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Higher IGFBP-1 to IGF-1 serum ratio predicts unfavourable survival in patients with nasopharyngeal carcinoma
© The Author(s). 2017
Received: 30 October 2015
Accepted: 18 January 2017
Published: 31 January 2017
The insulin-like growth factor (IGF) system plays an important role in the development and progression of cancer. However, little is known about the expression of the IGF system components and their clinicopathological significance and prognostic value in nasopharyngeal carcinoma (NPC).
IGF system components (IGF-1, IGF-2, IGF-1SR, IGFBP-1, IGFBP-2, IGFBP-3, IGFBP-4 and IGFBP-6) were quantified from the plasma of NPC patients and healthy individuals using the RayBio Human Cytokine Antibody Array. IGFBP-1 and IGF-1 mRNA levels were quantified by real-time qPCR, and protein expression was detected by western blot in nine NPC cell lines and four immortalized nasopharyngeal epithelial (NPE) cell lines. Tissue-specific expression of IGFBP-1 and IGF-1 was detected by immunohistochemistry in paraffin-embedded NPC tissues. ELISA analysis was used to measure the serum levels of IGFBP-1 and IGF-1 in 142 NPC patients and 128 healthy controls and determine potential correlation with clinicopathological parameters.
Significantly higher levels of circulating IGFBP-1 and lower levels of IGF-1 and IGF-2 were detected in NPC patients compared to healthy controls by Cytokine Antibody Array analyses (P = 0.034, 0.012, 0.046, respectively). IGFBP-1 expression was detected in the majority of NPC cell lines, but not in NPE cell lines, and was shown to localize to the nucleus of tumour cells, in contrast to the cytoplasmic staining observed in normal cells. Importantly, IGFBP-1 expression was stronger in NPC tumour tissues compared to peritumoural tissues. In contrast, IGF-1 expression was weak or absent in NPC and NPE cell lines, with the exception of the EBV-infected C666 cell line, and was found to be expressed at lower levels in tumour tissues compared to tumour-adjacent normal tissue. Levels of serum IGFBP-1 were shown to be significantly higher in patients with NPCs compared to healthy control individuals (55.23 ± 41.25 μg/L vs. 32.08 ± 29.73 μg/L, P < 0.001), whereas serum levels of IGF-1 were significantly lower in NPC patients compared to healthy controls (98.14 ± 71.48 μg/L vs. 164.01 ± 92.08 μg/L, P = 0.001). Consistently, the IGFBP-1/IGF-1 serum ratio was shown to be significantly higher in NPC patients compared to healthy control individuals (P = 0.002). Serum levels of IGFBP-1 and the IGFBP-1/IGF-1 ratio significantly correlated with age (P = 0.020; P = 0.016), WHO histological classification (P = 0.044; P = 0.048), titre of EA (EB Virus Capsid Antigen-IgA) and NPC (P = 0.015; P = 0.016). In contrast, higher IGFBP-1 serum levels and IGFBP-1/IGF-1 ratio significantly correlated with poor RFS (P = 0.046; P = 0.037) and OS (P = 0.038; P = 0.009). Multivariate analysis revealed that the IGFBP-1/IGF-1 ratio, but not serum IGFBP-1 level, represents an independent risk factor for poor RFS (P = 0.044) and OS (P = 0.035).
A higher IGFBP-1/IGF-1 serum ratio is significantly associated with poor prognosis in NPC patients.
Nasopharyngeal carcinoma (NPC) is a malignant head and neck tumour with a distinct racial and geographical distribution that is highly prevalent in Southeast Asia . Although radiotherapy and chemotherapy are efficient therapeutic approaches for treating NPC, the disease remains a deadly due to late presentation of the disease and poor prognosis. Because NPC tumours are asymptomatic, advanced disease at time of diagnosis and high rates of recurrence and metastasis underlie the high mortality rate in NPC patients. Therefore, finding new biomarkers or risk factors will contribute to earlier diagnosis and better prognosis for NPC patients.
