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ORIGINAL ARTICLE
Year : 2020  |  Volume : 16  |  Issue : 2  |  Page : 269-275

Clinical significance of hypoxia-inducible factor 1α, and its correlation with p53 and vascular endothelial growth factor expression in resectable esophageal squamous cell carcinoma


1 Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
2 Department of Interventional Therapy, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
3 Department of Thoracic Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China

Date of Submission21-Sep-2019
Date of Decision19-Oct-2019
Date of Acceptance05-Feb-2020
Date of Web Publication28-May-2020

Correspondence Address:
Wei Song
Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_781_19

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 > Abstract 


Background: Hypoxia-inducible factor 1α (HIF-1α), p53, and vascular endothelial growth factor (VEGF) are important factors that facilitate tumor progression. The aims of our study were to investigate the expression of HIF-1α, p53, and VEGF in esophageal squamous cell carcinoma (ESCC) treated by curative surgery and to analyze their association with clinicopathological parameters and clinical outcome.
Materials and Methods: The surgical specimens from 120 patients who had undergone potentially curative resection for ESCC were immunohistochemically assessed using monoclonal antibodies against HIF-1α, p53, and VEGF.
Results: Positive rates of HIF-1α, p53, and VEGF expression were 61.7%, 56.7%, and 78.3%, respectively. No significant relationship was found between HIF-1α, p53, VEGF expression, and the analyzed clinicopathological parameters. There was no significant correlation between the expression of HIF-1α, p53, and VEGF. Univariate analysis revealed that overexpression of HIF-1α was associated with poor disease-free and overall survival (P = 0.023 and 0.01, respectively). Multivariate analysis demonstrated that upregulation of HIF-1α is an independent predictor for poor overall survival (P = 0.044).
Conclusions: HIF-1α was a useful independent prognostic factor for surgically treated ESCC. Further studies with larger sample size are required to determine the relationship between the expression of HIF-1α, p53, VEGF, and clinicopathological parameters.

Keywords: Esophageal squamous cell carcinoma, hypoxia-inducible factor 1α, p53, vascular endothelial growth factor


How to cite this article:
Shao N, Han Y, Song L, Song W. Clinical significance of hypoxia-inducible factor 1α, and its correlation with p53 and vascular endothelial growth factor expression in resectable esophageal squamous cell carcinoma. J Can Res Ther 2020;16:269-75

How to cite this URL:
Shao N, Han Y, Song L, Song W. Clinical significance of hypoxia-inducible factor 1α, and its correlation with p53 and vascular endothelial growth factor expression in resectable esophageal squamous cell carcinoma. J Can Res Ther [serial online] 2020 [cited 2020 Aug 15];16:269-75. Available from: http://www.cancerjournal.net/text.asp?2020/16/2/269/285201




 > Introduction Top


Esophageal cancer is the eighth most common cancer type and the sixth leading cause of cancer deaths, accounting for 572,034 new cases and 508,585 deaths worldwide. In China, esophageal cancer is the fourth leading cause of cancer death and ranks third in terms of the incidence.[1] Squamous cell carcinoma accounts for more than 90% of esophageal cancer in Chinese patients and has a relatively dismal prognosis with a 5-year survival rate of <15%.[2],[3] Although diagnostic and therapeutic strategies have been improved in recent years, the prognosis of esophageal cancer remains poor.[4],[5]

Hypoxia is an inevitable pathological feature of solid tumors, caused by the lack of blood supply and rapid growth of tumor cells.[6] In response to anoxic or hypoxic conditions, tumor cells produce several important proteins that facilitate their invasiveness, angiogenesis, metastasis, and treatment resistance.[6],[7],[8] Hypoxia-inducible factor (HIF), which is composed of two subunits (HIF-α and -β), plays a central role in the regulation of the adaptive response of cells to hypoxia. The three HIF-α isoforms, HIF-1α, HIF-2α, and HIF-3α, are oxygen sensitive because of their oxygen-dependent degradation domains. Under normoxia, the HIF-1α protein is constitutively synthesized and degraded at the same time, thus maintaining a steady state level of the protein that is often below the detection limits. Under hypoxia, HIF-1α becomes stabilized, translocates into the nucleus, and heterodimerizes with HIF-1β to form the complex HIF-1, which transactivates the expression of a set of downstream genes in respond to the hypoxic stress.[9] The HIF target gene family includes glycolytic enzymes, glucose transporters, angiogenic factors, growth factors, and apoptosis resistance-related proteins.

