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Table of Contents
ORIGINAL ARTICLE
Year : 2019  |  Volume : 2  |  Issue : 3  |  Page : 123-129

Association of galectin-3 and hypoxia-inducible factor-1α with progression of oral squamous cell carcinoma


Department of Oral and Dental Pathology, Faculty of Dental Medicine for Girls, Al Azhar University, Cairo, Egypt

Date of Web Publication1-Jul-2019

Correspondence Address:
Gihan Adel Balbola
7321, Airport Devision, Gizan
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/JNSM.JNSM_48_18

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  Abstract 


Background: Oral squamous cell carcinoma (OSCC) represents more than 90% of all malignancies of the head and neck. Some biochemical and molecular changes in cells precede the establishment of neoplasms, and in this case, the deregulation of various proteins, such as hypoxia-inducible factor-1 and galectins-3 can strongly influence tumor progression through their effects on immunological surveillance, angiogenesis, cell migration, adhesion and cellular response to chemotherapy. Objective: In this study we investigated the association of both HIF-1α and galectin-3 in oral carcinogen. Materials and Methods: Five cases of normal oral epithelial tissues, 15 cases of severe epithelial dysplasia and 40 cases of different grades of OSCC were collected.Immunohistochemical staining for HIF-1α and galectin-3 antibodies were done for all specimens. Results: For both antibodies, statistically, the greatest mean area percent was recorded OSCC, whereas the lowest values were recorded in normal tissue. Conclusions: These results confirm that there is a dynamic regulation of galectin-3 in response to the tumor microenvironment associated hypoxia.

Keywords: Galectin-3, hypoxia-inducible factor-1α, invasion, oral squamous cell carcinoma


How to cite this article:
Radi NA, Balbola GA. Association of galectin-3 and hypoxia-inducible factor-1α with progression of oral squamous cell carcinoma. J Nat Sci Med 2019;2:123-9

How to cite this URL:
Radi NA, Balbola GA. Association of galectin-3 and hypoxia-inducible factor-1α with progression of oral squamous cell carcinoma. J Nat Sci Med [serial online] 2019 [cited 2019 Sep 15];2:123-9. Available from: http://www.jnsmonline.org/text.asp?2019/2/3/123/250753




  Introduction Top


Oral cancer is pathology with high morbidity and mortality worldwide, being a very common pathology in certain populations.[1] Oral squamous cell carcinoma (OSCC) represents more than 90% of all malignancies of the head and neck.[2],[3] It shows a high propensity for invasive growth and cervical lymph node metastasis. Five-year survival rates of patients with OSCC have remained in the vicinity of 50% over the last few decades.[4],[5],[6] Stressed microenvironments such as hypoxia would cause a selection and malignant cells with more aggressive behaviors related to migration and metastasis may eventually become the dominant cell groups.[7] Tumor cells are also responsible for the secretion of some proteins, responsible for the degradation of the extracellular matrix and consequent spread of malignant cells and several regulatory molecules that influence cell adhesion and mobility. Thus, a protein secreted by the tumor, or its “protein signature,” can be used for early diagnosis and better prognosis of the disease.[8],[9]

Hypoxia is a common feature in solid malignant tumors and contributes to local and systemic cancer progression, resistance to therapy, and poor outcome. Hypoxic conditions may occur due to changes in neoplastic cells and angiogenesis. It has been proven that stressed microenvironments such as hypoxia would cause a selection and malignant cells with more aggressive traits related to migration and metastasis may eventually become the dominant cell groups. Hypoxia-inducible factor-1 (HIF-1) is a key regulator of the cellular response to hypoxia. It is a heterodimer composed of two subunits: HIF-1α and HIF-1β. HIF-1α is expressed in niches of tumor cells, where it mediates invasion and metastasis. HIF-1α functions as a transcriptional activator in hypoxia and binds specifically to the promoters of more than 100 genes involved in multiple aspects of tumor biology. Among these genes is galectin-3 which plays different roles in the process of tumor growth including cell differentiation, adhesion, migration, invasion, and metastasis.[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21]