The insulin-like growth factor (IGF) system consists of a complex network of ligands (IGF-1 and 2), their cognate receptors (IGFR-1 and 2), IGF-binding proteins (IGFBP1-6), and IGFBP proteases. The IGF signalling pathway, which facilitates communication between cells and their physiologic environment, may be involved in human cancer progression and can be targeted for therapeutic intervention . Within the blood stream, IGF-1 is bound to IGFBPs and activates IGF-1R following its release from the complex. The interaction between IGFs, IGFBPs and IGFRs promotes cellular proliferation and inhibits apoptosis .
Several studies have reported a correlation between circulating levels of IGF-1 and IGFBP-1 in healthy people and the risk of cancer development. IGF-1 plasma or serum levels have been reported to be increased in patients with a variety of cancers, including colorectal adenoma, malignant melanoma, breast cancer, non-small cell lung cancer [4–6]. However, conflicting results have been observed in studies conducted in prostate cancer, epithelial ovarian cancer, breast cancer, and oral cancer [7–10]. In addition, serum levels of IGFBP-1 have been reported to be increased in metastatic prostate and oral cancers, but not in pancreatic, non-metastatic colorectal or endometrial cancers [11–13]. Despite considerable research, the role of IGFs in cancer remains unclear, and clinical trials have been unsuccessful . Moreover, how IGF-1 and IGFBP-1 are regulated at the expression level remains equivocal in tumour tissues and within the circulating blood stream.
In the present study, we examined the expression patterns of IGF-1 and IGFBP-1 in different NPC and normal nasopharyngeal epithelial (NPE) cells lines. Furthermore, we assessed the serum levels of IGF-1 and IGFBP-1 in NPC patients and healthy control individuals and determined whether altered IGF-1 and IGFBP-1 levels were associated with clinical outcome to assess the potential value of IGF-1 or IGFBP-1 as a prognostic biomarker for NPC.
Patients, blood and tissue samples
Plasma from 10 NPC patients and 10 healthy volunteers were obtained in October 2012 and used for 8 IGF-related cytokine arrays. Plasma samples were stored at 80 °C and were measured in 3 months.
Clinical characteristic of 142 patients with NPC
T1 + T2
T3 + T4
Lymphoid nodal states
1 + 2
3 + 4
WHO histological classification
OS rate (%)
Overall survival (OS) was defined as the interval between the date of surgery and the date of death or the last known follow-up visit. Relapse-free survival (RFS) was defined as the interval between the operation and the date that tumour recurrence or metastasis was diagnosed. All follow-up data from the NPC patients used in this study were available and complete. A total of 31 (21.8%) patients died during follow-up period.
Sera from 128 healthy volunteers (95 males, 33 females) with ages ranging from 21 to 77 years (mean: 47.8 years) were collected and used as controls. Healthy controls were selected from an archive of blood samples, and the control samples were matched as closely as possible to the NPC group with respect to previous handling and the time period of sample collection.
A 5-ml blood sample from each participant was allowed to clot for 30 to 60 min at room temperature. Each clotted sample was centrifuged at 1500 g for 10 min. All sera were then aliquoted and frozen at −80 °C until use.
Paraffin-embedded tumour tissue samples were obtained from 20 NPC patients who underwent surgery between May and December of 2013. None of the patients had received anticancer treatment prior to surgery, and all of the patients had histologically confirmed primary NPC in this retrospective study.
All of the blood and tissues sample were collected at the Cancer Center of Sun Yat-sen University. The study was approved by the Ethics Committee of Sun Yat-sen University Cancer Center and informed consent was obtained from each patient.
Eight IGF system members (IGF-1, IGF-2, IGF-1SR, IGFBP-1, IGFBP-2, IGFBP-3, IGFBP-4 and IGFBP-6) were quantified in the plasma of 10 NPC patients and healthy volunteers using the RayBio Human Cytokine Antibody Array (#AAH-CYT-5, RayBiotech Inc, GA, USA) according to the manufacturer’s instruction.