p53 is one of the most important tumor suppressors. Following DNA damage induced by oxidative stress, p53 undergoes extensive posttranslational modifications, including phosphorylation at its N-terminus, leading to its accumulation in the nucleus and subsequent activation of genes involved in DNA repair, cell-cycle arrest, and apoptosis.[10] Hypoxic stress upregulates p53; however, the accumulation of p53 requires severe and prolonged periods of hypoxia.[10] The divergent effects of p53 likely depend on the degree of oxidative stress to the cell.[11]

Vascular endothelial growth factor (VEGF) is one of the most recognized endothelial growth factors involved in several aspects of cancer progression, and it synergizes and interacts with p53 and HIF-1α. p53 and HIF-1α can positively regulate VEGF expression by directly binding to conserved sites in the VEGF promoter.[12],[13] Hypoxia cooperates with other signals such as DNA-damage or acidosis to provoke p53 activation, which subsequently represses HIF-1 activity. Loss of p53 has been shown to enhance hypoxia-induced HIF-1 level and to augment HIF-1-evoked VEGF expression in tumor cells.[14]

In esophageal cancer, the prognostic effect of HIF-1α remains inconclusive. Although several studies have demonstrated that the expression of HIF-1α in tumor cells is significantly associated with tumor stage and lymph node metastasis,[15] in a study on European population, HIF-1α was found not to be an independent prognostic factor for disease-free or overall survival.[16] HIF-1 could regulate p53 and VEGF; however, the relationship between them in esophageal cancer patients remains unclear. Since squamous cell carcinoma accounts for most of the esophageal cancer in high-risk regions such as China, it is of great importance to elucidate the clinical significance of these molecules in esophageal squamous cell carcinoma (ESCC), which may improve our current prognostic system based on TNM staging.

The objectives of the current study were to evaluate the expression of HIF-1α, p53, and VEGF in tumor specimens from ESCC treated by curative surgery and to elucidate their relationship with clinicopathological parameters and clinical outcome.


 > Materials and Methods Top


Patients and specimens

One hundred and twenty patients, who underwent radical esophagectomy for ESCC between January 1, 2007 and March 1, 2008, were included in the study. Patients that were excluded were those with neoadjuvant treatment, perioperative mortality, distant metastasis, lost to follow-up, and lack of tumor tissue. The demographic and clinical data of all the patients including age, gender, TNM stage, histological grade, and lymph node status were extracted from the clinical records. The stage of disease was determined according to the TNM staging system of the International Union Against Cancer (6th edition) following the surgical resection of the tumor.[17] A thorough histological examination was made using hematoxylin and eosin-stained tissue preparations, and the histological grade was determined according to the degree of tumor differentiation.

Immunohistochemistry

The expression of HIF-1α, p53, and VEGF was determined immunohistochemically on sections cut from formalin-fixed paraffin-embedded tumor specimens. Histological sections, 4 μm in thickness, were deparaffined in xylene and rehydrated through a series of graded ethanol. Antigen retrieval was performed by heating for 10 min in a pressure cooker with citrate buffer. Endogenous peroxidase activity was blocked by incubation in 3% hydrogen peroxide in ethanol for 10 min. Primary antibodies were incubated at 4°C overnight. Tissue slides were incubated with the following primary antibodies: Mouse anti-HIF-1a monoclonal antibody (Abcam, Cambridge, UK) at 1:50 dilution for 30 min, ready-to-use mouse anti-p53 monoclonal antibody (Dako Corporation, Carpinteria, CA, USA) for 45 min or mouse anti-VEGF monoclonal antibody (Abcam, Cambridge, UK) at 1:100 dilution for 30 min, respectively. The EnVision™ reagent (Dako Corporation, Carpinteria, CA, USA), a peroxidase-conjugated polymer backbone carrying secondary antibody molecules, was used to detect the primary antibodies. The immunohistochemical staining was visualized with the DAB reagent.

