|Year : 2023 | Volume
| Issue : 2 | Page : 119-126
Expression of signaling molecules in ameloblastoma using cDNA microarray: A systematic review
Sangamithra Surendran1, Nausathkhan Ubayathulla2, Pratibha Ramani1, Monal Yuwanati1
1 Department of Oral and Maxillofacial Pathology, Saveetha Dental College and Hospital, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, Tamil Nadu, India
2 Department of Oral and Maxillofacial Surgery, Fujairah Specialized Dental Center and Hospitals, Fujairah, United Arab Emirates
|Date of Submission||06-Jun-2022|
|Date of Decision||08-Jan-2023|
|Date of Acceptance||13-Jan-2023|
|Date of Web Publication||28-Apr-2023|
Dr. Pratibha Ramani
Department of Oral and Maxillofacial Pathology, Saveetha Dental College and Hospital, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai 600077, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Aim: Ameloblastoma is a benign but locally aggressive epithelial odontogenic tumor. The present review aimed to identify the most commonly expressed signaling molecule in ameloblastoma detected using cDNA microarray. Materials and Methods: It is a systematic review. In this review, articles were searched using databases—PubMed and Google Scholar and were also searched using Hand Search. All the studies which used cDNA microarray to detect the expression of signaling molecules were included. All the variants of ameloblastoma were included for the review. A total of 22 ameloblastoma cases were included in this systematic review. Out of three studies, 67% of the cases demonstrated upregulation of smoothened (SMO) and sonic hedgehog (SHH). Results: Out of three studies, 33% of the cases showed upregulation of toll-like receptor 2 (TLR2), fos proto-oncogene (FOS), Wnt family member 10a (Wnt10a), and patched and down-regulation of insulin-like growth factor 2 (IGF2). Of the 67% of the studies which described SMO and SHH, significant expression of SMO (73 times fold change) was noted. SHH expression was noted to have 0.88 times fold change. Of the 33% of the studies included, the highest average fold change was noted to be associated with FOS (14-fold change time) followed by Wnt10a (5.1-fold change times) and TLR2 (3.29-fold change times). However, downregulation of IGF2 by 0.09-fold change times was observed in 33% of the studies. Conclusion: The SMO gene from the SHH pathway was the highest expressed signaling molecule in ameloblastoma.
Keywords: Ameloblastoma, cDNA Microarray, Molecular Expression, Signaling Molecules
|How to cite this article:|
Surendran S, Ubayathulla N, Ramani P, Yuwanati M. Expression of signaling molecules in ameloblastoma using cDNA microarray: A systematic review. J Int Oral Health 2023;15:119-26
|How to cite this URL:|
Surendran S, Ubayathulla N, Ramani P, Yuwanati M. Expression of signaling molecules in ameloblastoma using cDNA microarray: A systematic review. J Int Oral Health [serial online] 2023 [cited 2023 Jun 1];15:119-26. Available from: https://www.jioh.org/text.asp?2023/15/2/119/375359
| Introduction|| |
Ameloblastoma is a rare odontogenic benign tumor, which accounts for less than 1% of head and neck tumors.,,,, Despite being rare, it is the second most commonly diagnosed odontogenic tumor. Ameloblastoma mainly affects younger patients in developing countries. There is not much gender predilection with males (53%) being slightly more affected than females (47%).
The conventional management is surgical resection. Even though most of the patients are cured with surgical resection, recurrences have been observed.,,,, The association between recurrence rate of ameloblastoma still remains a mystery. The morbidity of the conventional management to the patient is high as a part of the jaws is removed. This often leads to loss of speech, mastication, and causes a permanent facial deformity. Furthermore, it can cause improper growth of the jaw in young patients.
The knowledge regarding the early events which lead to the promotion of tumorigenesis in ameloblastoma still remains scarce mostly because the studies done to identify the molecular factors which initiate and cause tumorigenesis are still inconclusive. Next generation sequencing (NGS) analysis has led to the identification of high frequency B-Raf proto-oncogene V600E (BRAF V600E) and SMO L412F mutations in ameloblastoma.,, Activating BRAF mutations suggests that there is involvement of a hyperactive RAS-RAF-MAPK pathway in the pathogenesis of ameloblastoma.,,, Studies reported that the mitogen-activated protein kinase pathway and/or sonic hedgehog (SHH) signaling pathway are the most commonly seen pathways activated in ameloblastoma.