Two well-differentiated NPC cell lines CNE1 and HK1, three poorly-differentiated NPC cell lines (CNE2, HONE1, SUNE1) and two SUNE-1 subclones (6–10B and 5–8 F) were cultured in DMEM medium (Sigma, Saint Louis, MO, USA). Two undifferentiated NPC cell lines, C666-1 (EBV-positive) and SUNE2 (extremely low concentrations of EBV), were cultured in RPMI 1640 medium (Sigma). Immortalized nasopharyngeal epithelial (NPE) cell lines (N5-Tert, N5Bmi-1, N2-Bmi-1) and normal NPE cell lines (NP460) were cultured in Keratinocyte-SFM medium (10744–019, Gibco) and used as a control. All of the cell lines were maintained in our laboratory, and all media were supplemented with 10% foetal bovine serum (Sigma).
RNA preparation and quantitative real-time PCR
Total RNA was extracted from NPC and nasopharyngeal epithelial cells lines using the Trizol reagent (Invitrogen, USA) according to the manufacturer’s instruction. Reverse transcription of total RNA (2 μg) was performed using SuperScript II reverse transcriptase (GIBCO BRL, Grand Island, NY, USA). The quantification of target and reference glyceraldehyde-3-phosphate dehydrogenase (GAPDH) genes was performed using the Power SYBR Green qPCR SuperMix-UDG (Invitrogen, USA) on an iCycler (Bio-Rad, Hercules, CA, USA). CT is defined as the cycle at which the fluorescence is determined to be statistically significant above background. The relative mRNA expression was normalized to the expression of GAPDH, which yielded a 2-ΔCT value (ΔCT = CT(target gene)–CT(GAPDH)). All reactions were performed in triplicate in three independent experiments. The primers used for real-time RT-PCR were as follows: IGF-1: forward 5′- GCT CTT CAG TTC GTG TGT GGA −3′ and reverse 5′- GCC TCC TTA GAT CAC AGC TCC −3′; IGFBP-1: forward 5′-CTA TGA TGG CTC GAA GGC TC-3 ′ and reverse 5′-CCC ATT CCA AGG GTA GAC G-3′; GAPDH: forward 5′-GCA CCG TCA AGG CTG AG AAC-3′ and reverse 5 ′-TGG TGA AGA CGC CAG TGG A-3′.
Total protein was extracted using a lysis buffer and protease inhibitor (Beyotime Biotechnology, China). Equivalent protein amounts were denatured in an SDS sample buffer and then were separated by SDS-PAGE and transferred onto polyvinylidene difluoride membrane. After being blocked with 5% non-fat dry milk in PBS containing 0.05% Tween-20, the blotted membranes were incubated with anti-human IGF-1 and IGFBP-1 antibodies, (1:5000, 1:1000, respectively, R&D systems, USA) and then incubated with a secondary antibody (1:5000, Boster, China). GAPDH protein levels were also determined by using the specific antibody (1:1000, Boster, China) as a loading control.
Formalin-fixed, paraffin-embedded NPC sections were incubated with a goat polyclonal anti-IGF-1 (1:100, AF-291-NA, R&D, USA) or anti-IGFBP-1 antibody (1:100, AF871, R&D, USA) overnight at 4 °C. After washing in PBST, the tissue sections were treated with a horseradish peroxidase-conjugated anti-goat secondary antibody (1:1000, Zymed). The tissue sections were then developed with 3-diaminobenzidine tetrahydrochloride for 10 s, followed by counterstaining with 10% Mayer’s haematoxylin. The degree of staining was reviewed by two independent observers.
Serum IGF-1 and IGFBP-1 levels were determined by double-antibody sandwich ELISA according to the manufacturer’s instructions (DY291, DY871, R&D systems, USA). Briefly, 96-well microplates were coated with 100 μl/well of the capture antibody (mouse anti-human IGF-1 or IGFBP-1, 4.0 μg/ml) overnight at 4 °C. After blocking with 3% BSA, 100 μl of the test samples (1:100 diluted in 1% BSA) was added and incubated for 2 h at room temperature. Subsequently, 100 μl/well of the detection antibody (biotinylated goat anti-human IGF-1 (150 ng/ml) or IGFBP-1(400 ng/ml)) was added and incubated for 2 h at room temperature. Next, 100 μl/well of Streptavidin-HRP (1:200) was added and incubated for 20 min at room temperature. Finally, the substrate (tetramethylbenzidine) solution was added, and the reaction was terminated using 2 N H2SO4 and read at an OD of 450 nm. Each test included a standard control (CV = 12%).