Immunohistochemical assessment

Immunostaining of HIF-1α, p53, and VEGF was evaluated in three visual fields at ×200 magnification under a Nikon microscope. The tumor cell immunoreactivity for HIF-1α and p53 was scored based on the number of cells exhibiting nuclear and/or cytoplasmic staining, and more than 10% of cells with nuclear staining and/or with distinct to strong cytoplasmic staining were considered as a positive expression pattern while the remaining were considered to be a low expression pattern. Cancer tissue with positive cytoplasmic staining in over 25% cells was defined as high expression for VEGF expression, and low expression was recorded when the cells staining positive was <25%.[18]

Statistical analysis

The associations between the expression of HIF-1α, p53, VEGF, and the clinicopathologic parameters (gender, age, tumor size, differential grade, depth of invasion, number of positive lymph nodes, and pathological stages) were assessed via Chi-square or Fisher's exact tests. Disease-free survival was measured from the date of surgery to the date of thefirst evidence of relapse or death, whichever was observedfirst. For surviving patients who had not relapsed, disease-free survival was recorded as the last date that the absence of relapse was confirmed. Overall survival was measured from the date of surgery to the date of death or last follow-up for surviving patients.[19] The Kaplan–Meier method was utilized to construct curves for disease-free and overall survival. To identify independent predictors for prognosis, we used the Cox's proportional hazard analysis with a stepwise procedure. All the tests were two-sided, and P < 0.05 was considered to be statistically significant. All the analyses were conducted using SPSS version 16.0 (SPSS Inc., Chicago, IL, USA).


 > Results Top


The ages of the 120 patients ranged from 42 to 78 years, with a median age of 60.5 years. A total of 15 (12.5%) patients had tumors in the upper one-third of the esophagus, 68 (56.7%) in the middle one-third, and 37 (30.8%) in the lower one-third. The tumor length ranged from 0.5 to 8.5 cm, with a mean length of 3.8 cm. A total of 75 patients (62.5%) had advanced T stages (T3–4) and 36.7% had positive lymph nodes. The pathological stages were 0, I, II, and III in 2, 20, 58, and 40 patients, respectively. Of these, 48 patients received adjuvant treatment, including chemotherapy and/or radiotherapy. A total of 58 patients died due to disease recurrence during 2.6–43.5 months (mean, 20.4 months; median, 18.7 months) after surgery. The time of follow-up ranged from 2.5–50 months (mean, 32.7 months; median, 39.8 months).

Of the 120 surgical specimens, 74 (61.7%), 68 (56.7%) and 94 (78.3%) were positive for HIF-1α, p53, and VEGF expression, respectively. Of these, 35 specimens were positive for all the three proteins, 50 were positive for either 2 proteins, and 31 were positive for only one protein. HIF-1α protein was expressed in the nuclei and/or the cytoplasm of tumor cells. For p53 protein, the immunoreactivity was confined to the nuclei of the tumor cells, and no cytoplasmic staining was detected. The immunoreactivity for VEGF was confined to the cytoplasm of the tumor cells [Figure 1].
Figure 1: Immunohistochemical staining of hypoxia-inducible factor 1α, p53, and vascular endothelial growth factor (positive expression: (a, c and e); negative expression: (b, d and f) respectively) (×200)

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Details of the relationship between the expression of HIF-1α, p53, and VEGF and clinicopathological parameters are listed in [Table 1]. No significant association was noted between the expression of HIF-1α, p53, or VEGF and gender, age, tumor location, tumor size, histological grade, depth of invasion, lymph node metastasis, or pathological stage. As shown in [Table 2], there was no significant association between the expression of HIF-1α, p53, and VEGF.
Table 1: Correlation between the expression of hypoxia-inducible factor-1α, p53, vascular endothelial growth factor, and clinicopathological parameters

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Table 2: Correlation of p53, hypoxia-inducible factor-1α, and vascular endothelial growth factor expression