In these studies, there are many ambiguous points regarding the mechanisms involving ameloblastoma. The factors that cause the formation of different histological variants in ameloblastoma are still unknown., The microenvironment of ameloblastoma has been found to have various mechanisms that cause the growth but the correlation between these mechanisms is still unclear. These ambiguities have setback the various treatment strategies that could be employed for the management of ameloblastoma. One such method is targeted/precision medicine.
Research regarding targeted therapy for management of ameloblastoma is well received. In recent days, drugs targeting various odontogenic drugs are given to shrink the tumor to an operable size which enables the surgeon to resect the bone with least morbidity to the patient.,,,,,
The techniques employed to identify the signaling molecules include an array of methods like RT-PCR, cDNA microarray, cDNA microarray is found to produce better results compared to the rest of the techniques when it comes to detecting signaling molecules.,,
The aim of this systematic review is to find the most commonly expressed signaling molecule in ameloblastoma that can be detected using cDNA microarray. The null hypothesis for this review is that there is no commonly expressed signaling molecule in ameloblastoma that can be detected using cDNA microarray.
| Materials and Methods|| |
This review was done in accordance with guidelines given by Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Guidelines of Systematic Review. The data collected for this review were taken till 2020. Advanced search of PubMed search engine was used using the following keywords: ((((Ameloblastoma) OR (ameloblastoma)) OR (Adamantinoma)) OR (adamantinoma)) AND ((((CDNA microarray) OR (cDNA microarray)) OR (micro array)) OR (Micro array)) AND (((Signaling molecule)) OR ((molecule expression)) OR ((protein)) OR ((proteins))) [Figure 1]. The research question to be answered by this review is “Which is the most commonly expressed signaling molecule involved in pathogenesis of ameloblastoma identified by cDNA microarray technique?” Two independent investigators were involved in the searching of the electronic databases, that is, PubMed, Google Scholar, and Hand Search.
Inclusion and exclusion criteria
All the original studies that evaluated the expression of signaling molecule in ameloblastoma using cDNA microarray were included. Studies carried out on ameloblastoma tissue samples from humans were included. Studies that were published in English language were included. Review articles, animal and cell line studies, case reports, communication and letter to editors were excluded from the review. Studies that did not use cDNA microarray or provided details of expression of molecules involved in ameloblastoma were excluded. Data extraction table was made with the author name, year of publication, genes studied, methodology imparted for observing expression of signaling molecules, type of sample collection, study group, control group, results and limitations summarized in [Table 1]. Quality analysis of the articles was done using ROBINS-I tool [Table 2]. Risk of bias was evaluated. Only articles with a good quality check were included in the review.
| Results|| |
The search identified a total of 47 articles from different databases. After removing duplicates, 44 articles titles and abstracts were screened. Out of these 44 articles, 9 were excluded based on exclusion and inclusion. 35fulltext articles were further screened for eligibility. Finally, three articles were found eligible for this review. The search strategy is described in the PRISMA flow chart [Figure 2].
This systematic review consisted of individual ethnicity studies. Hence this systematic review critically appraises the expression of signaling molecules in ameloblastoma using cDNA microarray using three ethnicities. Two out of three articles included were of case-control studies. One study did not use control. Only in one study, the case included tissue samples as well as ameloblastoma cell line. 17 out of 22 ameloblastomas included were from the mandible. All the studies had a major disparity between the distribution of case and control subjects. Sample collection was done either by tissue samples or tissue and cell lines. DNA extraction was done using the RT-PCR method. Multiple genes were expressed in all the variants of ameloblastoma included in the review.