Galectins are a family of carbohydrate-binding proteins which have high affinity and specificity for β-galactoside. In normal tissue and blood, galectins are expressed at low levels, but they are increased in serum, plasma, and urine in neoplastic diseases. Galectin-3 is one of the best studied, which mediates multiple processes of tumor growth. Galectin-3 has been proven to be associated with the metastasis and invasion of different cancers through various mechanisms such as Wnt/β-catenin signaling pathway and AKT phosphorylation and increases the expression of matrix metalloproteinase-1 through the activation of protease-activated receptor-1 signaling, hence resulting in metastasis. Furthermore, circulating galectin-3–mucin-1 leads to neoplastic cell embolus formation and the survival of circulating neoplastic cells.[22],[23],[24],[25] Galectin-3 was believed to modulate the adaptive strategies of cancer cells in stressed tumor microenvironments. Galectin-3 overexpression was observed in hypoxic fields of cancer tissues. Under hypoxic conditions, upregulation of galectin-3 expression might act either as inducers of cell death or a prosurvival response triggered by stressed microenvironments.[26],[27],[28]

Until now, the correlation of expression of both galectin-3 and HIF-1α in the normal oral stratified squamous epithelium, dysplastic oral epithelium, and different grade of OSCC is not explored; therefore, the aim of this study is to evaluate the association of both galectin-3 and HIF-1α in oral carcinogenesis by means of the immunohistochemical technique.


  Materials and Methods Top


Case selection

The specimens of this study were collected as formalin-fixed paraffin-embedded blocks from archives of Oral and Dental Pathology Department, Faculty of Dental Medicine for Girls, Al-Azhar University. The specimens were divided into five groups: normal oral epithelial tissues (5 cases of fresh normal oral tissues adjacent to hyperplastic gingival tissues excised from patients undergoing gingivectomy), severe oral epithelial dysplasia (OED) (15 cases), and 40 cases of different grades of OSCC, such as 15 cases of well-differentiated OSCC (WDOSCC), 10 cases of moderately differentiated OSCC (MDOSCC), and 15 cases of poorly differentiated OSCC (PDOSCC). The study protocol was approved by the ehtics committee in our institute.

Histopathological analysis

Using hematoxylin and eosin for a reassessment of the above-mentioned cases was occurred to confirm their diagnosis and establish the histopathologic grading according to the WHO classification.[29]

Immunohistochemical analysis

Streptavidin–biotin immunohistochemical method[30] was applied to 4-μm section thickness which mounted on electrically positive charged glass slides. They first deparaffinized by overnight incubation with xylene and then rehydrated in gradual descending concentrations of ethanol followed by phosphate-buffered saline (PBS) wash. Blocking the endogenous peroxidase activity was performed by 3% (H2O2) for 5 min at room temperature. For antigen retrieval, tissue section was put in a glass jar containing 0.01 M sodium citrate buffer (pH 6.0) and boiled in a microwave oven twice for 5 min each to enhance immunoreactivity. The slides were allowed to cool and rinsed with PBS, pH 7.2. The immunohistochemical staining for HIF-1α and galectin-3 antibodies was done according to the manufacturer's instructions using galectin-3 (Cat. No. AP-9003. Thermo scientific, USA) and HIF-1α (Cat. No. SC 53546. Santa Cruz Biotechnology, Inc., USA); both of them were mouse monoclonal antibody. The dilution used was 1:50 in PBS.

Detection was carried out using the universal kit (DAKO, Denmark) by washing slides in PBS for 5 min and incubated with a secondary antibody that was biotinylated goat serum conjugated rabbit and mouse sera for 30 min. Sections were then washed for 5 min in PBS followed by the development of antigen–antibody visualization by diaminobenzidine in PBS containing 40% H2O2. Sections were washed under running tap water for 10 min and then counterstained with Mayer's hematoxylin and mounted.

Histomorphometric analysis

Immunoreactivity for both galectin-3 and HIF-1α was evaluated by estimating the percentage of positive immunostained cells in relation to the area examined in each field, using Leica image analyzer computer system image analysis controlled by Leica Qwin 500 software (Germany). The image analyzer was calibrated automatically to convert the measurement units (pixels) produced by the image analyzer program into actual micrometer units. The area percentage of both galectin-3 and HIF-1α reactive areas was measured with reference to a standard measuring frame of area 11434.9 μm2 using magnification (×200). Using the color detection, reactive areas of positive immunostaining were masked by a blue binary color. Ten fields per each slide section of each patient were successively taken to be histomorphometrically evaluated. Mean values were then obtained for each specimen.

