|Ahead of print publication
Expression of epithelial–mesenchymal transition biomarkers: Discoidin domain receptor 2, Snail-1, and Ovol-2 as predictors of clinical outcome in patients with epithelial ovarian carcinoma
Ola A Harb1, Mariem A Elfeky1, Wafaa El-Beshbishi2, Ahmed A Obaya3, Wael M Abdallah4, Amr Ibrahim4, Amr A Awd5, Ahmed Embaby6
1 Department of Pathology, Zagazig University Faculty of Medicine, Zagazig University, Egypt
2 Department of Clinical Oncology and Nuclear Medicine, Faculty of Medicine, Mansura University, Egypt
3 Department of Clinical Oncology and Nuclear Medicine, Faculty of Medicine, Zagazig University, Egypt
4 Department of General Surgery, Faculty of Medicine, Zagazig University, Egypt
5 Department of Gynecology and Obstetrics, Faculty of Medicine, Zagazig University, Egypt
6 Department of Internal Medicine, Faculty of Medicine, Zagazig University, Egypt
|Date of Submission||15-Aug-2019|
|Date of Acceptance||17-Oct-2019|
|Date of Web Publication||10-May-2021|
Ola A Harb,
Department of Pathology, Faculty of Medicine, Zagazig University, Zagazig, 44519
Source of Support: None, Conflict of Interest: None
Context: Discoidin domain receptor 2 (DDR-2), which belongs to the receptor tyrosine kinase family, Snail-1, which is a member of zinc-finger transcription factor family, and Ovol-2, which is a member of Ovol family, are incriminated in epithelial–mesenchymal transition (EMT) during cancer progression.
Aim: In the current study, we aim to clarify the extent to which EMT biomarkers, DDR-2, Snail-1, and Ovol-2 expression, are involved in the progression of EOC aiming at identification of novel markers for predicting the prognosis of EOC patients.
Settings and Design: This was a prospective cohort that was performed in the Faculty of Medicine, Zagazig University.
Materials and Methods: We evaluated DDR-2, Snail-1, and Ovol-2 expression in 60 patients of EOC using immunohistochemistry. We followed our patients for about 36 months and analyzed the relationship between markers expression and the prognosis of patients.
Statistical Analysis Used: SPSS program (Statistical Package for the Social Sciences).
Results: High expression of both DDR-2 and Snail-1 was related to higher grade (P = 0.006) and advanced FIGO stage of the tumor (P < 0.001). Ovol-2 high expression was associated with lower grade of the tumor (P = 0.002) and early stage of the tumor (P < 0.001). High Ovol-2 and low DDR2 and Snail-1 expression were strongly correlated with better response to therapy (P = 0.003 and 0.005, respectively) and increased 3-year survival rates (P < 0.001).
Conclusion: DDR-2 and Snail-1 are markers of poor prognosis in EOC while Ovol-2 is a marker of good prognosis.
Keywords: Discoidin domain receptor 2, epithelial–mesenchymal transition, epithelial ovarian carcinoma, immunohistochemistry, Ovol-2, prognosis, Snail-1
|How to cite this URL:|
Harb OA, Elfeky MA, El-Beshbishi W, Obaya AA, Abdallah WM, Ibrahim A, Awd AA, Embaby A. Expression of epithelial–mesenchymal transition biomarkers: Discoidin domain receptor 2, Snail-1, and Ovol-2 as predictors of clinical outcome in patients with epithelial ovarian carcinoma. J Can Res Ther [Epub ahead of print] [cited 2021 Nov 28]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=315670
| > Introduction|| |
Ovarian cancer is considered the 7th most common cancer in females, accounting for 2.5% of all female malignancies and 5% of cancer-related female deaths because of aggressive course and low survival rates that are largely driven by late stage diagnoses. Epithelial ovarian carcinoma (EOC) is the most common type of ovarian cancer.