All statistical analyses were carried out using the SPSS 20.0 statistical software package (SPSS Inc., Chicago, IL). The Mann–Whitney U test was used to evaluate the difference in IGF-1 and IGFBP-1 serum levels between NPC patients and healthy controls. Pearson's chi-squared test was used to analyse the association between IGF-1 and IGFBP-1 levels and the observed clinicopathological characteristics of patients with NPC. Survival curves were plotted by the Kaplan-Meier method and compared using the log rank test. The significance of various variables for survival was analysed using the Cox proportional hazards model (univariate and multivariate analysis). P < 0.05 was considered to be statistically significant in all cases.
Circulating levels of IGF-related cytokines differ between NPC patients and healthy control individuals
Characterization of IGFBP-1 and IGF-1 expression in NPC and NPE cell lines
IGF-1 mRNA and protein were detected in only 5 NPC cell lines, with the highest expression level of IGF-1 observed in C666 cells, which consistently harbours Epstein-Barr virus (EBV), and weaker expression of IGF-1 detected in three poorly differentiated NPC cell lines (CNE2, 5-F8, SUNE2) and well-differentiated cell lines CNE1. IGF-1 expression was shown to be absent in the other 4 NPC cell lines. Moreover, mRNA and protein levels of IGF-1 were expressed at moderate levels in the immortalized NPE cell line, N5Bmi-1, but not in the other 3 NPE cell lines. ELISA analysis showed that detectable secretory IGF-1 only in C666 cell line.
Those results showed that the stronger expression of IGFBP-1 in tumour cell lines than the normal cell lines, but weak expression of IGF-1 in both of tumour and normal cell lines.
Characterization of IGFBP-1 and IGF-1 expression in NPC tissues
Serum levels of IGFBP-1 and IGF-1 correlate with distinct NPC clinicopathological characteristics
Clinicpathological associations of IGF-1 and IGFBP-1 expression levels and IGF-1/IGFBP-1
(Mean ± SD)
(Mean ± SD)
55.08 ± 41.66
88.26 ± 60.75
55.93 ± 40.05
135.98 ± 88.78
47.18 ± 36.51
103.65 ± 69.31
63.85 ± 44.47
89.02 ± 66.48
T1 + T2
47.54 ± 36.71
87.09 ± 55.78
T3 + T4
57.01 ± 42.18
100.71 ± 74.63
Lymphoid nodal states
51.02 ± 41.80
96.69 ± 75.17
59.99 ± 40.41
99.79 ± 67.59
1 + 2
39.11 ± 37.45
99.42 ± 58.73
3 + 4
57.11 ± 41.40
97.99 ± 73.02
49.59 ± 39.68
117.07 ± 88.62
55.94 ± 41.55
95.76 ± 69.08
43.16 ± 41.80
58.52 ± 27.71
55.96 ± 41.20
97.42 ± 68.94
WHO histological classification
57.05 ± 41.94
98.25 ± 73.73
38.18 ± 25.70
96.88 ± 36.79
44.34 ± 36.35
104.31 ± 78.59
61.64 ± 42.79
94.51 ± 67.14
57.45 ± 43.73
102.20 ± 50.26
55.39 ± 41.05
95.68 ± 70.16
Prognostic significance of serum IGF-1 and IGFBP-1 levels in NPC patients
Multivariate Cox regression analysis for OS of 142 patients with NPC
Male vs. Female
< 46 vs. ≥46
T1 + T2 vs. T3 + T4
Lymphoid nodal states
N0-1 vs. N2-3
1 + 2 vs. 3 + 4
Yes vs. NO
Yes vs. No
WHO histological classification
NKUC vs. NKDC
≤ 1:10 vs. >1:10
≤ 1:40 vs. >1:40
Low vs. High
Low vs. High
> 1 vs. ≤1
Here, our study showed that patients with NPC display significantly higher serum levels of IGFBP-1 and significantly lower serum levels of IGF-1 compared to healthy control individuals. Moreover, we observed that higher serum IGFBP-1 levels and an IGFBP-1/IGF-1 ratio significantly correlated with decreased overall survival.
