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Prognostic value of NOTCH1 and OCT4 in gastric carcinoma Ibrahim DA, Elsebai EA, Fayed A, Abdelrahman AE



   Abstract  

Background: NOTCH1 pathway activation has been recently described to be a key player in gastric carcinogenesis, enhance the survival and proliferation of cancer stem cells (CSCs) and mediate chemoresistance in several malignancies. Aim: This study investigated the correlation between NOTCH1 and CSC marker OCT4 (octamer binding transcription factor-4) expression and the clinicopathological properties, survival and treatment outcome in patients with gastric carcinoma (GC) receiving adjuvant chemotherapy. Materials and Methods: NOTCH1 and OCT4 were immunohistochemically detected in 50 post-operated specimens of GC. Patients’ data regarding disease-free survival (DFS), overall survival (OS), and the response to the chemotherapy was statistically analyzed. Results: NOTCH1 and OCT4 overexpression was detected in 60% and 52% of GC tissues, respectively, and that was significantly higher than the rates in adjacent non-neoplastic gastric mucosa (P < 0.05). A significant correlation was detected between overexpression of NOTCH1 and OCT4 in GC and aggressive clinicopathological features; poor differentiation (P = 0.021, P = 0.037, respectively), depth of tumor invasion (P < 0.001 for both), TNM stage (P < 0.001 for both), lymph node metastasis (P = 0.002, P = 0.003, respectively) and distant metastasis (P < 0.001 for both). NOTCH1 was positively correlated with OCT4 (P = 0.002). Survival analysis disclosed that upregulation of NOTCH1 and OCT4 was associated with worse DFS (P = 0.013, P < 0.001, respectively) and OS (P < 0.001 for both). Overexpression of NOTCH1 and OCT4 correlated with poor response to chemotherapy (P = 0.013, P = 0.005, respectively) and worse clinical outcome. Conclusion: Combined detection of these proteins might disclose even better predictive value for shorter survival and resistance to chemotherapy.

Keywords: Gastric carcinoma, NOTCH1, OCT4, prognosis

How to cite this article:
Ibrahim DA, Elsebai EA, Fayed A, Abdelrahman AE. Prognostic value of NOTCH1 and OCT4 in gastric carcinoma. Indian J Pathol Microbiol 2022;65:328-35




   Introduction   Top

Worldwide, gastric cancer (GC) is the fifth most frequently diagnosed cancer. The high mortality rate is probably due to the fact that many cases are diagnosed at an advanced stage and the high frequency of metastasis.[1] In Egypt, GC represents 1.6% of the total cancers and 2.2% of cancer-related death.[2] It is proposed that GC might arise from the complex interaction of genetic and environmental factors that deregulate oncogenic signaling pathways.[3] Many studies have demonstrated that NOTCH signaling pathway is commonly activated in tumors.[3],[4],[5] It is involved in controlling cell differentiation, survival, proliferation, tumor angiogenesis, apoptosis, and stemness maintenance, which are mediated through interaction with other signaling pathways.[4],[5] The NOTCH family is composed of four transmembrane proteins (NOTCH 1–4) that regulate the action of some membrane proteins and nuclear transcriptional agents. NOTCH signaling can be both oncogenic or tumor-suppressive.[4],[5] Most of the published data had reported that NOTCH signaling pathway is activated through a series of proteolytic cleavage with subsequent release of NOTCH intracellular domain (NICDs) that translocated to the nucleus and activate several NOTCH downstream target genes that stimulate GC. These downstream proteins includes COX-2, TWIST, CD133, c-myc, cyclin D1, which further mediated the function of this signaling pathway.[4],[5],[6] Earlier studies revealed that the increased expression of NOTCH pathway correlated with shorter survival and worse prognosis of cancer and was also involved in drug resistance and maintaining the self-renewal of cancer stem cells (CSCs).[6]