EOC consists of many distinct histopathological subtypes and the most common subtypes are serous, mucinous, and endometrioid carcinomas, whereas the less common subtypes are clear cell, transitional, mixed, squamous, and undifferentiated subtype. Despite different histological subtypes, the treatment of EOC patients is surgical debulking followed by taxane/platinum-based chemotherapy. Hence, there is a need for better patient stratification depending on tumor phenotypes, as well as discovering more targeted, phenotype-specific management strategies. The epithelial–mesenchymal transition (EMT) is the process, during which epithelial cells lose their epithelial criteria and acquire mesenchymal phenotypes, and subsequently, epithelial cells become motile, more migratory, and invasive and thus invade and metastasize., Apart from its role in normal development, EMT could be utilized by malignant cells to acquire chemoresistance, to maintain their stemness, and to evade from host immunity. Thus, targeting EMT pathways which are mediated by several biomarkers in EOC could be a novel therapeutic option to improve the prognosis of such aggressive cancer. Discoidin domain receptor 2 (DDR2) belongs to the receptor tyrosine kinase (RTK) family which is activated by collagen that is present in the extracellular matrix. RTKs are important for the communication of cells with their microenvironment and are involved in the regulation of cell growth, differentiation proliferation, and metabolism. DDR2 is composed of an extracellular region which contains the discoidin region, a transmembrane region connected to a cytoplasmic region, and a catalytic region. The intracellular region of DDR2 plays a crucial role in cancer progression. Collagen was found to stimulate EMT, so DDR2 is incriminated in EMT during cancer progression. Snail1 is a member of zinc-finger transcription factor family, it is one of the EMT-related transcriptional regulators, and it has been implicated in the EMT which occurred during tumor progression, invasion, metastasis, and poor prognosis of plethora of malignancies. DDR2 has been implicated in a number of cancer types; additionally, it was found that DDR2 might contribute to breast cancer cells invasion and spread via maintenance of stability and activity of Snail1. However, the exact mechanisms which are controlling role of DDR2 expression during EMT in cancer cells and its relation to Snail1 expression in EOC are not clear. Ovo-like zinc finger (Ovol) family members are considered zinc finger transcription factors which act as regulators of epithelial development. Ovol family includes Ovol1, Ovol2, and Ovol3, which could regulate the formation of a wide variety of organs, including the hair follicles and kidneys. Ovols are considered downstream regulators of many signaling pathways, including those of epidermal growth factor signaling pathway which was recently discovered as a transcriptional repressor of EMT. Ovol-2 is a member of Ovol family that is involved in many important physiological processes and EMT regulation. Downregulation of Ovol-2 has been found in a variety of cancers.,, However, the effects of expression of DDR-2, Snail-1, and Ovol-2 in EOC and association with its progression have not been fully clarified. In the current study, we aimed to clarify the extent to which EMT biomarkers, DDR-2, Snail-1, and Ovol-2 expression, are involved in the progression of EOC aiming at identification of novel markers for predicting the prognosis of EOC patients.
Patients and tissue specimens
The study design
This is a prospective cohort study where we have included sixty female patients with ovarian cancer, who underwent surgical resection at the General Surgery Department, Oncology Unit, Faculty of Medicine, Zagazig University, and Gynecology and Obstetrics Department, Faculty of Medicine, Zagazig University. None of our patients received preoperative chemotherapy or radiation therapy. After surgery, resected specimens were processed routinely for pathological assessment, histopathological subtyping, grading, and staging at the Pathology Department, Faculty of Medicine, Zagazig University. The stage of ovarian cancer was classified according to the International Federation of Gynecology and Obstetrics criteria. Prior informed consent was obtained from each patient, and this study was approved by the local Ethics Committee of Faculty of Medicine, Mansoura University and Zagazig University. Cases were followed up from January 2016 to January 2019 in both Clinical Oncology and Nuclear Medicine Departments, Faculty of Medicine, Zagazig University and Mansoura University, where the overall survival time and recurrence-free survival time were calculated starting from the date of the initial surgery to the time of death or recurrence or the last date of follow-up as the endpoint.
The types of materials used are sections from formalin-fixed paraffin-embedded tissue blocks that were derived from included sixty female patients with ovarian cancer.
Immunohistochemical staining was performed to assess the tissue protein expression of DDR-2, Snail-1, and Ovol-2 in specimens from EOC patients using streptavidin–biotin complex. Samples were incubated overnight at 4°C with monoclonal rabbit anti-DDR-2 antibody (3B11E4) (ab63337), anti-Snail1 antibody (ab180714), and anti-Ovol-2 antibody (ab83265) (Abcam, Cambridge, UK; dilution 1:200). Immunostaining was separately reviewed and scored by two independent pathologists who were blinded as to the patients.