In this study, IGF-1 was more weakly expressed in the majority of nasopharyngeal tumour and normal epithelial cell lines, which is in line with previous studies showing that IGF-1 expression is lower in EBV-negtive NPC cell lines . In addition, IGF-1 expression was also weaker in NPC tumour tissues compared to adjacent normal tissues. Together, these results are consistent with the lower IGF-1 serum levels observed in NPC patients compared to the healthy controls in our study.
Our result that IGF-1 is reduced in NPC patients contradicts those of other studies showing that serum IGF-1 levels are elevated in cancer patients. High serum concentrations of IGF-1 have been associated with an increased risk of breast, prostate, colorectal and HCC [16, 17]. However, expression of IGF-1 appears to be inconsistent across different types of tumours. For example, IGF-1 protein expression has not been detected in the serum of patients with adrenocortical carcinoma , and IGF-1 mRNA levels are weak or absent in oesophageal squamous cell carcinoma cell lines . Moreover, no alterations in IGF-1 mRNA levels are found in head and neck squamous cell carcinoma (HNSCC) . However, in line with our findings, lower serum levels of IGF-1 have been reported in oral cancer patients compared to healthy controls . In addition, reduced IGF-1 serum levels have been reported in epithelial ovarian cancer  and lower IGF-1 mRNA levels have been observed in HCC compared to corresponding non-malignant liver tissues . Thus, it is possible that serum levels of IGF-1 are dependent on the type of tumour, as well as the local release ratio of IGF-1.
Although IGF-1 functions as an epithelial cell mitogen and has been in implicated in cancer development , increased IGF-1 levels have not been associated with tumour malignancy in some models. For example, hepatic IGF-I-deficient mice with reduced circulating IGF-I levels showed a reduced incidence of colon and breast tumorigenesis [24, 25]; however, this effect was not observed in models of prostate cancer or osteosarcoma [26, 27]. Furthermore, transgenic mice with modestly increased serum IGF-I levels did not show an increased onset or progression of breast tumorigenesis . These results contradict a previous study showing that higher IGF-1 levels were associated with cancer mortality , but are consistent with our NPC study, suggesting that IGF-1 may play an important role in the development and progression of specific tumour types, such as NPC.
IGFBP-1 is a hepatocyte-derived secreted protein that undergoes various phosphorylation events and localizes to the nucleus and/or cytoplasm in hepatocellular carcinoma [29, 30]. In our study, however, IGFBP-1 was mainly observed within the nucleus of cancer cells and in the cytoplasm of normal cells, which is consistent with previous work showing nuclear localization of IGFBP −2, −3 -5, and −6 in tumour cells [29, 30].
By binding and sequestering IGF-1, IGFBP-1 antagonized IGF-1 which could stimulate the proliferation of cancer cells . However, accumulating evidence supports the idea that IGFBPs may drive cancer, rather than exert tumour suppressive functions in some tumour types. For example, IGFBP-2 induction has been shown to activate cell invasion, and increased levels of IGFBP-2 have been reported in ovarian tumour tissues and serum , as well as increased IGFBP-3 mRNA expression in HNSCC compared to healthy tissue . In our study, an increased serum level of IGFBP-1 was detected in patients with NPC, which is consistent with findings observed for oral cancer , which suggests that IGFBP-1 may play a cancer-promoting role in NPC rather than a tumour-suppressing role.