Despite the progress in treatment of GC by surgery and adjuvant chemoradiotherapy, yet, many patients are still at high risk of tumor recurrence and metastasis although they received the standard treatment.[7] Introduction of the concept of CSCs has been implicated to explain tumor heterogeneity and the cause of therapy resistance, tumor recurrence, and metastasis. CSCs might arise from transformed progenitor cells that have regained self-renewal due to aberrant signaling pathways and accumulation of genetic changes.[7],[8] Octamer binding transcription factor-4 (OCT4) is a CSC marker and a transcription factor that is responsible for self-renewal of human stem cells and maintenance of pluripotency through controlling some genes (SOX2, FGF4, and STAT3) and other components of key signaling pathways.[7],[8] This study investigated the role of NOTCH signaling and OCT4 in GC and their relationship with the clincopathological variables, survival and treatment outcome in patients with GC receiving adjuvant chemotherapy.

   Materials and Methods   Top

Patients and tissue specimens

This retrospective study was carried out on 50 paraffin-embedded sections of GC. They were obtained from 50 patients who were diagnosed in the Pathology department, Faculty of Medicine, Zagazig University in the period from March 2014 to January 2017. All Patients fulfilled the inclusion criteria. None of the patients received neoadjuvant therapy before surgery. The clinicopathological information, including age, gender, histological type, histological grade, TNM stage, lymph node metastasis, distant metastasis, and clinical follow-up data should be available and were obtained from the pathology reports and case medical records. All patients had follow-up records for 2 years. Otherwise, were excluded. Re-evaluation of the histopathological diagnosis of hematoxylin and eosin-stained sections was done. This study (protocol No. 6110) was approved by the ethics committee.

Chemotherapy protocol

All patients had surgical intervention in the form of either total or subtotal gastrectomy with lymph node dissection at the general surgery department. They were referred to clinical oncology department for further treatment and follow-up, where patients were evaluated by complete history, physical examination, radiological and laboratory investigations. They were treated with 5FU-based chemotherapy regimen or chemoradiation for locally advanced stage with adjuvant radiotherapy (45Gy in 25 fractions over 5 weeks) concomitant with Capecitabine. Our patients underwent follow-up after treatment by clinical examination and radiological evaluation.

Evaluation of the response to adjuvant chemotherapy

The response to therapy was evaluated by RECIST criteria [version 1;1] in which complete response (CR) was defined as complete disappearance of all detected lesions after adjuvant treatment. Partial response (PR) was defined as at least a 30% decrease in the diameters of detected lesions, taking the baseline diameters as a reference. Progressive disease (PD) was defined as at least a 20% increase in the diameters of the detected lesions. In addition, the appearance of one or more new lesions was also considered progression. Stable disease (SD) was defined as neither sufficient decrease to consider (PR) nor sufficient increase to consider (PD).

Immunohistochemical staining

Sections 4 μm thick were deparaffinized in an oven, dewaxed in xylene, and rehydrated through graded alcohol. Antigen retrieval was done by microwaving in 10 mM citrate buffer (pH 6.0) for 25 min. The sections were placed in an endogenous peroxide for 15 min. Rabbit polyclonal NOTCH1 antibody (RB-10311P0) (Labvision, Fremont, CA, USA) and rabbit anti-OCT4 (ab19857, Abcam, USA, dilution 1:100) were applied to the tissue sections for 60 min. Secondary antibodies were applied for 30 min at room temperature then the slides were incubated with streptavidin-biotin-peroxidase. Diaminobenzidine (DAB) was added for 15 min. The sections were counterstained with hematoxylin, dehydrated and mounted and placed under a cover slip.