A total of 22 ameloblastoma cases were included in this systematic review. Out of three studies, 67% of the cases demonstrated upregulation of SMO and SHH. Out of three studies, 33% of the cases showed upregulation of TLR2, FOS, Wnt10a, and patched and downregulation of IGF2 [Figure 3]. Of the 67% of the studies which described SMO and SHH, significant expression of SMO with 73 times fold change was noted. SHH expression was noted to have 0.88 times fold change. Of the 33% of the studies included, the highest fold change average was noted to be associated with FOS (14-fold change time) followed by Wnt10a (5.1-fold change times) and TLR 2 (3.29-fold change times). However, downregulation of IGF2 by 0.09-fold change times was observed in 33% of the studies [Figure 4].
|Figure 3: Pie chart representing the total number of studies with various molecules expressed in ameloblastoma. 33% of the studies showed upregulation of TLR2, FOS, Wnt10a, and patched and downregulation of IGF2 and 67% of the studies showed upregulation of SMO and SHH. Blue indicates expression of TLR2, FOS, Wnt10a, patched, and IGF1 and orange represents expression SMO and SHH|
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|Figure 4: Line graph demonstrating the fold change of various molecules in ameloblastoma where the x-axis represents the molecules and y axis represents the fold change in times|
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Level of evidence
All the included articles had the expected level of evidence; hence, no further categorization was done among them [Table 3].
| Discussion|| |
Ameloblastoma is an aggressive benign tumor of the oral cavity. In this review, the expression of various signaling molecules in ameloblastoma which were detected by cDNA microarray was analyzed. Among the various pathways found that expressed signaling molecules in ameloblastoma, the SHH pathway is found in higher frequency. In the SHH pathway, the SHH and SMO signaling molecules were most commonly expressed. These signaling molecules were found to play a major role in tumorigenesis of ameloblastoma.
In 67% of the studies, SHH shows 73 times fold increase in ameloblastoma. SHH control cell–cell interactions and cell proliferation in tissue patterning during development and SHH signal transduction are vital to embryonic development. SHH signaling molecules may play a role in epithelial-mesenchymal interaction and cell proliferation in ameloblastoma. It was stated that the overexpression of upstream and downstream genes in the SHH pathway leads to the constitutive activation of this pathway in ameloblastoma and may suggest a mechanism for the development of this type of tumor. SHH was also found to have anti-apoptotic properties which help in the proliferation of ameloblastoma. Studies have found that there is an increased expression of SHH induced Bcl-2 in solid variant of ameloblastoma. They found out that Bcl-2 was expressed in the outer layer of ameloblastoma cells, whereas the protein was expressed in the inner stellate reticulum and squamoidcells., With this, it can be suggested that SHH plays an important role in the tumorigenesis and proliferation of ameloblastoma.
SMO was found to be over expressed in ameloblastoma in 67% of the studies. Missense mutation of SMO was observed more in malignant and metastasizing ameloblastoma. This feature, although found in conventional ameloblastoma, was not a common finding. These missense mutations cause an increase in the rate of tumorigenesis. It alters SHH pathway and promotes tumorigenesis by affecting cell proliferation, differentiation and apoptosis. It increases the rate of cell proliferation, its differentiation. These features are found more in the periphery than in the center of the tumor. Thus, SMO could be one of the possible targeted therapies in treating ameloblastoma. Both SHH and SMO proteins work via the SHH pathway. This shows that the SHH pathway is one of the common routes of pathogenesis in ameloblastoma.
The second most commonly found signaling pathway is the Mitogen Activated Protein Kinase (MAPK) pathway. Within this pathway, the most commonly expressed signaling molecules were found to be IGF2, TLR2, and FOS. These signaling molecules were found to play a major role in the mechanism of development of ameloblastoma. IGF2 signaling molecule was found to enhance proliferation of ameloblastoma cell line in AMU-AM1 ameloblastoma cell line with BRAF mutation in 33% of the studies. The biological activities of IGFs include stimulation of collagen production and downregulation of collagenase synthesis in fibroblasts. The increased expression of IGF could be due to the fact that IGF levels are especially high in cells that are undergoing proliferation and differentiation. It is also closely related to expression of anti-apoptotic factor Bcl-2. RAS-RAF-MAPK pathway promotes cell growth of ameloblastoma by mediating IGF2 signaling molecule stimulation. Thus, expression of IGF2 may suggest a mechanism for the development of ameloblastoma.
TLR2 signaling molecule was found to enhance cell survival signaling in ameloblastoma in 33% of the studies. There is recent evidence which states that TLRs play a vital role in tumor survival and growth. Studies also report that TLR2 activates myeloid cells to stimulate metastasis. MAP Kinase pathway is seen to upregulate TLR2 signaling molecules in ameloblastoma. TLR2 is seen to promote tumorigenesis independent of tumor inflammation, deviating from its usual course and may function proactively as it is seen to promote cell growth in ameloblastoma. Enhancing cell survival and cell growth are both favorable to the tumorigenesis of ameloblastoma. Because it is found that MAP Kinase pathway upregulates TLR2 signaling molecules, it can be stated that MAPK pathway is one of the common routes in the pathogenesis of ameloblastoma.
