $P<$ 0.001). This study also found that the high expression level of serum NT5E was closely associated with nerve invasion and degree of tumor differentiation, and the results were statistically significant ( $P=$ 0.049, $P=$ 0.013; Table 1).

3.3 Effects of the expression level of serum NT5E on the prognosis of patients with colorectal cancer

By September 2017, 68 patients died and 15 lost to follow-up among the 232 patients with colorectal cancer in this study. The Kaplan-Meier survival curve showed that the OS of patients with high expression of serum NT5E protein was lower than that of patients in the low-expression group. The difference was statistically significant ( $\chi^{2}=$ 11.184, $P=$ 0.001; Fig. 3). Univariate (log-rank test) and multivariate (Cox proportional hazard model) analyses were further performed for the clinical and pathological factors that might affect the survival and prognosis of patients with colorectal cancer. The univariate survival analysis showed that lymph node metastasis ( $P<$ 0.001), vascular tumor thrombus ( $P<$ 0.001), nerve invasion ( $P<$ 0.001), cancer nodules ( $P<$ 0.001), distant metastasis ( $P<$ 0.001), serum CEA ( $P<$ 0.001), serum CA19-9 ( $P<$ 0.001), and the expression level of NT5E ( $P<$ 0.001) were associated with postoperative survival in patients with colorectal cancer. However, age and gender did not significantly correlate with the postoperative survival of patients with colorectal cancer (Table 2). Further analysis using multivariate COX proportional hazards regression model demonstrated that nerve invasion ( $P=$ 0.042), distant metastasis ( $P<$ 0.001), and serum CEA ( $P=$ 0.005) were independent risk factors for the prognosis of patients with colorectal cancer (Table 2).

Figure 3.

Kaplan-Meier survival analysis showing that patients with high NT5E expression had a shorter overall survival than those with low NT5E expression ( $\chi^{2}=$ 11.184, $p=$ 0.001).

4. Discussion

In the recent years, the incidence rate of colorectal cancer in China has increased significantly with population aging, changes in lifestyle and dietary habits, excessive intake of animal fat and high protein, and insufficient intake of dietary fibers. Colorectal cancer has become the third common malignant tumor that seriously endangers human health, following lung cancer and breast cancer [1]. Surgical resection is still the main treatment for colon cancer. Early detection and diagnosis are keys to improve efficacy and prognosis. At present, the clinical diagnosis of colorectal cancer mainly relies on colonoscopy and pathological examination, but patient compliance is poor. The detection of tumor markers has received increasing attention in the early screening and diagnosis of colorectal cancer due to its painless nature. Therefore, the identification of molecular tumor markers for early diagnosis of colorectal cancer is particularly important.

Recently, the enzymatic activity of NT5E has been found to elevate in tissues and serum of some patients with digestive tract tumors and is associated with tumor invasion and metastasis as well as short survival time, thus having significance in the early diagnosis and prognosis of digestive tract tumors [9, 12, 13, 14]. The expression level of serum NT5E is significantly increased in a variety of cancers, including melanoma, malignant glioma, bladder cancer, breast cancer, prostate cancer, stomach cancer, colorectal cancer, ovarian cancer, and so on. Zhang et al. detected the expression level of NT5E in human rectal adenocarcinoma, and found that NT5E expression was increased in both tumoral and stromal compartments where the protein and messenger RNA (mRNA) expression levels of NT5E were significantly increased compared with paracancerous controls [13]. And in-depth study revealed that NT5E might promote proliferation and migration via potentiating EGFR/Akt and VEGF/Akt pathway, which was independent of its enzyme activity [7]. Many mechanisms can explain the possible causes of NT5E overexpression in tumors. Studies related to breast cancer suggested that the loss of estrogen receptors might be the cause of NT5E overexpression [15]. Moreover, the hypoxic state in the tumor microenvironment is also an important reason for promoting the expression level of serum NT5E in tumor cells [16]. Studies have confirmed that the inhibition of Hypoxia-inducible factor-1 $\alpha$ (HIF-1 $\alpha$ ) by antisense oligonucleotide technology can significantly reduce the high expression of NT5E induced by hypoxia [17]. Multiple studies have shown that the overexpression of NT5E can promote tumor cell proliferation. Bavaresco et al. found that the proliferation activity of tumor cells reduced by 30% after glioma cells were treated with NT5E-specific inhibitor [18]. However, the proliferation activity of tumor cells treated with adenosine increased by 35%. Yegutkin et al. also obtained similar conclusions: primary lesions of melanoma were significantly reduced in mouse models with NT5E deletion [19]. At present, many animal models and related studies of clinical patients have demonstrated a significant role of NT5E in promoting tumor metastasis and affecting tumor proliferation. Two independent studies have reached the same conclusion that NT5E is closely related to lymph node metastasis in breast cancer [15, 20]. Meanwhile, some retrospective clinical studies have also shown that high expression of NT5E was significantly associated with metastasis of gastric cancer [21], prostate cancer [22], malignant melanoma [23], and so on. The enzymatic activity of NT5E could hydrolyze adenosine monophosphate to adenosine, a key factor in immune escape. When the hydrolyzed adenosine bound to G protein-coupled receptors, such as A1R, A2AR, A2BR, and A3R, adenosine could act in the immune system through a variety of pathways, thus inhibiting the anti-tumor immune response through multiple signaling pathways [6].