Although clear evidence that tumour growth or migration is stimulated by IGFBP-1 is still lacking, IGFBP-1 has also been repored to have IGF-independent actions, such as activating α5β1 integrin . Preclinical in vivo work has shown that deletion of IGFBP-I in the c-Myc transgenic mouse model resulted in decreased proliferation of prostatic tissue but had no effect on the development of prostate cancer . Recently, one study showed that high expression levels of MMP9 and IGFBPs were associated with poor prognosis in patients with breast cancer . In contrast, high expression of IGFBPs was associated with a favorable prognosis in patients with breast cancer when MMP9 was expressed at low levels. Their study suggests that in the presence of high MMP9 levels, IGFBP is digested, and then IGF is released and activates IGF signaling pathways that promote tumorigenesis in breast cancer. Because studies indicate that high levels of MMP9 expression are observed in most NPC tissues , the interaction between MMP9 and IGFBP-1 in NPC tumours may contribute to NPC patients with higher levels of IGFBP-1 and an unfavourable survival. While this represents an attractive hypothesis, the underlying mechanism remains unclear and should be investigated by further studies.
In addition, the balance between IGFs and IGFBPs may represent an important factor in tumour progression . While higher levels of IGF-I and IGF-I/IGFBP-3 ratio are associated with an increased risk of death from breast cancer and CRC [36, 37], alternative findings have been observed in other studies. For example, elevated IGFBP-2 and reduced IGF-1 levels or high levels of an IGFBP-2/IGF-1 ratio were shown to stratify an ovarian cancer patient subgroup with poor prognosis . Similar to this result, our study showed that a higher IGFBP-1/IGF-1 ratio predicts NPC patients with unfavourable survival. Our data indicate that IGFBP-1 may play a more important role in NPC progression than IGF-1.
Iwakiri et al. reported that EBV infections induce the expression of IGF-1 mRNA and support the growth of NPC-derived cell lines . EBV latent membrane protein 1 (LMP1) selectively activates IGF1R by increasing IGF-1 expression and alters the phosphorylation of IGF1R, but not the expression . However, increasing levels of IGF-1 have not been associated with EA or VCA-titre levels in NPC patients in our data, although the EBV-positive C666 cell lines were characterized by higher IGF-1 expression, which is in line with Iwakiri’s findings regarding EBV-positive NPC cell lines , suggesting that the circulating levels of IGF-1 are inconsistent with IGF-1 expression after EBV infection in vitro. However, the increasing level of IGFBP-1 was associated with EA-positive, but not VCA-positive NPC sera, suggests that the association of EBV infection and the role of IGFs in NPC require further investigation.
Taken together, our study shows that higher serum IGFBP-1 levels and IGFBP-1/IGF-1 ratio correlate significantly with decreased overall survival in NPC patients. Further validation of these results is needed to determine the potential usefulness of these biomarkers for risk assessment.
Our data reveal that IGFBP-1 expression is upregulated in NPC cell lines and NPC tumour tissues and that IGFBP-1 serum levels are elevated in NPC patients. In addition, we showed that IGF-1 is more weakly expressed in NPC cell lines and tumour tissues and that decreasing serum levels of IGF-1 are observed in NPC patients. Furthermore, we observed that elevated serum levels of IGFBP-1 were significantly associated with shorter OS and RFS in NPC patients. Moreover, higher levels of IGFBP-1 and lower levels of IGF-1 were shown to predict worse outcome in NPC patients, suggesting that the ratio of serum IGFBP-1/IGF-1 represents a potential biomarker for NPC patient prognosis. These findings also highlight the more complex biological activities of IGFBP-1 and IGF-1 and reinforce the need to further clarify the role of the IGF system in NPC.
This work was supported by the National Natural Science Foundation of China (No. 81472008).
Availability of data and materials
The datasets during and/or analysed during the current study available from the corresponding author on reasonable request.
GZ, WLL, and XWF contributed to the conception and design of the study, data acquisition, data analysis and manuscript writing. XWF participated in data acquisition and statistical analysis. SX participated in RT-PCR data collection, read and critical revision of the manuscript. JHL provided patient samples, clinical and laboratory data. All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
Consent for publication
Ethics approval and consent to participate
This study was approved by the Ethics Committee of Sun Yat-sen University Cancer Center. All patients and healthy volunteers in this study gave written consent, and all relevant investigations were performed according to the principles of the declaration of Helsinki.
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