Evaluation of the immunohistochemical staining
We have evaluated cytoplasmic DDR-2, nuclear Snail-1, and Ovol-2 expression according to both the proportion and intensity of positively stained cancer cells. The extent of stain were evaluated as follows: (1) number of positive stained cells ≤5%, scored 0; 6%–25%, scored 1; 25%–50%, scored 2; 51%–75%, scored 3; and >75%, scored 4; and (2) intensity of stain: as four grades – 0, negative; 1, weak; 2, moderate; and 3, strong. The intensity and fraction of positive cell scores were multiplied and thus the scoring system was defined as low expression for scores of 0–3 and as high expression for scores of 4–12.,,
Type and details of the statistical analysis used
We collected data from the patient throughout the period of follow-up, summarized them, and then statistically analyzed them using SPSS program (Statistical Package for the Social Sciences) version 24. We used Shapiro–Wilk test to test normal distribution of data and used Chi-square test and Fisher's exact to calculate difference between qualitative variables. Spearman's correlation test was used for correlating variables. The + sign was an indication for direct correlation and − sign as indication for inverse correlation. All statistical comparisons were two tailed with significance level of P ≤ 0.05 indicating significant and P < 0.001 indicating highly significant difference. Kaplan–Meier method was used to estimate the overall and event-free survival and log-rank test compared the survival curves. All comparisons are two sided to enable replication.
| > Results|| |
Patient clinicopathological results
We included sixty cases with EOC; their age ranged from 29 to 79 years and the mean age was 55.53 ± 10.53 years. Our cases included 34 (56.67%) serous ovarian carcinoma, 16 (26.67%) mucinous, and 10 (16.67%) endometrioid ovarian carcinoma. All clinical and pathological parameters are included in [Table 1].
|Table 1: Demographic, clinical, pathological parameters of patients and correlation with markers expression in the studied population (n=60)|
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Discoidin domain receptor 2 immunoreactivity results and association with pathological parameters
DDR-2 high expression was present in 35 (%) cases of EOC and its expression was related to older age of the patients (P = 0.002), higher grade of the tumor (P = 0.006), advanced FIGO stage of the tumor (P < 0.001), presence of distant metastases (P = 0.021), and lymph node metastases (P = 0.006) [Table 1] and [Figure 1].
|Figure 1: Immunohistochemical expression of DDR2 in epithelial ovarian carcinoma: (a) High expression in the cytoplasm of high grade serous ovarian carcinoma; stage IV ×100. (b) High expression in the cytoplasm of high grade serous ovarian carcinoma; Stage IV, ×400. (c) High expression in the cytoplasm of high grade endometrioid ovarian carcinoma; Stage III, ×400. (d) Low expression in the cytoplasm of low grade serous ovarian carcinoma Stage II, ×100 (e) Low expression in the cytoplasm of low grade endometrioid ovarian carcinoma Stage I, ×400|
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Snail-1 immunoreactivity results and association with pathological parameters
Snail-1 high expression was present in 36 (%) cases of EOC and its expression was related to older age of the patients (P = 0.003), higher grade of the tumor (P = 0.001), advanced stage of the tumor (P = 0.001), presence of distant metastases (P = 0.032), and lymph node metastases (P = 0.008) [Table 2] and [Figure 2].
|Table 2: Outcome of all patients in correlation with markers expression in the studied population (n=60)|
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|Figure 2: Immunohistochemical staining of Snail1 epithelial ovarian carcinoma: (a) High expression in the nucleus of high grade serous ovarian carcinoma; Stage IV, ×400. (b) High expression in the nucleus of high grade serous ovarian carcinoma; Stage III, ×400. (c) High expression in the nucleus of high grade endometrioid ovarian carcinoma; Stage III, ×400. (d) Low expression in the nucleus of low grade serous ovarian carcinoma Stage II, ×400 (e) Low expression in the nucleus of low grade endometrioid ovarian carcinoma Stage I, ×400|
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Ovol-2 immunoreactivity results and association with pathological parameters
Ovol-2 high expression was present in 25% of cases of EOC and its expression was associated with younger age of the patients (P = 0.004), lower grade of the tumor (P = 0.002), early stage of the tumor, absence of distant metastases (P < 0.001), and absence of lymph node metastases (P = 0.007) [Table 2] and [Figure 3].
|Figure 3: Immunohistochemical expression of Ovol2 in epithelial ovarian carcinoma: (a) High expression in the nucleus of low grade serous ovarian carcinoma; Stage II, ×400. (b) High expression in the nucleus of low grade endometrioid ovarian carcinoma Stage I, ×400. (c) Low expression in the nucleus of high grade serous ovarian carcinoma Stage III, ×400 (d) Low expression in the nucleus of high grade endometrioid ovarian carcinoma Stage IV ×400|
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After a median follow-up period of 30.5 months with range (1–60) months, 48.33% of patients died (29/60 patients).