Although a large number of studies are available on the relevant functions of NT5E in various types of tumors, reports on the expression levels of serum NT5E and the prognosis of cancer patients are relatively limited. Therefore, in this study, the expression levels of serum NT5E in patients with colorectal cancer and normal population were detected using ELISA. The results showed significantly high expression of serum NT5E in patients with colorectal cancer compared with that in the normal population. Further analysis combined with clinicopathological features of patients revealed that high expression of serum NT5E was closely associated with various clinical features, including family history of the patients, expression of CA19-9, lymph node metastasis, distant metastasis, nerve invasion, TNM staging, and so on. These data once again demonstrated that the overexpression of NT5E was closely related to the malignant behaviors of colorectal cancer and tumor progression. In the recent years, Wu et al. reported the relationship between the NT5E expression and tumor prognosis in colorectal cancer patients [14]. In their study, the expression level in tumor tissues was detected by immunohistochemistry, and statistical analysis was performed combined with prognosis of the patients. Their findings suggested that the high expression of NT5E significantly correlated with adverse prognosis of the patients. However, in this study, the expression level of serum NT5E was detected, and the Kaplan-Meier survival analysis showed that the OS rate of patients with high expression of NT5E was significantly lower than that of patients with low expression of NT5E after the surgery. Further univariate regression analysis revealed that lymph node metastasis, vascular tumor thrombus, nerve invasion, cancer nodules, distant metastasis, serum CEA, serum CA19-9, and expression level of serum NT5E were associated with postoperative survival in patients with colorectal cancer. The expression level of serum NT5E was not statistically significant, as detected using Cox proportional multivariate risk model in this study, which might be caused by the difference in model fitting due to the difference in study data and variables. Moreover, the study results needed further confirmation due to short follow-up time and small sample size. This study confirmed the relationship of the expression level of serum NT5E with the invasion and metastasis of colorectal cancer as well as the value of serum NT5E in evaluating the survival prognosis of patients with colorectal cancer from the perspective of clinical utility. This study suggested that the detection of NT5E protein in serum had a better clinical application value for the diagnosis and prognosis of colorectal cancer because serum testing is more noninvasive, economical, safe, and convenient. It is easy to be clinically promoted and applied. Therefore, it has a good feasibility for early screening and long-term follow-up together with detection of cancer patients.

In summary, this study investigated the expression of NT5E in colorectal cancer tissues and its relationship with clinicopathological features as well as survival prognosis in patients with colorectal cancer. It was speculated that the high expression of serum NT5E might have an important role in the malignant progression of colorectal cancer. Moreover, serum NT5E can be used as an independent risk factor for the prognosis of patients with colorectal cancer, thus having significance in evaluating the survival prognosis of patients with colorectal cancer. Moreover, NT5E may be a potential target for blocking the invasion and metastasis of colorectal cancer. However, the specific molecular mechanism of NT5E in promoting the occurrence and development of colorectal cancer still requires further investigation.

Footnotes

Acknowledgments

This work was supported by the Zhejiang Provincial Natural Science Foundation of China (nos. LY15H160 005).

Conflict of interest

None.

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Expression and clinical significance of serum NT5E protein in patients with colorectal cancer

Abstract

OBJECTIVE:

METHODS:

RESULTS:

CONCLUSIONS:

Keywords

1. Introduction

2. Materials and methods

2.1 Study participants

2.2 Detection method

2.3 Evaluation criteria

2.4 Follow-up

2.5 Statistical analysis

3.1 Expression level of serum NT5E in patients with colon cancer

3.3 Effects of the expression level of serum NT5E on the prognosis of patients with colorectal cancer

Footnotes

Acknowledgments

Conflict of interest

References