Immunohistochemical evaluation

Positive expression was considered if membranous and/or cytoplasmic staining was detected for NOTCH1 and when nuclear staining was detected for OCT4. Evaluation of both markers was assessed according to the percentage and staining intensity of immunoreactive cells. The percentage of immunoreactive cells was scored as: 0 (<5%); 1 (5–25%); 2 (25–50%); 3 (50–75%) and 4 (>75%). The staining intensity was also semi-quantitatively assessed as follows: 0, negative; 1, weak; 2, moderate; 3, strong. Immunoreactivity score (IRS) range (0–12) was calculated by multiplying the intensity of staining and the percentage of positively stained cells. Scores <8 were considered as low NOTCH1 expression, while scores ≥8 were considered as high NOTCH1 expression.[9] Scores <4 were regarded as low OCT4 expression, while scores ≥4 were regarded as high OCT4 expression.[7] Sections of colorectal carcinoma and seminoma were used as positive control for NOTCH1 and OCT4, respectively. Negative control sections were incubated with normal mouse serum instead of the primary antibody.

Statistical analysis

All statistics were performed using SPSS 22.0 for windows (IBM Inc., Chicago, IL, USA) and MedCalc windows (MedCalc Software bvba 13, Ostend, Belgium). The relationship of NOTCH1 and OCT4 with the clinicopathological factors was analyzed using Fisher’s exact test, Pearson’s Chi-square test and Chi-square test for trend. Stratification of OS and DFS was done according to immunohistochemical markers. Disease-free survival (DFS) was defined as the time from the date of surgery (or complete remission) to relapse diagnosis. Overall survival (OS) was defined as the time from diagnosis to death or the most recent follow-up contact (censored). Kaplan–Meier plot method and two-sided exact log-rank test were used to estimate the survival analysis. Results were considered statistically significant if the P value was <0.05.

   Results   Top

Clinicopathological features

The clinicopathological features of studied GC cases enrolled in this study were reported in [Table 1]. Most of the studied cases (58%) presented at advanced stages (stages III and IV), 19 patients (38%) were grade 3 GC while 35 patients (70%) had lymph node metastasis and 14 patients (28%) had distant metastasis. The median follow-up duration was of 15.5 months (range 10–24 months), during which relapse was detected in 10 patients (35.7%) and 20 patients (40%) died. During the follow-up duration, seven patients (24.1%) showed complete clinical response to the chemotherapy, 12 patients (41.4%) manifested progressive disease, 31% cases showed stable disease while 3.4% cases showed partial response.

Table 1: Clinicopathological features, immunohistochemical markers, and outcomes of 50 patients with GC

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Correlation between NOTCH1 expression and the clinicopathological features in GC

NOTCH1 overexpression was observed in 60% of GC. The expression level was elevated in tumor tissues compared with adjacent non-neoplastic gastric mucosa (P < 0.05) [Figure 1]. In addition, NOTCH1 expression level significantly increased with higher tumor grades (P = 0.021), advanced pT (P < 0.001), TNM (P < 0.001), lymph node metastasis (P = 0.002) and distant metastasis (P < 0.001). No significant association was detected between NOTCH1 expression and the patients’ age, tumor size, sex, and Lauren classification (P > 0.05) [Table 2].

Figure 1: Immunohistochemical expression of NOTCH1 in gastric carcinoma. (a) mild NOTCH1 expression in non-neoplastic gastric mucosa (×400); (b) mild NOTCH1 expression in well differentiated GC (×400); (c) strong expression of NOTCH1 in moderately differentiated GC (×400); (d) moderate NOTCH1 expression in poorly differentiated GC (×400)

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Table 2: Relation between NOTCH1 and OCT4 expression and the clinicopathological features in 50 patients with GC

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Correlation between OCT4 expression and the clinicopathological features in GC

OCT4 expression was observed mainly in the nucleus of cancer cells. OCT4 overexpression was detected in 26/50 (52%)of GC [Figure 2]. High OCT4 expression was significantly related to tumor grade (P = 0.037), pT stage (P < 0.001), TNM stage (P < 0.001), lymph node metastasis (P = 0.003), M1 stage (P < 0.001). There was no correlation between OCT4 expression and age, tumor size, sex, and Lauren classification (P > 0.05) [Table 2].