Statistical analysis

Data were presented as mean and standard deviation values. Analysis of variance (ANOVA) test used to compare means of more than two groups. Tukey–Kramer multiple comparisons were used in the procedure of pair-wise comparisons between the groups when ANOVA test is significant. P ≤ 0.05 was considered as statistically significant. Statistical analysis was performed using Instate GraphPad version 3.10 (San Diego, California, USA) and Microsoft® Excel 2007.


  Results Top


Histopathological findings

The normal gingival tissue specimen showed epithelium of normal thickness of keratinized stratified squamous epithelium. The connective tissue showed condensed collagen fibers interspersed with fibroblast and few inflammatory cells in some areas. In the severe dysplasia tissue, all epithelial layers are involved by criteria of malignancy with the intact basement membrane. Cytological and architectural changes were very prominent as basilar hyperplasia, loss of polarity, pleomorphism, and hyperchromatism. The connective tissue showed engorged blood vessels and infiltrated by chronic inflammatory cells in some areas.

WDOSCC specimens showed invasive nests and islands within the underlying connective tissue that display large neoplastic cells with the distinct cell membrane. One of the most prominent features was the presence of individual cell keratinization and formation of numerous keratin pearls of varying sizes, while in MDOSCC, the resemblance of tumor cells of invasive nests to the squamous epithelial cells was less prominent. The characteristic shape of the cells was altered as well as their typical arrangement of one to the other. There was cellular pleomorphism with minimal of keratin formation. In PDOSCC, the tumor cells showed no resemblance to the squamous epithelial cells with the atypical histological pattern. Extremely anaplastic cells invaded deeply in the underlying connective tissue with no keratin formation. The connective tissue showed abnormal shaped blood vessels and infiltrated by chronic inflammatory cells [Figure 1]a, [Figure 1]b, [Figure 1]c, [Figure 1]d, [Figure 1]e.
Figure 1: (a) Normal gingival tissue showing basal cells, spinous cells, granular cells, and parakeratin layers, (b) severe dysplastic tissue showing basilar hyperplasia, loss of polarity, pleomorphism, and hyperchromatism, (c) well-differentiating oral squamous cell carcinoma showing cell nests and numerous keratin pearls, (d) moderately differentiating oral squamous cell carcinoma showing nests of tumor cells having less resemblance to epithelial cells, (e) poorly differentiating oral squamous cell carcinoma showing highly anaplastic cells (H and E, ×200), (f) normal oral epithelial tissue showing hypoxia-inducible factor-1α immunostaining in cytoplasm and nucleus of the suprabasal cell layer, (g) severe dysplastic tissue showing hypoxia-inducible factor-1α immunostaining in cytoplasm and nucleus of the dysplastic cells, (h) well-differentiating oral squamous cell carcinoma showing hypoxia-inducible factor-1α immunostaining in cytoplasm, nucleus, keratin of the epithelial, and keratin pearls, (i) moderately differentiating oral squamous cell carcinoma showing hypoxia-inducible factor-1α immunopositivity in cytoplasm and nucleus of the neoplastic cells, (j) poorly differentiating oral squamous cell carcinoma showing hypoxia-inducible factor-1α immunopositivity in cytoplasm and nucleus of the neoplastic cells, (k) normal oral epithelial tissue showing galectin-3 immunostaining in cytoplasm and nucleus of basal and suprabasal cells, (l) severe dysplastic tissue showing galectin-3 immunostaining in cytoplasm and nucleus of the dysplastic epithelial cells, (m) well-differentiating oral squamous cell carcinoma showing galectin-3 immunostaining in cytoplasm, nucleus, keratin of the epithelial, and keratin pearls, (n) moderately differentiating oral squamous cell carcinoma showing galectin-3 immunopositivity in cytoplasm and nucleus, (o) poorly differentiating oral squamous cell carcinoma showing galectin-3 immunopositivity in cytoplasm and nucleus

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Immunohistochemical findings

HIF-1α immunostaining of all cases was detected in both the cytoplasm and nucleus. For the normal cases, it was seen in the parabasal cell layers in contrast the basal cells were negative, while for severe dysplasia, it was detected in the whole dysplastic cell layers. HIF-1α immunostaining was assessed in all neoplastic epithelial cells of the three grades of OSCC as well as keratin pearls in WDOSCC [Figure 1]f, [Figure 1]h, [Figure 1]i, [Figure 1]j.