High OVOL2 and low DDR2 and Snail-1 expression were strongly correlated with better response to therapy (P = 0.003 and 0.005, respectively), increased chemosensitivity of the tumor (P = 0.004 and <0.001, respectively), low incidence of recurrence after therapy (P = 0.006, 0.003, and 0.002, respectively), increased the liability of optimal surgical eradication of the tumor (P = 0.005, 0.002, and 0.004, respectively), and increased 3-year recurrence-free and overall survival rates (P < 0.001) [Table 3], [Table 4] and [Figure 4].
|Table 3: Mean survival time and rates in correlation with markers expression in the studied population (n=60)|
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|Table 4: Univariate and multivariate Cox regression analyses of different prognostic factors for overall survival and Relapse-free survival|
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|Figure 4: Kaplan Meier plot, (a-d): Recurrence free survival; (a) All studied patients, (b) Stratified by DDR-2, (c) Stratified by Snail-1 (d) Stratified by Ovol-2. Overall Survival; (e) All studied patients, (f) Stratified by DDR-2, (g) Stratified by Snail-1 (h) Stratified by Ovol-2|
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In univariate analysis and in multivariant analysis, DDR-2 expression is the most important parameters of assessment of RFS and OS in patients with EOC (P < 0.001, 0.016, and 0.004, respectively).
Ovol-2 expression was negatively correlated with DDR-2 and Snail-1 expression, r correlation coefficient = −0.828 and there is a positive association between DDR-2 and Snail-1 expression, r correlation coefficient = +0.828 (P < 0.001).
No significant association was found between DDR-2, Snail-1, and Ovol-2 expression with the presence of peritoneal implants, ascites, or histopathological subtype of the tumor.
| > Discussion|| |
EMT is a dynamic biological process that is crucial in the development of invasiveness and metastatic potential of many cancers and it is particularly associated with negative prognosis in patients with EOC. In the current study, we have passed the expression of three biomarkers of EMT: DDR-2, Snail-1, and Ovol-2.
We have proved that DDR2 is upregulated in EOC tissues and its expression was associated with aggressive phenotype and dismal patients' outcome; similarly, Grither et al. have shown that the collagen receptor DDR2 contributes to the mesothelial clearance, invasion, and metastasis of ovarian cancer cells. Their findings demonstrate that DDR2 expression is associated with worse prognosis in high-grade serous cancers; moreover, Fan et al. proved that DDR-2 is upregulated in ovarian cancer tissues in comparison with that in normal ovarian surface tissues.
We have found that the expression level of DDR-2 was significantly associated with advanced tumor stage and presence of peritoneal metastasis in EOC patients. Similarly, Fan et al. found that high DDR2 expression was an important indicator of poor clinical prognosis for patients with ovarian cancer.
Thus, DDR2 represents a novel predicative and prognostic marker for ovarian cancer patients.
Xie et al. revealed that DDR-2 expression was significantly higher in malignant hepatic tissues than matched normal adjacent tissues. Moreover, high DDR2 level was correlated with tumor number, presence of vascular invasion, higher grade, and advanced tumor node metastasis stage in hepatocellular carcinoma (HCC). In addition, our results indicate that overexpression of DDR2 was correlated with shorter OS and DFS, so it is an assumed molecular marker for poor prognosis in EOC that was similar to results of Xie et al. in HCC, our results demonstrated that increased DDR-2 expression promotes tumor progression and is a critical factor for prognosis determination in EOC patients. Similar results were found by Gonzalez et al., in breast cancer that the collagen receptor DDR2 is upregulated in breast cancer with advanced stage.