The review identified that FOS had an eightfold increase in the expression in ameloblastoma in 33% of the studies. The FOS protein belongs to the activating protein-1 family of transcription factors and is encoded by proto-oncogene. It participates in the control of oncogenic transformation, apoptosis, cell proliferation and cell differentiation. This protein is very important for the development of bone and plays as a key regulator of osteoclast-macrophage lineage determination and remodeling of bone. Although many cancers display an overexpression of FOS gene in vitro,, its role in the pathogenesis of human tumors is yet to be understood. It participates in the control of oncogenic transformation, apoptosis, cell proliferation and cell differentiation. Thus, expression of FOS may suggest a mechanism for the development of ameloblastoma.
Although not common, the WNT-beta-catenin-TCF signaling pathway is seen to be involved in ameloblastoma. Within this pathway, the WNT10A signaling molecule was found to be commonly expressed in ameloblastoma. WNT10A was found to play a role in the tumorigenesis of ameloblastoma. In 33% of the studies, WNT10A had a fivefold increase in the expression in ameloblastoma. WNT10A’s function is mostly related to developmental process including the regulation of fate of cells and its patterning during embryogenesis. It plays a key role in various carcinogenesis by the activation of WNT-beta-catenin-TCF signaling pathway. The expression of WNT10A is said to be mediated by the tumor necrosis factor-α. This factor was also found to have a high expression in ameloblastomas. It is suggested to cause cytodifferentiation in ameloblastoma but further studies are needed to understand its pathogenesis. Hence, WNT10A can be seen as a crucial molecule in understanding the tumorigenesis of ameloblastoma.
Among the various signaling molecules seen being expressed in ameloblastoma, the molecules found in the SHH pathway and WNT-beta-catenin-TCF pathway were found to be playing a major role in tumorigenesis. Further studies can be conducted that can provide a better understanding of these two pathways and to find the presence of any correlation between them.
In this review, cDNA microarray was chosen as the technique of choice for analyzing the various signaling molecules that are expressed by ameloblastoma. The use of cDNA microarray as a technique for the quantification of genetic expression is a smart method in this growing era of high-level technological developments. Ameloblastoma, as recorded in various studies, can express various signaling molecules. Although a lot of studies have been devoted to finding the most common signaling molecule expressed in ameloblastoma, limitations in technology have restricted the studies to analyze only one or few signaling molecules at a time. CDNA microarray has overcome this limitation. CDNA microarray allows us to study thousands of genes at the same time. It also simultaneously measures the transcription level of every gene in a cell. This allowed the studies to evaluate multiple signaling molecules that were expressed by ameloblastoma at the same time. This reduces the overall cost and time spent on the technical process. The reviews found numerous signaling molecules that were expressed by ameloblastoma. It also found the level of expression of each signaling molecule. With the data it provided, we were able to identify the most commonly expressed signaling molecule by ameloblastoma.
Report on quality of evidence looked up on
Two out of three studies included in this review were case-control studies. One article did not use control in their study. The level of evidence of these articles included in this review is of high quality. SMO gene from the SHH pathway was the highest expressed signaling molecule in ameloblastoma. However, further studies are required to consider the level of these expressions in other ethnicities.
The present systematic review considers only the published data for results. The unpublished raw data of the studies have not been included for interpretation. Due to the heterogeneous nature of the various genes assessed in this review, pooling of data was not possible. The sample distribution between the case and control was uneven. However, low sample size is a major limitation.
Studies with increased sample size, standardization of study design, methodology, and method of evaluation are needed to assess the expression of signaling molecules in ameloblastoma.
| Conclusion|| |
After critically appraising the studies, this review concluded that the SMO gene from the SHH pathway was the highest expressed signaling molecule in ameloblastoma.
We would like to acknowledge all the authors who have contributed their efforts for this systematic review.
Financial support and sponsorship
Conflict of interest
The authors declare no conflict of interest.
Ethical policy and Institutional Review board statement
Patient declaration of consent
Data availability statement
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3]