Statistically, OSCC showed higher values than severe dysplasia (39.978%), whereas the lowest values were recorded in normal tissue (21.072%). Among OSCC cases, the greatest mean area percent was recorded in PDOSCC (66.075%). One-way ANOVA test revealed a significant difference between all groups (P < 0.0001). Tukey post hoc test revealed a significant difference between normal tissue and severe dysplasia. All three grades of OSCC were not significantly different. Moreover, there was a significant difference between severe dysplasia and WDOSCC [Table 1] and [Figure 2].
Table 1: Area percent of hypoxia-inducible factor-1α, immunoexpression between groups, and significance of the difference (analysis of variance test)

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Figure 2: Column chart showing mean area percent of hypoxia-inducible factor-1α immunoexpression

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The galectin-3 immunostaining of all cases was detected in both the cytoplasm and nucleus. For the normal cases, it was seen in only basal and parabasal layers of the epithelium, while for severe dysplasia, it was detected in the whole dysplastic cell layers. Galectin-3 immunostaining was assessed in all neoplastic epithelial cells of the three grades of OSCC as well as keratin pearls in WDOSCC [Figure 1]k, [Figure 1]l, [Figure 1]m, [Figure 1]n,[Figure 1]o.

Statistically, OSCC showed higher values than severe dysplasia (32.12%), whereas the lowest values were recorded in normal tissue (16%). Among OSCC cases, the greatest mean area percent was recorded in PDOSCC (59.431%). One-way ANOVA test revealed a significant difference between all groups (P < 0.0001). Tukey post hoc test revealed a significant difference between normal tissue and severe dysplasia. There was a significant difference between WDOSCC, MDOSCC, and PDOSCC, but there was no significant difference between MDOSCC and WDOSCC [Table 2] and [Figure 3].
Table 2: Area percent of galectin-3 immunoexpression between groups and significance of the difference (analysis of variance test)

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Figure 3: Column chart showing mean area percent of galectin-3 immunoexpression

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Pearson correlation test revealed a strong positive extremely significant correlation between galectin-3 and HIF-1α immunoexpression in all groups (P = 0.0006) [Table 3] and [Figure 4].
Table 3: Correlation between hypoxia-inducible factor-1α and galectin-3 immunoexpression in different groups (Pearson correlation test)

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Figure 4: Scatter plot showing correlation between galectin-3 and hypoxia-inducible factor-1α immunoexpression

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  Discussion Top


Some biochemical and molecular changes in cells precede the establishment of neoplasms, and in this case, the deregulation of various proteins, such as HIF-1α and galectins-3, can strongly influence tumor progression through their effects on immunological surveillance, angiogenesis, cell migration, and adhesion and cellular response to chemotherapy.[22],[31]

Interestingly, the present study showed that HIF-1α immunopositivity was detected in the normal oral epithelium, with nuclear and cytoplasmic localization in the suprabasal cell layers. This is inconsistent with that reported by Lin et al.,[10] who found that normal oral epithelium shows very weak nuclear HIF-1α staining in lower two-thirds of suprabasal epithelial cells but not in basal cells. Jokilehto et al.[32] reported that PHD2 which is the most important isoform for the downregulation of HIF in normoxic as well as mild hypoxic conditions was strongly expressed in the basal proliferating layer of normal stratified squamous epithelium, and the expression was weaker in the suprabasal cell layers and was completely lost in the flattened superficial cells. The expression of PHD2 was restrained to the cytoplasm. This interprets the expression of HIF-1α in all layers of normal oral epithelial tissue except the basal cell layer.

Concerning the expression of HIF-1α in sever epithelial dysplasia cases, it was observed that in all layers of the dysplastic epithelium, the results of the present study revealed that there is increasing in the immunopositivity in severing epithelial dysplasia than normal oral epithelial tissues. The immunopositivity was detected in the cytoplasm and nucleus of the dysplastic cells. These results are in agreement with those reported by Lin et al., 2008, and Zhang et al., 2013[10],[33] who found that severe epithelial dysplasia shows strong nuclear and moderate cytoplasmic HIF-1α staining in nearly all dysplastic epithelial cells with a significant elevation in nuclear HIF-1α than normal oral epithelium, suggesting that the expression of HIF-1α is an early event in oral carcinogenesis.