Gonzalez et al., study explained our results by proving that the collagen receptor DDR2 could mediate mesenchymal stem cell (MSC)-cancer cell crosstalk to enhance cancer cells proliferation, migration and metastasis, through induction of collagen type I deposition and activation of DDR2 signaling. These results point to a role for DDR2 positive MSC in metastasis which suggested a therapeutic approach for management of metastatic EOC.
More over Ren et al., found that DDR2 participates in breast cancer metastasis by regulation of cell migration, invasion, and EMT, thus it may serve as a therapeutic target for the treatment of advanced breast cancer and to prevent metastasis of many other types of human cancers.
Results of Velmurugan et al., study were in line with our results and indicated that DDR2 is a potent biomarker which could be used as an effective therapeutic target for treating oral squamous cell carcinoma (OSCC) patients with lymph node metastasis. Additionally they stated that aberrant activation DDR2 was associated with a worsen survival in lymph node metastasis OSCC patients which indicated that DDR2 could be a novel therapeutic targets in EOC too.
Ren et al. reported that DDR2 plays an important role in EMT regulation in cancer cells. Xie et al. revealed that DDR2 facilitates HCC cell invasion, migration and EMT via activating ERK2, stabilizing Snail 1, reducing E-cadherin level and increasing Vimentin level. In the present study, we showed that the DDR2 expression was significantly associated with tumor stage and peritoneal metastasis of ovarian cancer patients. Thus, our present results are consistent with the previous findings in that DDR2 may play an important role in promoting EOC cells migration and progression. Xie et al., clarified another mechanism of action of DDR2 as they stated that activated DDR2 up-regulate the expression of MMP-1, MMP-2 and MMP-13 thus facilitate tumor invasion and metastases. Grither et al., suggested that DDR2 signaling lead to stabilization of SNAIL1 and regulation of MMPs which might be an important cause in EOC metastasis, thus targeting DDR2 could be therapeutic targets for ovarian cancer metastases. DDR2 could be a highly selective therapeutic target in EOC with minimal toxicity to normal cells. Previous studied clarified the relation between both DDR2 and Snail1 in cancer progression but there are few data regarding their role in EOC so in the current study we tried to assess the expression of both markers in such type of cancer. We have proved that high expression of Snail-1 was related to higher grade and advanced FIGO stage of the tumor, presence of distant metastases and L. N metastases and low Snail-1 expression was correlated with better response to therapy and increased 3-year survival rates of the patients, which was similar to Brenot et al., who proved that SNAIL1 expression in primary breast cancer cells is associated with higher recurrence, more aggressive tumors, and poorer outcomes. The presence of SNAIL1 in human primary breast tumors predicts for poor clinical outcomes with increased tumor grade, nodal metastasis, and tumor recurrence. Similarly results of Li et al., review in lung cancer and other cancer types. It was previously stated that Snail1 triggers EMT by repression of E-cadherin gene transcription. Szynglarewicz et al., findings suggested Snail1 might be an indicator of the invasive liability of DCIS and may identify its aggressive subtypes. Moreover, as an EMT regulator, it may be a potential therapeutic target to inhibit the progression from non-invasive to invasive breast cancer. Similar to our results, Merikallio et al., supported that the expression of snail1 was strongest in advanced small cell lung cancer. However, the prognostic role of snail is contradictory in NSCLC Yanagawa et al., indicated that lung adenocarcinoma patients with elevated snail expression had a significant reduction of survival time, while the high expression of snail was not a prognostic biomarker in lung squamous cell carcinoma. Different results were found by Sun et al., indicated that snail was not a prognostic factor in lung adenocarcinoma. Many previous researchers proved that the expression of snail has been associated with invasion and metastasis as well as poor prognosis of many malignancies.,, E-cadherin acts as a tumor suppressor which is inhibiting invasion and metastasis, while, down-regulation of E-cadherin expression increases tumor cell motility and promotes invasion. Snail1 mainly repress expression of E-cadherin to reduce cell adhesion during the EMT. Therefore, snail is an important factor in regulating EMT and its high expression is related to the enhancement of invasion, metastasis, and progression. Moreover, SNAIL1 regulates expression of genes which regulate tumor cell migration, adhesion, proliferation, and survival which are involved