Figure 2: Immunohistochemical expression of OCT4 in GC. (a) mild OCT4 expression in non-neoplastic gastric mucosa (×400); (b) strong OCT4 expression in well-differentiated GC (×400); (c) strong OCT4 expression in moderately differentiated GC (×400); (d) moderate OCT4 expression in poorly differentiated GC (×400)

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Correlation between NOTCH1 and OCT4 expression in GC

Evaluating the relationship between the expression of NOTCH1 and OCT4 in GC, revealed that a total of 15 GC cases (30%) had low expression of both NOTCH1 and OCT4, whereas 21 GC cases (42%) had high expression of both NOTCH1 and OCT4 (P = 0.002) [Table 2].

The prognostic impact of NOTCH1 and OCT4 expression on survival and response to chemotherapy in patients with GC

The correlation between NOTCH1 and OCT4 and survival in patients with GC after surgery was investigated and the median follow-up period was 15.5 months. The Kaplan–Meier survival analysis showed a significant association between overexpression of NOTCH1 and reduced DFS and OS and (P = 0.013, P < 0.001). GC with high OCT4 expression had a significantly lower OS and DFS than that in patients with low OCT4 expression (P < 0.001, for each) [Table 3] and [Figure 3], [Figure 4].

Table 3: Relation between NOTCH1 and OCT4 expression and outcome in 50 patients with GC

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Figure 3: Kaplan–Meier plot for disease-free survival (DFS): (a) stratified by NOTCH1 IHC staining (P = 0.013), (b) stratified by OCT4 IHC staining (P < 0.001)

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Figure 4: Kaplan–Meier plot for overall survival (OS): (a) stratified by NOTCH1 IHC staining (P < 0.001), (b) stratified by OCT4 IHC staining (P < 0.001)

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Regarding the response to chemotherapy, the current study revealed a significant association between up-regulation of NOTCH1 and OCT4 and chemoresistance in GC (P = 0.013 and P = 0.005, respectively) [Table 3].

   Discussion   Top

Recent studies have implicated NOTCH signaling as an essential hallmark of cancer.[3],[5] Traditional predictive methods relying on TNM stage for (GC) patients’ outcome is limited due to the fact of tumor heterogeneity. So, studying the molecular mechanisms underlying GC might provide better prediction for patient outcomes and developing targeted therapies.[10] Previous studies reported that NOTCH signaling pathway can act as an oncogene or tumor suppressor gene. Hence, the increased or decreased expression in different cancer types including GC are still debatable.[5],[11],[12],[13]

Increased expression of NOTCH signaling had been discovered in some types of lymphoma and leukemia, sarcomas, gliomas, and different epithelial tumors of the lung, breast, cervix, prostate, colon, head and neck, pancreas, and kidney.[11],[12],[13],[14]

The present study revealed that NOTCH1 was significantly overexpressed in GC tissues than adjacent non-neoplastic gastric mucosa, suggesting that NOTCH1 is activated in GC and that was similar to the results obtained by Du et al.[15] In contrast, Zhang et al.[16] reported NOTCH1 downregulation in gastric tumors compared to normal tissue, and that was in contrast to the traditional concept. However, other data reported absent expression in normal gastric mucosa.[17] The current study showed that overexpression of NOTCH1 in GC was closely correlated with higher tumor grade, depth of invasion, poor TNM stage, lymph node metastasis and distant metastasis. Other studies revealed similar results that were in accordance with our study.[9],[14],[18]

In a meta-analysis study, Du et al.[15] reported that higher expression rates of NOTCH1 was significantly associated with GC patients with larger tumor size, lymphovascular invasion and distant metastasis suggesting that NOTCH1 may also play an important role in tumor progression and metastasis of GC. However, they found no relation with tumor grade. On the contrary, Huang et al.[19] reported no significant association between NOTCH1 expression and the clinicopathological features in GC except for lymph node metastasis.