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Survival analysis

Univariate analysis demonstrated that increased depth of invasion (P = 0.022), lymph node metastasis (P = 0.002), advanced pathological stages (P = 0.001), and postoperative radiotherapy (P = 0.015) were significantly associated with poor disease-free survival. Patients with HIF-1α-positive tumors had lower disease-free survival rates than patients with HIF-1α-negative tumors [P = 0.023, [Figure 2]a. However, the expression of p53 or VEGF was not significantly associated with disease-free survival (P = 0.332 and P = 0.533, respectively). Histological grade (P = 0.042), depth of invasion (P = 0.001), lymph node metastasis (P = 0.001), pathological stage (P < 0.001), and postoperative radiotherapy (P = 0.024) were significantly associated with overall survival. Positive HIF-1α expression was significantly associated with shorter overall survival [P = 0.01; [Figure 2]b. On the other hand, the expression of p53 and VEGF was not significantly correlated with overall survival (P = 0.32, P = 0.85, respectively) [Table 3]. In multivariate analysis, only pathological stage was an independent prognostic predictor of disease-free survival (P < 0.001). Depth of invasion (P = 0.047), pathological stage (P = 0.012), and HIF-1α expression (P = 0.044) were identified as independent predictors of overall survival [Table 4].
Figure 2: Disease-free (a) and overall (b) survival curves according to hypoxia-inducible factor 1α expression (P = 0.023 and P = 0.01, respectively)

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Table 3: Univariate analysis of clinicopathological parameters

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Table 4: Predictors of survival by multivariate analysis

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 > Discussion Top


The poor ability to prognosticate ESCC is mainly due to variations in the biological behavior of tumors and inadequacies of the present staging system. Therefore, it is essential to identify new molecular markers that can distinguish the biological characteristics of tumor cells and augment the predictive power of the current prognostic system. The purpose of our study was to examine the expression of HIF-1α, p53, and VEGF and to analyze their association with clinicopathological parameters and clinical outcome in surgical treated ESCC. After analyzing 120 cases of ESCC treated by curative surgery, we found that HIF-1α expression was a predictor for disease-free and overall survival in univariate analysis, and identified as an independent indicator for overall survival in multivariate analysis. However, we did not find any significant relationship between the expression of HIF-1α, p53, VEGF and clinicopathological parameters.

Hypoxia contributes to the rapid and unlimited growth of malignant cells. It plays an important role in promoting genetic instability and facilitating tumor invasiveness, metastasis, angiogenesis, and multidrug resistance.[20] HIF, a heterodimeric transcriptional factor, plays a crucial role in the regulation of adaptive response of cells to hypoxia.[21] In hypoxia, HIF-1α becomes stabilized and heterodimerizes with HIF-β to activate the expression of a set of downstream genes in response to the hypoxic stress. Many putative target genes of HIF, including glycolytic enzymes, glucose transporters, angiogenic factors, growth factors, and proteins related to apoptotic resistance, have been identified.[22] However, studies implicating the role of HIF-1α in promoting tumor progression of esophageal cancer have yielded inconsistent results.

For instance, Ogawa et al. found that HIF-1α expression is significantly correlated with initial response to concurrent chemoradiation, and is predictive of disease-free survival in patients with esophageal cancer receiving concurrent chemoradiation.[23] Matsuyama and colleagues examined the immunoreactivity for HIF-1α protein in 215 surgically treated ESCC.[24] Upregulation of HIF-1α protein was found to have a significant effect on disease-free survival in univariate analysis, but was of no predictive value for survival in multivariate analysis. Munipalle et al. showed a positive rate of 52.8% for HIF-1α expression in tumor specimens from 36 patients with ESCC from European population, but revealed no prognostic value.[16] Given the physiological functions of HIF-1α, differences in the therapeutic modality (surgery or radiotherapy) may explain these discrepancies as hypoxia may notably influence the response to radiotherapy. On the other hand, some of the previous studies have been performed in patients with mixed pathology (both squamous cell carcinoma and adenocarcinoma) or from different ethnicities. Owing to these concerns, in the present study, we selected a group of patients with ESCC, who were treated with curative surgery to elucidate whether HIF-1α overexpression (alone or in combination with p53 and VEGF) indicates tumor aggressiveness. In this study, the expression of HIF-1α protein was immunohistochemically detected in 61.7% of esophageal cancer tissues. No significant relationship was found between the overexpression of HIF-1α and clinicopathological parameters such as pathological grade, invasion depth, lymph node metastasis, TNM stage, and so on. However, we found that overexpression of HIF-1α was significantly correlated with disease-free and overall survival in univariate analysis and was an independent prognostic factor for overall survival in multivariate analysis.