in cancer growth and metastasis, additionally; SNAIL1 is involved in the regulation of the immune compartment, which is another role of Snail1 expression in cancer progression and metastasis. Snail1 also regulates tumor resistance to many chemotherapeutic drugs and immunotherapies. And, it was found that, Snail1 knockdown, as a result of siRNA treatment, stops tumor metastasis in melanoma. Similarly, Snail1 reduction leads to cisplatin sensitization in lung adenocarcinoma, head and neck squamous and ovarian cancers.,,, Snail1 has been incriminated in resistance to radiation and paclitaxel in ovarian cancer as well as protection against 5-fluorouracil and gemcitabine in Panc-1 cells., So targeting Snail1 in EOC could sensitize the cells to currently used therapeutic agents. Snail1 also is involved in survival pathways; the repression of NF-κB the downstream target of Snail1 sensitizes tumor cells to cisplatin and TNF-related apoptosis. There are recently discovered chemical inhibitors which target Snail1 directly; LSD and HDAC inhibitors, as well as drugs targeting Snail1/p53 and Snail1/E-cadherin interactions, have shown efficacy. The DDR2 and Snail1 roles in EOC metastasis, recurrence, and resistance to currently used chemotherapeutic agents make them novel theraputic target in such type of cancer, and improving our understanding of them could provide new ways of management of metastatic cancer but due to conflicting results of previous studies we assessed the expression of another transcription factor which is incriminated in regulation of EMT in cancer cells; Ovol-2. We have proved that down regulation of Ovol-2 in EOC tissues was associated with higher grade, advanced stage and poor patients outcome, which was similar to Similarly Liu et al., in osteosarcoma Ovol2 expression is associated with mesenchymal epithelial transition, thus inhibit malignant cells invasion and metastases by suppression of the EMT biomarker ZEB1 expression. Similar results were found by Wu et al., in breast cancer, and they have explained their result by that Ovol-2 antagonizes TGF-β signaling to regulate EMT during mammary tumor metastasis. More over Ye et al., proved that OVOL2, reduced invasive capability of cancer cells through inhibition of Wnt Signaling, also, Ovol-2 down regulation promotes Wnt signaling and colorectal cancer (CRC) metastasis. Ovol-2 plays a critical role in CRC metastatic spread and is considered an endogenous “metastasis suppressor. This was in line with our results in EOC. Qi et al., and Fu et al., proved that expression of Ovol2 is related to a favorable clinical outcome in nasopharyngeal carcinoma and HCC respectively. We have chosen to assess the expression of Ovol-2 in EOC as it was recently discovered as a transcriptional repressor of EMT. Down-regulation of Ovol-2 has been found in a variety of cancers., Loss of Ovol-2 expression causes activation of EMT state that drives metastasis and contributes to drug resistance and invasion phenotypes. Thus, restoring OVOL2 expression is a potential therapeutic approach of cancer management, and that OVOL2 could inhibit EMT and metastasis by suppressing TWIST in lung cancer, c-Myc in squamous cell carcinoma, Wnt signaling in CRC and TGF-β signaling in breast cancer. Fu et al. reported that Ovol-2 expression is significantly lower in HCC than in adjacent noncancerous tissues and those patients with high Ovol-2 expression level showed a high expression level of E-cadherin and low expression levels of Snail and Slug. Similarly, our study demonstrated that Ovol2 up-regulation correlates with low expression levels of the EMT related biomarkers; DDR2 and Snail1 and increases the migration and invasion capabilities of EOC cells.
| > Conclusion|| |
In EOC cells, high expression of the EMT-inducing biomarkers, DDR2 and Snail 1, and low expression of the EMT suppressor biomarker, Ovol-2, were related to poor clinicopathological and prognostic criteria of EOC patients. DDR2 expression was upregulated as a product of the mesenchymal program which is induced by TWIST1, and it maintains the mesenchymal phenotype through SNAIL1 stabilization and Ovol-2 inhibition. Hence, DDR2 and Snail1 are critical factors which contribute to the steps of ovarian cancer metastasis. Therapeutic modulation of DDR2, Snail1, and Ovol-2 could provide a means of improving treatment for patients with advanced EOC.
The development of chemical inhibitors for both Snail1 and its targets has begun. However, to our knowledge, no sufficient studies about regarding targeted therapies against DDR2 or therapeutic agents to increase the levels of Ovol2 which might help to inhibit EOC metastasis. Hence, a large-scale study is needed to confirm our results and assessed the possibility of discovering novel targeted therapy against such aggressive malignancy.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4]