With regard to HIF-1α expression with different grades of OSCC, the present study revealed the positive correlation of HIF-1α expression with the increasing grades of OSCC. The percentage of distribution of HIF-1α-positive staining cells was found to be increased in carcinoma cells with MD-to-PD pattern compared to those with the WD pattern. These results are in agreement with Zhu et al.[34] who reported that HIF-1 α was significantly associated with T-stage, lymph node involvement, histologic differentiation, microvessel density, and poor overall and disease-free survival rates. Furthermore, Eckert et al.[11] who found that the expression of HIF-1α is an early event in oral carcinogenesis also showed a stepwise and significant increase in the expression of nuclear HIF-1α from normal oral mucosa to OED and from OED to OSCC.

Regarding the galactin-3 results of the current study, the immunopositivity was detected in the normal oral epithelium, with nuclear and cytoplasmic localization in basal and suprabasal cell layers. This is inconsistent with that reported by Honjo et al.,[35] who found that in the normal squamous epithelium, cells positive for nuclear or cytoplasmic galectin-3 are distributed in the basal and parabasal layers, respectively. Nuclear and cytoplasmic galectin-3 is likely to be linked with proliferation and differentiation, respectively. This assumption may be supported by previous findings such as (a) mitogenic stimulation of quiescent fibroblasts results in a prompt increase of nuclear galectin-3 expression and (b) nuclear galectin-3 is involved in ribonuclear complexes and identified as a factor in pre-mRNA splicing. In contrast, Saussez et al.[36] and de Vasconcelos et al.[37] found that histologically normal oral mucosa generally stained weakly to moderately in the intermediate to superficial layers. Staining of the basal cellular layer was absent or only faint. Galectin-3 tends to concentrate in the more superficial layers.

Concerning galectin-3 expression in sever epithelial dysplasia cases, the results of the present study revealed that there is increasing in the immunopositivity in severe epithelial dysplasia than normal oral epithelial tissues. The immunopositivity was detected in the cytoplasm and nucleus of the dysplastic cells. The staining was observed in all layers of the dysplastic epithelium. These results are in agreement with those reported by Saussez et al.[36] and de Vasconcelos et al.,[37] and they found that the differences in the immunostaining of galectin-3 between different grades of OED suggested the involvement of this protein in the progression of OEDs.

With regard to galectin-3 expression with different grades of OSCC, the present study revealed the positive correlation of galectin-3 expression with the increasing grades of OSCC. The percentage of distribution of galectin-3-positive staining cells was found to be increased in carcinoma cells with MD-to-PD pattern compared to those with the WD pattern.

These findings agree with that reported by Weber et al.[38] They found that galectin-3 is deeply involved in the biology of head-and-neck squamous cell carcinoma (HNSCCs), including cell proliferation, cell death, and cell migration. Several studies investigating the expression of galectin-3 in HNSCCs demonstrated the close relationship between the galectin-3 expression and the biological behavior in various types of HNSCCs. Galectin-3 was found to modulate the adaptive strategies of cancer cells in stressed tumor microenvironments, sounder hypoxic conditions, and the increase of galectin-3 expression might act either as inducers of cell death or a prosurvival response triggered by stressed microenvironments.[20],[26],[28]

HIF-1α is a master regulator of gene transcription under hypoxia, upregulating several genes, including galectin-3, to maintain cellular homeostasis and promote cell survival in skeletal tissues. The expression of galectin-3 was modulated by HIF-1α. This was proven by both the existence of a HIF-1α-binding site in the galectin-3 promoter region and the galectin-3 upregulation in mice fibroblasts transfected with HIF point to a crucial role of the molecule in galectin-3 regulation. In addition, Zheng et al.[20] reported that inhibition of HIF-1α with MeOE2 caused a significant decrease in galectin-3 expression. Furthermore, reverse transcription polymerase chain reaction analysis was also performed to confirm the regulatory function of HIF-1α on galectin-3.


  Conclusion Top


From the previous results, we can conclude that concomitant overexpression of both HIF-1α and galectin-3 is considered a turning point of normal oral tissue to dysplastic change and enhances invasion and progression to OSCC. Furthermore, there is a dynamic regulation of galectin-3 in response to the tumor microenvironment and the current study point to the importance of HIF-1α in the later. Hence, antiangiogenic therapy induces hypoxia and that hypoxia-dependent pathways lead to decreased cell death. Galectin-3 might be an interesting target to overcome this.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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