Kaplan–Meier survival analysis revealed that GC patients with higher expression of NOTCH1 showed lower OS and DFS. Several studies reported that positive expression of NOTCH1 was a predictive biomarker for shorter survival and poorer prognosis.[9],[18],[20]

Conversely, Bauer et al.[21] demonstrated that increased NOTCH1 level was associated with a good prognosis of GC, indicating an anti-tumor role of NOTCH1. While Huang et al.[19] demonstrated that the overall survival of patients with GC wasn’t affected by expression level of NOTCH1. Thus, the function of NOTCH signaling in GC is still controversial and the regulatory mechanisms involved need to be further investigated.

Our analysis revealed that NOTCH1 upregulation was associated with chemoresistance in GC. Recently, several reports have revealed that activation of NOTCH signaling pathway may play a key role in the resistance to chemotherapy through promoting stem-cell like property. Some studies assumed that inactivation of NOTCH1 may restore the sensitivity of tumor to chemotherapy treatment.[6],[22],[23],[24],[25]

In the present study, OCT4 was significantly overexpressed in GC compared with the peritumoral gastric tissues. A similar conclusion was reached by Jiang et al.[7] and Kong et al.[26] The current study showed that high expression of OCT4 was significantly related to higher grades of GC, pT stage, lymph node metastasis, TNM stage, and distant metastasis. These findings were consistent with other studies.[7],[8],[26] In contrast, Matsuoka et al.[27] declared that lower expression of OCT4 was closely related to worse clinicopathologic factors such as depth of tumor invasion, lymphatic invasion, and lymph node metastasis.

Kaplan–Meier method was used for evaluating the impact of OCT4 on GC patient’s survival. We observed that OCT4 overexpression was significantly associated with lower survival than that in patients with low OCT4 expression. In agreement, most of the studies comparing OCT4 expression with clinical prognosis reported that overexpression of OCT4 was closely related to worse prognosis, tumor aggressiveness, poor survival, and chemoresistance.[7],[8],[26],[28] However, Matsuoka et al.[27] reported that patients with negative OCT4 showed poor overall survival than those with positive OCT4 expression.

OCT4 expression had previously been reported to promote pluripotency and is closely related to more aggressive tumor behavior.[29],[30] The current study suggested a significant correlation between OCT4 overexpression and resistance to chemotherapy, tumor progression and even recurrence in GC cases that showed previous response to chemotherapy. This observation was consistent with the previously reported results.[8],[28]

In addition, this study analyzed the correlation between the expression of NOTCH1 and OCT4 in GC. We observed a positive association between the expression levels of NOTCH1 and OCT4 in GC. Previous research also reported a correlation between NOTCH1 expression and CSCs in cancer.[24],[25] Recently, Konishi et al.[24] showed that NOTCH1 directly regulated stem-like cell marker, CD133, and so maintained a cancer stem-like phenotype in GC. The present study suggested that overexpression of NOTCH1 may have a bad impact in GC, possibly through up-regulation of the active nuclear form of OCT4.

Based on our results and those of the previous studies, we suggested that tumor cells co-expressing NOTCH1 and OCT4 not only maintain primitive features of CSCs, but also showed invasive phenotype, contributing to chemoresistance, cancer relapse and metastasis in GC, suggesting a possible interaction between them and synergistic effect in promoting GC.

Therefore, combined therapeutic targeting of specific signaling pathway together with CSC might represent a promising strategy of anti-relapse therapy for the patients with GC after surgery.

Further studies are warranted to elucidate the cause of this discrepancy in the results and verify the possible use of these markers in prognostic prediction and as target therapy.

   Conclusion   Top

The present study suggested that NOTCH1 signaling pathway and OCT4 were activated in GC suggesting their roles in tumorigenesis and tumor aggressiveness. Combined detection of NOTCH1 and OCT4 might be able to predict poor overall survival, cancer therapy resistance, and poor prognosis in patients with GC.

Acknowledgements

This research received no funds or grants from any organization.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 

   References   Top


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Correspondence Address:
Doaa Abdelaziz Ibrahim
Department of Pathology, Faculty of Medicine, Zagazig University, Sharkia
Egypt
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/IJPM.IJPM_871_20

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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
 
[Table 1], [Table 2], [Table 3]

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