p53, a tumor suppressor gene, encodes a transcription factor that is activated by various cellular stresses, including DNA damage. The relationship between p53 and HIF-1 has already been investigated in previous studies, but the results are controversial. The earliest study by An et al. reported that the stabilization of p53 under hypoxia is HIF-1 dependent.[25] However, this concept was challenged by other studies showing that hypoxic conditions, while sufficient to cause HIF-1α accumulation and HIF-1 transactivation, did not cause an accumulation of p53.[26] This can be explained by the fact that p53 accumulation requires severe hypoxia, close to or equivalent to anoxia, for prolonged periods along with other signals such as DNA damage or acidosis.[27] Ravi et al. demonstrated that accumulated p53 inhibits HIF-1 activity by targeting HIF-1 for Mdm2-mediated ubiquitination and 26S proteasomal degradation.[14] More recent data proposed a competition between p53 and HIF-1 for limiting amounts of the shared transcriptional coactivator p300. Under more severe hypoxia, p53 starts to accumulate and competes with HIF-1α for binding to p300, which results in repression of HIF-1-mediated gene activation.[28],[29] As a result, HIF-1α induces PFKL and VEGF to facilitate cellular adaptation to mild and moderate hypoxia, respectively, while p53 is activated to induce apoptosis under severe hypoxia.[29] In the present study, we found a positive rate of 56.7% for p53 expression. However, we did not observe any correlation between the expressions of HIF-1α and p53. Overexpression of p53 was not associated with clinicopathological parameters or clinical outcome.

VEGF is a highly specific mitogen for vascular endothelial cells and a major initiator of tumor angiogenesis.[30] Inhibition of VEGF activity by neutralizing antibodies or by the introduction of dominant-negative VEGF receptors in endothelial cells of tumor-associated blood vessels resulted in the inhibition of tumor growth and in tumor regression.[31] The VEGF gene contains a number of HIF-1-binding sites in its regulatory region, and HIF-1α can activate the VEGF promoter to stimulate angiogenesis during hypoxia.[28] The effect of p53 on VEGF production is mainly mediated through HIF-1α activity.[32] Ravi et al. found that loss of p53 enhances hypoxia-induced HIF-1α levels and augments HIF-1-dependent expression of VEGF in tumor cells.[14] Several studies have investigated the expression patterns and prognostic effect of VEGF in ESCC. All the recent studies reported the expression of VEGF to some degree (24%–93%) with various cut-off values. Some studies demonstrated a significant correlation of VEGF with local lymph node metastases, depth of tumor invasion, or patient outcome;[33],[34],[35] however, others failed to demonstrate any association of VEGF expression with those parameters.[36] In our study, we found a high positive rate of 78.3% of VEGF expression, suggesting that this protein could be a possible treatment target. However, VEGF expression was not correlated with HIF-1α or p53 expression, or with any clinicopathological parameter.


 > Conclusion Top


In conclusion, our study provided evidence that overexpression of HIF-1α predicts poor survival in ESCC patients treated with surgery. However, no significant correlation was found between the expression of HIF-1α, p53, VEGF proteins, and clinicopathological parameters. This may be due to the limited sample size. Further studies, with a larger sample size, are needed to elucidate the relationship between the expression of HIF-1α, p53, and VEGF and the interactions between them.

Financial support and sponsorship

The work was supported by Medical and Health Science and Technology Development Plan of Shandong province (NO: 2016WS0415).

Conflicts of interest

There are no conflicts of interest.



 
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